Nuclear DUX4 immunohistochemistry is a highly sensitive and specific marker for the presence of CIC::DUX4 fusion in CIC-rearranged sarcomas: a study of 48 molecularly confirmed cases.

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.

Superficial low-grade fibromyxoid sarcoma.

BACKGROUND: 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. METHODS: We retrieved our cases of superficial LGFMS diagnosed between 2008 and 2020. Available slides were reviewed, and clinical data and follow-up information were obtained. RESULTS: The patients included nine males and 14 females with a median age of 29 years; eight (35%) were children (<18 years) and five (22%) were young adults (18-30 years). The majority involved the lower extremities (65%). The tumors were primarily centered in the subcutis (91%) and dermis (9%). Microscopically, they had typical features of LGFMS with alternating fibrous and myxoid zones composed of bland, slightly hyperchromatic spindled cells. All were positive for MUC4 by immunohistochemistry and/or FUS rearrangement by FISH. Follow-up on 14 cases ranged from 11 to 148 months (median 61 months) with no evidence of recurrences or distant metastases. CONCLUSIONS: Compared to conventional deep-seated counterparts, superficial LGFMS is more likely to occur in the extremities of children and young adults and may have a better clinical outcome. Further studies with longer follow-up will likely help support these findings.

Dedifferentiated Liposarcoma: A Comprehensive Historical Review With Proposed Evidence-based Guidelines Regarding a Diagnosis in Need of Further Clarification.

Among all sarcoma types, liposarcoma is the most common sarcoma that develops "dedifferentiation." Since its initial description by Dr Harry Evans, the spectrum of what is now acceptably included under the rubric of "dedifferentiated liposarcoma" (DL) has expanded, sometimes supported by cytogenetic and molecular advances. Similarly, the range of morphologic appearances considered to represent the precursor of DL, atypical lipomatous tumor (ALT)/well-differentiated liposarcoma, also has broadened, not uncommonly creating variants with significant, almost indistinguishable, morphologic overlap with occasional forms of DL, especially problematic in small biopsy specimens. More specifically, the precise criteria separating cellular forms of ALT from what some consider "low-grade" variants of DL remains controversial and inconsistently applied, even among individual pathologists within institutions. For this separation, the only objective and reproducible criteria historically shown to accurately predict a statistically significant difference in prognosis and survival is mitotic rate, alone or incorporated into a histologic grade [eg, Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC)], consistently identifying a higher grade neoplasm capable of metastases. While DL may have a better prognosis than other nonmyoid adult pleomorphic soft tissue sarcomas, definitive conclusions are difficult to establish due to nonuniform criteria for staging and establishing tumor size/volume of the high-grade component, compounded by variable definitions and thresholds for rendering the diagnosis of DL. If appropriate therapeutic approaches are to be applied to DL, there needs to uniform agreement regarding the histologic definition, grading, and staging of DL. Herein, is a comprehensive historical perspective on DL and ALT/well-differentiated liposarcoma, seeking to provide insights, updates, and a proposal for uniform, evidence-based guidelines.

Ossifying pyogenic granuloma: A rare variant usually not recognized.

Pyogenic granuloma (PG) represents a polypoid and lobular, capillary lesion, resembling granulation tissue, usually occurring on skin or mucosal surfaces. The occurrence of metaplastic ossification is extremely rare in PG. We present three cases of PG with metaplastic ossification. All three patients were men, aged 18-66 years. In all cases, the lesions occurred on the digits, particularly in or around the nail bed. Histopathologically, these superficial dermal-based tumors were characterized by classic features of PG, namely circumscribed, exophytic to polypoid proliferations of capillary-sized blood vessels in a lobular arrangement. The characteristic vascular component also was intimately associated with spicules and trabeculae of metaplastic bone formation rimmed by osteoblasts and osteoclasts. This osseous component was diffusely distributed in two cases and more localized in another. We speculate that ossification in PGs possibly represents a reactive process in response to chronic injury. We believe that ossifying PG is likely under-recognized and often mistaken for other entities also arising in the extremities and characterized by osseous metaplasia.

Genetic and molecular reappraisal of spindle cell adamantinoma of bone reveals a small subset of misclassified intraosseous synovial sarcoma.

