Gnathic osteosarcoma (OS), which includes mandibular and maxillary jaw OSs, account for 6%-9% of OS. Single-institutional and multi-institutional retrospective studies, as well as population-level databases, suggest that clinical differences exist among gnathic OS and OS of other sides, including other craniofacial OS. To date, no specific prospective studies of gnathic OS have been reported, and aspects of clinical management are controversial. Some elements of care are aligned with extragnathic OS, e.g., margin negative (R0) surgery, whereas others, such as chemotherapy and radiation, are not clearly defined. The authors reviewed the available literature for the diagnosis, treatment, and supportive/survivorship care patients with gnathic OS and offer consensus statements for the comprehensive management of this rare disease.

Rhabdomyosarcomatous transdifferentiation is a rare but well-documented phenomenon in melanoma, and, in these cases, recognition of a conventional component by either morphology or immunophenotype is essential for the correct diagnosis. However, tumors that are entirely transdifferentiated can be impossible to distinguish from primary rhabdomyosarcoma. We analyzed a cohort of cases diagnosed as cutaneous epithelioid/pleomorphic rhabdomyosarcoma using genetic/epigenetic techniques and compared them with melanoma. Cases diagnosed as cutaneous epithelioid/pleomorphic rhabdomyosarcoma were retrieved, and clinicopathologic features were documented. NRAS p.Q61R and BRAF p.V600E immunohistochemistry, targeted DNA next-generation sequencing, and DNA methylation profiling were performed. A total of 13 cases of cutaneous epithelioid/pleomorphic rhabdomyosarcomas were identified in 10 males and 3 females (62-90 years; median, 83 years). Cases included tumors arising in the head and neck (n = 9), upper extremity (n = 2), lower extremity (n = 1), and back (n = 1). Using immunohistochemistry, 1 tumor (of 13) was positive for NRAS Q61R; all were negative for BRAF V600E expression (0/13). Targeted DNA next-generation sequencing revealed 1 case each to harbor HRAS c.34G>A p.G12S and BRAF c.1363G>A p.G455R mutations, respectively. Tumor mutation burden was interpretable in 5 cases and ranged from 3 to 80 Mut/Mb (median 38 Mut/Mb); 4 of 5 cases had tumor mutation burden > 10 Mut/Mb. A DNA UV light mutational signature was present in all cases with evaluable data (6/6). DNA methylation profiling showed 7 (of 9) cases to cluster with desmoplastic melanoma, whereas 1 case formed a partial match for head and neck squamous cell carcinoma, and the final case matched with TFCP2-rearranged rhabdomyosarcoma. At the last follow-up, 4 patients died from the disease, 2 died from unknown causes, 2 were alive without disease, and 1 was alive with disease. The majority of cutaneous epithelioid/pleomorphic rhabdomyosarcoma show clinical, genetic, and epigenetic profiles similar to melanoma, suggesting that a major subset represents transdifferentiated melanoma.

Although monosodium urate and calcium pyrophosphate dihydrate (CPPD) crystals have been documented together in synovial fluid, there are no descriptions regarding their simultaneous histologic presence within the same tophi. Furthermore, the incidence, significance, and clinicopathologic features of such patients have not been analyzed. We retrospectively reviewed consecutive cases of pathologic specimens over an ~4-year period with a confirmed histologic diagnosis of "gout" or "gouty tophi", focusing on concomitantly documented CPPD. A total of 159 gout cases involved 156 patients, including 127 males and 29 females (ratio 4.4:1), with ages ranging from 14 to 99 years (median 67). Nine (5.7%) patients (6 males; 3 females; ratio 2:1; age range 49 to 91 years, median 74) had evidence of both gout and CPPD crystals within the same tophaceous deposits. Concomitant gout/CPPD were more commonly associated with the upper extremities (5 [3, hands; 2, elbows]) than lower extremities (4, feet). Seven patients had a prior history of gout and 1 CPPD. The 150 cases from 147 patients of gout alone occurred in 121 males and 26 females (ratio 4.7:1), with ages ranging from 14 to 99 years (median 67). Gout alone was far more common in the lower extremities (109 cases) than the upper extremities (41). For combined gout/pseudogout, deposits of CPPD were intimately associated with the gouty tophi, deposited in irregular, curvilinear to serpiginous aggregates onto a significantly higher volume of uric acid crystals but never observed away from the tophaceous deposits. Confirmation of the uric acid crystals required polarization of unstained sections. In conclusion, the presence of concomitant CPPD and gouty crystals in the same tophaceous deposits is infrequently observed in pathology specimens. Compared with gout only, preliminary data suggests that patients with combined gout/pseudogout tophi are more likely to be older, female, and exhibit upper extremity involvement. Most such patients also have a prior history of gout.