Adamantinoma represents a distinct group of bone tumors showing both mesenchymal and epithelial differentiation most commonly involving the tibial diaphysis. Most adamantinomas contain a fibro-osseous component and an epithelial component consisting of squamous or basaloid cells. Adamantinomas are considered malignant neoplasms requiring en bloc excision that frequently recur locally and can rarely metastasize. Rare adamantinomas show an epithelial component consisting predominantly of monomorphic spindle cells, which, combined with an epithelial immunophenotype, can mimic monophasic synovial sarcoma. Synovial sarcoma is very rare in bone. It is considered a high-grade sarcoma that typically necessitates chemotherapy. However, the relationship between spindle cell adamantinoma and intraosseous synovial sarcoma has not been investigated. The current study was prompted by identification of a presumed spindle cell adamantinoma of the tibia with diffuse keratin expression that harbored a SS18 gene region rearrangement. FISH of eight additional bone tumors initially classified as spindle cell adamantinoma based on clinicoradiopathologic findings revealed one additional case with SS18 rearrangement. Histologically, both intraosseous synovial sarcoma and spindle cell adamantinoma demonstrated uniform fusiform nuclei with scant cytoplasm, short fascicles and low mitotic activity. The adamantinomas, but not the synovial sarcomas, were more likely to show overt epithelial differentiation in the form of pseudoglands or squamous nests. Immunohistochemistry of all cases, irrespective of SS18 status, showed diffuse keratin positivity in the spindle cell component, and less consistent EMA positivity. Clinical follow-up was available in both intraosseous synovial sarcomas, one of which recurred and the other metastasized. Two of the six spindle cell adamantinomas with follow-up metastasized. The above findings highlight the morphologic and immunophenotypic overlap between spindle cell adamantinoma and intraosseous synovial sarcoma of the tibia. Investigation of SS18 status to exclude synovial sarcoma is suggested prior to rendering a diagnosis of spindle cell adamantinoma.

Upper extremity myxofibrosarcoma mimicking an erosive inflammatory arthritis: a case report.

Myxofibrosarcoma is a malignant fibroblastic soft tissue neoplasm containing a variable amount of myxoid stroma that commonly presents as a slow-growing mass in elderly patients. The neoplasm may be superficial or deep to the muscle fascia and characteristically has an infiltrative growth pattern with a dominant or multinodular mass. We describe an unusual case of high-grade myxofibrosarcoma of the wrist and forearm that infiltrated the muscles, tendons, and wrist joint, causing bone erosions. The tumor was mistakenly diagnosed as synovitis and a chronic, erosive, inflammatory process. The diffuse nature, absence of a dominant mass, and radiographic appearance complicated the diagnosis. Although neoplasms of the synovial spaces are rare, this case demonstrates that tumors with a highly infiltrative growth pattern can mimic inflammatory synovitis and that neoplasms should be considered in the differential diagnosis when clinical and laboratory features are discordant with the imaging appearance.

Ewing Sarcoma and the History of Similar and Possibly Related Small Round Cell Tumors: From Whence Have We Come and Where are We Going?

The diagnosis of small round cell tumors always has been extremely difficult, and our current classification systems continue to evolve. Since its initial discovery by Dr James Ewing, the historical context of what is acceptably included under the designation "Ewing sarcoma" has changed. Although Ewing sarcoma and primitive neuroectodermal tumor were both initially described in the early 20th century, these tumors were considered likely distinct entities until the end of that same century, almost 75 years later. With modern immunohistochemistry and more recent advances in molecular techniques, the understanding of Ewing sarcoma and Ewing-like tumors has improved dramatically but also raises new questions and challenges. We now know that this category of tumors is remarkably more heterogenous than initially thought, especially in regards to its cytogenetics and molecular properties, and some of these differences likely have prognostic relevance. Whether we are now expanding the spectrum of Ewing sarcoma or simply recognizing new entities is controversial. Therapeutic approaches to address these new categories and/or entities need further focus and attention. Herein, we provide a comprehensive historical perspective on Ewing sarcoma, Ewing-like tumors (CIC and BCOR-rearranged sarcomas), and related and/or similar small round cell tumors, often included in the differential diagnosis, including mesenchymal chondrosarcoma, desmoplastic small round cell tumor, and small cell osteosarcoma. We also seek to provide updates and insights into the evolving classification and clinical relevance of the Ewing family of tumors.