BACKGROUND Radiation-induced sarcoma (RIS) is an exceptionally rare occurrence following radiation therapy, and manifestation usually occurs after a several-year latency period. Herein, the authors report the development of a radiation-induced osteosarcoma of the frontoparietal calvaria following treatment for an oligodendroglioma in an 84-year-old woman. OBSERVATIONS The patient had been diagnosed with a grade III anaplastic oligodendroglioma when she was 78 years old. She had undergone resection and subsequent chemoradiation therapy for treatment of the tumor. In the following years, she experienced progressive neurological decline, which was complicated by multiple ischemic strokes and seizure episodes. When she was approximately 84 years of age, a small mass was noted overlying the previous craniotomy site during examination. Several months later, approximately 5 years after chemoradiation therapy, she presented to the emergency department with a suspected stroke. Examination revealed that the mass had rapidly grown and was pressing into the intracranial space. She underwent craniotomy, and specimens were taken. Pathological analysis demonstrated a high-grade osteosarcoma. LESSONS Despite the lesion's rarity, suspicion for RIS should be raised with the rapid growth of a mass at the site of previous radiotherapy. Furthermore, it is especially important to carefully monitor vulnerable patients who may not be able to recognize or report the development of a growing mass.

Malignant chondroblastoma is a recently described variant of chondroblastoma showing a distinct age/site distribution and morphology along with the typical H3-3B p.K36M mutation. We sought to further compare conventional and malignant chondroblastoma. Malignant chondroblastomas were collected. H3-3 K36M immunohistochemistry, as well as DNA methylation and copy number profiling, were performed and compared with conventional chondroblastoma. Forty-one samples from 26 patients were identified (20 males, 6 females; age: 19-62 years; median: 39 years). Anatomical sites included rib (7), pelvis (4), acromion (4), scapula (4), spine (2), long bone (3), calcaneus (1), and talus (1). Imaging showed an expansile mass with variable cortical erosion and/or breakthrough. Most patients (n = 17) showed sheets of atypical ovoid cells deposited in a myxoid stroma. Osteoclast-like giant cells/matrix formation was scarce. Six patients had tumors with features of conventional chondroblastoma but significant cytologic atypia. Three tumors demonstrated a morphology indistinguishable from conventional chondroblastoma except for extensive permeation, and one of these cases showed a transition to high-grade sarcoma. The final case was composed only of high-grade pleomorphic sarcoma that harbored an H3F3A p.K36M mutation. When an adjacent host bone was present, permeative growth through the cortex and native trabeculae was noted. All samples tested positive for the H3-3 K36M-specific antibody (26 of 26). Methylome profiling of 28 specimens from 24 patients revealed that 26 of these specimens formed a distinct cluster on a uniform manifold approximation and projection dimension reduction plot separate from conventional chondroblastoma and high-grade osteosarcoma. Of 26 methylomes from which interpretable copy number profiles can be derived, 12 had no variations, whereas 14 had copy number changes. Of 22 patients, 11 experienced local recurrence, 8 patients developed metastasis, and 3 patients died of disease. Malignant chondroblastoma is a rare, clinically and epigentically distinct variant of chondroblastoma with a predilection for the flat bones of skeletally mature individuals and high rates of local recurrence and distant metastases. A subset transforms into high-grade pleomorphic sarcoma, either de novo or in subsequent recurrences. Malignant chondroblastoma with high-grade features and/or copy number variations appears to have a higher propensity for adverse events, including death from disease.

Despite representing <1% of all musculoskeletal surgical pathology cases, primary musculoskeletal neoplasms are disproportionately emphasized in the surgical pathology literature, compared with non-neoplastic orthopedic pathology. Yet, there remains significant interest among practicing pathologists and their clinical colleagues to maintain expertise in the non-neoplastic arena, as evidenced by increasing volumes of non-neoplastic orthopedic diseases, often reflected in consult cases. Recent literature has renewed the discussion of arthroplasty, emphasized the clinical importance of pathologic examination, and provided updated diagnostic clarification for separating avascular necrosis from degenerative joint disease (DJD)/osteoarthritis (OA) with secondary osteonecrosis, acute infectious osteomyelitis from pseudoabscesses of DJD/OA, and revisited the diagnoses of subchondral insufficiency fracture and rapidly destructive arthropathy. Providing accurate neutrophil counts to help determine periprosthetic joint infection has rapidly become one of the most common sources of frozen section evaluation in the United States. Distinguishing periprosthetic joint infection from aseptic loosening has significant intraoperative implications. In addition to acute arthritis and mass effect, calcium pyrophosphate dihydrate (CPPD) deposition disease may lead to DJD/OA. However, most histologically confirmed examples of CPPD, involving the large extremity joints, are not identified preoperatively or radiologically, requiring pathologic evaluation to reliably establish the diagnosis. The incidence of CPPD deposits appears highest in the humeral head/shoulder, followed by the knees and hips/femoral head. Recent evidence has documented infrequent examples of combined gout and CPPD/pseudogout within the same tophi, associated with unique clinicopathologic features compared with those with gout alone. Carpal tunnel syndrome, trigger finger, and lumbar stenosis represent potential early red flags for the development of transthyretin (TR) cardiac amyloidosis. Although previously discarded at many institutions, excised tissue removed from such specimens, particularly tenosynovium from the carpal tunnel flexor retinaculum, are now routinely evaluated histologically with Congo red staining and, when positive, followed by mass spectrometry for confirmatory amyloid subtyping. With the use of a recently developed TR stabilizer, such as tafamidis, early histologic detection and treatment of TR cardiac amyloidosis has improved clinical outcomes. Herein is a summary of recent relevant developments in non-neoplastic orthopedic surgical pathology, updated diagnostic criteria and pitfalls, and the resulting clinical impact, where applicable.

Primary tumors of bone encompass a wide array of lineages of differentiation, including osteogenic, chondrogenic, fibrogenic, vascular, hematopoietic, and notochordal, amongst other mesenchymal lineages of origin. Osteogenic neoplasms of bone are defined by tumor cell production of osteoid matrix and/or mature bone by the neoplastic cells themselves, encompassing the full biologic spectrum, ranging from benign to intermediate (locally aggressive or rarely metastasizing) and malignant entities. Herein we provide an updated overview focused on benign bone-forming tumors: osteoma, osteoid osteoma, osteoblastoma and variants, atypical sclerosing osteoblastic neoplasm, and both benign and malignant neoplasms within the differential diagnosis of these entities.

Even though the average surgical pathologist reviews far more non-neoplastic orthopaedic pathology on a daily basis, most current research focuses on rare tumours and their even less frequent molecular events. Our experiences among consults and focused conferences strongly suggest that there remains a practice gap regarding knowledge and diagnosing specific non-neoplastic orthopaedic conditions. One of the most frequent intraoperative consultations performed in the USA, among both academic and private institutions, relates to revision arthroplasty and the determination of infection in periprosthetic joints. Pathologists play a critical role in this algorithm, helping determine intraoperatively whether patients require antibiotic spacers prior to reimplantation. Many pathology departments have abandoned the examination of arthroplasty specimens because they (and their surgeons) mistakenly believe there is little clinically relevant information to be gained by thorough pathological examination. However, recent literature has challenged this concept, emphasising the importance of distinguishing avascular necrosis (from osteoarthritis/degenerative joint disease with secondary osteonecrosis), subchondral insufficiency fracture, septic arthritis (from so-called 'sterile' osteomyelitis/pseudoabscesses), underlying crystalline diseases and incidental/occult neoplasia. Histological evaluation of historically insignificant orthopaedic specimens, such as tenosynovium from carpal tunnel syndrome/trigger finger, is now seen as valuable in early diagnosis of cardiac amyloidosis. Not infrequently, orthopaedic conditions like haemosiderotic synovitis, osteocartilaginous loose bodies or rheumatoid nodules, may histologically mimic bona fide neoplasms, notably diffuse tenosynovial giant cell tumour, synovial chondromatosis and epithelioid sarcoma, respectively. Here is a review of the more common non-neoplastic orthopaedic conditions, those likely to be examined by the practising surgical pathologist, with updates and guidelines for establishing clinically relevant diagnoses.

In last few decades our understanding of bone and soft tissue tumors has evolved significantly, expanding and clarifying our current classification system. Due largely to increased utilization of ancillary testing, particularly molecular tools, new entities are continually emerging and/or being further refined. In addition to morphological and molecular differences, in many instances, the recognition of a new entity carries significant prognostic and potentially therapeutic relevance. In this review on practice updates, we endeavor to discuss five recently described tumors including pseudoendocrine sarcoma, NUT-rearranged sarcoma, VGLL3-rearranged spindle cell rhabdomyosarcoma of head and neck, superficial neurocristic FET::ETS fusion tumors, and NFATC1/2-rearranged epithelioid vascular tumors.

Background. Dedifferentiated liposarcoma (DDLPS) is an aggressive subtype of liposarcoma that can arise within an atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDLs). The primary goal of treatment for DDLPS is wide-margin resection, but it remains unclear if ALT/WDLs surrounding DDLPS also necessitates wide-margin resection for optimal local control. Methods. Patients treated surgically for a biopsy showing DDLPS at a single institution were identified. Margin status for both DDLPS and ALT/WDLs were categorized into one of the following categories: wide, marginal or intralesional. All patients were categorized as either “wide throughout” or “wide on DDLPS, marginal on ALT/WDLs”. Chi-square tests were used to compare margin status and oncologic outcome. Results. Eighteen patients met the inclusion criteria for the study. Twelve patients had surgical margins wide on DDLPS/marginal on ALT/WDLs, and 6 patients had surgical margins wide throughout. Two patients with surgical margins wide on DDLPS/marginal on ALT/WDLs developed local recurrence compared with no patients with margins wide throughout ( P = .289). Six patients with surgical margins wide on DDLPS/marginal on ALT/WDLs developed metastases compared to 1 patient with margins wide throughout ( P = .289). Conclusions. Compared with patients with wide margins throughout, patients with margins wide on DDLPS/marginal on ALT/WDLs had more local recurrences, new metastases, and death from disease. While no statistically significant difference was found between subgroups for these comparisons, cohort size limits our ability to conclude that no clinical difference exists. This study forms the basis for a future, larger, multi-institutional study to improve external validity and power to identify clinically relevant differences.

There is no shortage of comprehensive review articles on bone and soft tissue pathology, almost always representing a regurgitation of the literature with little to no guidance on personal “best practices,” recommended applications of ancillary testing, and alternative points of view. This special issue of Human Pathology uniquely unites evidence-based medicine, where appropriate, with the collective personal experiences of a wide range of accomplished pathologists from varying institutions and backgrounds, addressing problematic areas, updated and sometimes imperfect classification systems, and their personal preferences for cost-effectively incorporating ancillary testing. For the preponderance of general pathologists (and specialists), whether academic or non-academic, non-neoplastic musculoskeletal diseases represent a far higher percentage of their practice than bone and soft tissue neoplasia. One of the most common frozen sections performed at many hospitals throughout the USA is revision arthroplasty, relying on the pathologist to help determine the presence (or absence) of periprosthetic joint infection, largely based on the hematoxylin & eosin (H&E) slide. Not every institution has access to the latest molecular techniques; fortunately, many of the current immunohistochemical antibodies serve as reliable surrogate markers of genetic mutations, allowing for cheaper but accurate diagnoses, when deemed necessary. Furthermore, molecular testing is often not necessary to establish a specific diagnosis, even among neoplasms with known underlying genetic abnormalities. It must be remembered that most bone and soft tissue tumors were recognized and classified correctly, before we uncovered and understood, among a subset, their underlying and unique molecular aberrations. Perhaps not surprisingly, in some cases, more than one molecular pathway may lead to the same histologic tumor subtype. Less commonly, an identical genetic driver/fusion may result in immunophenotypically and biologically distinct neoplasms, sometimes with entirely different clinical behaviors. “Dedifferentiation,” a concept recognized among a variety of bone and soft tissue neoplasms, including but not limited to chondrosarcoma, parosteal osteosarcoma, and liposarcoma, needs to be objectively reassessed, particularly for liposarcoma. The following reviews attempt to address the above concepts, re-emphasizing the important role the practicing pathologist continues to (and must) play in the differential diagnoses of neoplastic and non-neoplastic musculoskeletal diseases.

Bone and soft tissue tumors (BST) are a highly heterogeneous group largely classified by their line of differentiation, based on their resemblance to their normal counterpart in adult tissue. Yet, rendering a specific diagnosis can be challenging, primarily due to their rarity and overlapping histopathologic features or clinical presentations. Over the past few decades, seemingly histogenetic-specific gene fusions/translocations and amplifications have been discovered, aiding in a more nuanced classification, leading to well-established objective diagnostic criteria and the development of specific surrogate ancillary tests targeting these genetic aberrations (e.g., immunohistochemistry). Ironically, the same research also has revealed that some specific tumor subtypes may be the result of differing and often multiple gene fusions/translocations, but, more interestingly, identical gene fusions may be present in more than one phenotypically and biologically distinct neoplasm, sometimes with entirely different clinical behavior. Prime examples include, EWSR1::ATF1 and, less commonly, EWSR1::CREB1 gene fusions present in both clear cell sarcoma, a malignant high-grade tumor with melanocytic differentiation, and angiomatoid fibrous histiocytoma, a mesenchymal neoplasm of intermediate malignancy with a generally indolent course. Similarly, MDM2 amplification, once deemed to be pathognomonic for atypical lipomatous tumor/well differentiated and dedifferentiated liposarcoma, has been documented in a range of additional distinct tumors, including low grade osteosarcomas (e.g. low grade central and surface parosteal) and high-grade intimal sarcomas, amongst others. Such findings reinforce the importance of careful attention to morphological and clinicoradiological features and correlation with molecular testing before rendering a specific diagnosis. Future classification systems in BST neoplasms cannot be solely based on molecular events and ideally will balance morphologic features with molecular analysis. Herein, we provide a narrative literature review of the more common BST neoplasms with shared genetic events but differing demographics, morphology, immunophenotype, and clinical behavior, re-emphasizing the importance of the hematoxylin and eosin slide and the “eye” of the practicing pathologist.

ObjectivesDetermine comparative tolerance of daily oral and weekly parenteral cobalamin supplementation, in hypocobalaminaemic dogs with chronic enteropathy. Determine whether oral is as effective as parenteral supplementation at achieving eucobalaminaemia, in hypocobalaminaemic dogs with protein‐losing enteropathy, severe hypocobalaminaemia or high canine inflammatory bowel disease activity index at inclusion.Materials and MethodsThirty‐seven client‐owned dogs with hypocobalaminaemia and clinical signs of chronic enteropathy were prospectively enrolled in three UK referral centres. Dogs were randomly allocated to daily oral for 12 weeks or weekly parenteral cobalamin supplementation for 6 weeks and one additional dose 4 weeks later. Serum cobalamin, body condition score, canine inflammatory bowel disease activity index and bodyweight were assessed at inclusion, weeks 7 and 13. Serum methylmalonic acid concentration was evaluated at inclusion and at week 13. Owners completed treatment adherence, palatability, tolerance and satisfaction questionnaires at week 13.ResultsNineteen dogs completed the study. All dogs orally supplemented achieved normal or increased cobalaminaemia at weeks 7 and 13. There was no statistical difference in cobalamin concentration at week 13 in dogs treated with oral or parenteral supplementation, regardless of presence of protein‐losing enteropathy, severity of hypocobalaminaemia or canine inflammatory bowel disease activity index at inclusion. Serum methylmalonic acid concentration was not significantly different between oral and parenteral groups, neither were treatment adherence, satisfaction, and tolerance scores at week 13.Clinical SignificanceOral is as effective and as well‐tolerated as parenteral cobalamin supplementation in hypocobalaminaemic dogs with chronic enteropathy and severe clinical or biochemical phenotypes, and should be considered as a suitable treatment option regardless of disease severity.

The classification and work-up of adipocytic neoplasms remains challenging and sometimes controversial. Since its initial description by Dr. Enterline, the variety of subtypes and morphological appearances considered to represent the spectrum of atypical lipomatous tumor/well differentiated liposarcoma (ALT/WDL) has expanded, resulting in significant morphologic overlap with other entities, including the recently described atypical spindle cell/pleomorphic lipomatous tumor (ASPLT), conventional spindle cell/pleomorphic lipoma (SPL), and so-called "low-grade" forms of dedifferentiated liposarcoma (DL). Nevertheless, the distinction of most examples of ALT/WDL from lipomas/lipoma-like lesions is easily performed on routine histologic examination but can be problematic if the characteristic atypical cells are poorly represented, particularly in small biopsy specimens, obscured by other cellular elements (inflammation), or simply not recognized. The discovery that lipomatous tumors harbor specific and unique karyotypes and molecular events has resulted in ancillary tests that can help provide more accurate diagnoses, especially in less-than-optimal scenarios. Confirmation of MDM2 immunohistochemical over-expression and detection of the MDM2 gene rearrangement via fluorescent in situ hybridization (FISH) have proven particularly reliable and useful. While FISH analysis for MDM2 gene amplification may be helpful for confirming (or excluding) ALT/WDL, it also can lead to overutilization and overdependence. Furthermore, a small subset of otherwise typical ALT/WDL lack MDM2 gene amplification, employing alternative molecular pathways. The recent recognition of ASPLT has introduced a tumor easily mistaken morphologically for ALT/WDL, often exhibiting bizarre and pleomorphic lipoblasts, but lacking the underlying molecular abnormalities and subsequent risk of dedifferentiation. ASPLT also have overlapping features with the better-established SPL but with a greater tendency to locally recur and more frequent involvement of the distal extremities. The precise criteria separating cellular forms of ALT from what some consider "low grade" forms of DL remains controversial and inconsistently applied, even among individual pathologists within institutions. Given their underlying shared cytogenetic abnormality, molecular testing has no utility in this distinction. Herein is a comprehensive historical overview of ALT/WDL, with updates on its distinction from other similar lipomatous tumors and DL, including practical evidence-based criteria for the appropriate cost-effective use of MDM2 testing.

AIMS:Epithelioid myxofibrosarcoma (eMFS) is an aggressive morphological variant associated with high rates of local recurrence and metastatic disease. The clinicopathological understanding of this disease is currently limited to a few small case-series. METHODS AND RESULTS:We reviewed 44 cases of eMFS and classified them based on the presence of focal (< 50%) or diffuse (> 50%) epithelioid morphology and Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grade. The patients (28 males; 16 females) had a median age of 71 years (range = 14-90 years). The proximal extremity was the most common site (n = 21), followed by the trunk (n = 11), distal extremity (n = nine) and head/neck (n = two). Of cases with known depth of involvement (n = 41), 39 involved the subcutis, one was limited to the dermis and one limited to the skeletal muscle. Most cases (n = 34, 77%) demonstrated diffuse (> 50%) epithelioid morphology and were FNCLCC grade 3 (n = 29, 66%). Follow-up data were available for 22 patients. Two developed local recurrence and 10 developed metastases, frequently to regional lymph nodes. All metastatic tumours had a primary lesion with diffuse epithelioid morphology (P = 0.09). There was no association between grade and recurrent or metastatic disease (P = 0.67 and 0.90, respectively). Three cases initially diagnosed as eMFS, one in the neck and two in the axilla, were found to have NRAS Q61R mutations and a high tumour mutation burden and/or ultraviolet (UV)-light DNA mutational signature. CONCLUSIONS:These findings suggest that UV-driven malignancies (including melanoma or sarcomatoid squamous cell carcinoma) may histologically mimic eMFS and should be considered in cases of eMFS presenting at atypical anatomical sites.

Introduction: Cardiac amyloidosis (CA) involves deposition of amyloid fibrils within cardiac myocardium, resulting in heart failure. Recent studies have shown an association between amyloid deposition in the ligamentum flavum (LF) and development of CA. Our study aims to investigate the prevalence of CA in patients identified with amyloid deposition in their LF at the time of spinal laminectomy for spinal stenosis, employing a comprehensive approach integrating multi-modality imaging and laboratory testing. Methods: This is a retrospective study of patients age >50 years old who underwent spinal laminectomy for non-congenital spinal stenosis or spondyloarthropathy. LF tissue samples obtained during surgery were examined histologically for amyloid deposition. Patients with positive findings underwent testing, including serum markers, echocardiography, and 99mtechnetium pyrophosphate (99mTcPYP) scintigraphy. Additionally, cardiac magnetic resonance imaging (cMRI) was obtained when clinically appropriate to assess for CA. Results: Among the 197 enrolled patients, 39 (19.3%) exhibited amyloid deposition in LF tissue. Patient demographics and clinical characteristics did not significantly differ between the positive and negative groups (Table 1). Of the 39 amyloid positive specimens, subtyping using mass spectrometry identified 1 (3%) light-chain, 28 (72%) transthyretin (TTR), and 10 (25%) were unable to be subtyped. Of the 28 TTR positive patients, 8 were of the wild type genotype. Furthermore, 18 of the 28 TTR patients underwent 99mTcPYP scintigraphy, of which none had cardiac uptake consistent with TTR amyloidosis; the other 10 declined work up. Of the 10 untyped patients, 6 had 99mTcPYP scintigraphy with none of the patients having cardiac uptake. Adjunctive cMRI in select positive patients showed findings inconsistent with amyloid deposition. Serum NT-proBNP, Troponin T, and serum pre-albumin levels were similar between groups. Conclusion: Amyloid deposition in LF tissue did not correlate with cardiac manifestations of amyloidosis at the time of surgery. Longitudinal investigation is ongoing to better understand the relationship between amyloid deposition in LF tissue and the development of CA over time.

AIMS:CIC-rearranged sarcomas (CRS) are clinically aggressive undifferentiated round cell sarcomas (URCS), commonly driven by CIC::DUX4. Due to the repetitive nature of DUX4 and the variability of the fusion breakpoints, CIC::DUX4 fusion may be missed by molecular testing. Immunohistochemical (IHC) stains have been studied as surrogates for the CIC::DUX4 fusion. We aim to assess the performance of DUX4 IHC in the work-up of CRS and its expression in non-CRS round cell or epithelioid neoplasms. METHODS AND RESULTS:Cases of molecularly confirmed CRS (n = 48) and non-CRS (n = 105) were included. CRS cases consisted of 35 females and 13 males, with ages ranging from less than 1 year to 67 years (median = 41 years). Among the molecularly confirmed non-CRS cases, C-terminal DUX4 expression was investigated in Ewing sarcomas (38 cases), alveolar rhabdomyosarcomas (18 cases), desmoplastic small round cell tumours (12 cases) and synovial sarcomas (n = five), as well as in non-mesenchymal neoplasms such as SMARCA4/SMARCB1-deficient tumours (n = five), carcinomas of unknown primary (n = three) and haematolymphoid neoplasms (four cases). DUX4 IHC was considered positive when strong nuclear expression was detected in more than 50% of neoplastic cells. When used as a surrogate for the diagnosis of CRS, the sensitivity and specificity of DUX4 IHC was 98 and 100%, respectively. Only one CRS case was negative for DUX4 IHC and harboured a CIC::FOXO4 fusion. CONCLUSIONS:DUX4 IHC is a highly sensitive and specific surrogate marker for the presence of CIC::DUX4 fusion, demonstrating its utility in establishing a diagnosis of CRS.

Low‐grade fibromyxoid sarcoma (LGFMS) typically involves deep soft tissue (beneath the fascia) of the proximal extremities and trunk. Long‐term follow‐up has shown a high rate of local recurrence, metastasis, and death. To the best of our knowledge, there is only one previous large series focusing on superficial LGFMS suggesting superficial tumors are disproportionately more common in children and may have a better prognosis. Our study's primary goals are to confirm these findings and increase general awareness that LGFMS may arise in superficial soft tissue.