Atypical lipomatous tumor/well differentiated liposarcoma and related mimics with updates. When is molecular testing most cost-effective, necessary, and indicated?

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.

Keeping it real: Merging traditional and contemporary practices in musculoskeletal pathology: A special issue of neoplastic and non-neoplastic bone and soft tissue pathology.

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.

Back to the future! Selected bone and soft tissue neoplasms with shared genetic alterations but differing morphological and immunohistochemical phenotypes.

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.

Updates in non-neoplastic orthopaedic pathology: what you don't know can hurt you!

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.

Fine-needle aspiration biopsy diagnosis of histiocyte-rich rhabdomyoblastic tumor (inflammatory leiomyosarcoma): A case report.

Histiocyte-rich rhabdomyoblastic tumor (HRRMT) is an exceedingly rare soft tissue tumor of primitive myogenic differentiation. We report herein a case involving the soft tissue in the left lateral peri-scapular region in a 68-year-old female with a 2-month history of a non-painful soft tissue mass. Ultrasound revealed a solid, ovoid subcutaneous mass lesion that lacked significant internal vascularity. Percutaneous fine-needle aspiration (FNA) biopsy with concomitant core needle biopsy was performed, and a diagnosis of HRRMT was rendered. Cytologic smears were hypercellular, composed of a mixture of foamy histiocytes and a variably cohesive population of epithelioid and plasmacytoid to vaguely spindled cells in cohesive clusters and singly dispersed. Histologic material showed sheets of epithelioid and plasmacytoid to spindled cells with admixed foamy histiocytes with distended, vacuolated cytoplasm. To our knowledge, this is the first reported example of HRRMT evaluated by FNA biopsy.

Routine EWS Fusion Analysis in the Oncology Clinic to Identify Cancer-Specific Peptide Sequence Patterns That Span Breakpoints in Ewing Sarcoma and DSRCT.

(1) Background: EWS fusion genes are associated with Ewing sarcoma and other Ewing family tumors including desmoplastic small round tumor, DSRCT. We utilize a clinical genomics workflow to reveal real-world frequencies of EWS fusion events, cataloging events that are similar, or divergent at the EWS breakpoint. (2) Methods: EWS fusion events from our next-generation sequencing panel (NGS) samples were first sorted by breakpoint or fusion junctions to map out the frequency of breakpoints. Fusion results were illustrated as in-frame fusion peptides involving EWS and a partner gene. (3) Results: From 2471 patient pool samples for fusion analysis at the Cleveland Clinic Molecular Pathology Laboratory, we identified 182 fusion samples evolved with the EWS gene. They are clustered in several breakpoints: chr22:29683123 (65.9%), and chr22:29688595 (2.7%). About 3/4 of Ewing sarcoma and DSRCT tumors have an identical EWS breakpoint motif at Exon 7 (SQQSSSYGQQ-) fused to a specific part of FLI1 (NPSYDSVRRG or-SSLLAYNTSS), ERG (NLPYEPPRRS), FEV (NPVGDGLFKD) or WT1 (SEKPYQCDFK). Our method also worked with Caris transcriptome data, too. Our primary clinical utility is to use this information to identify neoantigens for therapeutic purposes. (4) Conclusions and future perspectives: our method allows interpretation of what peptides result from the in-frame translation of EWS fusion junctions. These sequences, coupled with HLA-peptide binding data, are used to identify potential sequences of cancer-specific immunogenic peptides for Ewing sarcoma or DSRCT patients. This information may also be useful for immune monitoring (e.g., circulating T-cells with fusion-peptide specificity) to detect vaccine candidates, responses, or residual disease.

Osteoid osteomas of the hands and feet: a series of 71 cases.

Osteoid osteomas typically arise in the long bones of extremities. Patients often report pain relieved by NSAIDS, and radiographic findings are often sufficient for diagnosis. However, when involving the hands/feet, these lesions may go unrecognized or misdiagnosed radiographically due to their small size and prominent reactive changes. The clinicopathologic features of this entity involving the hands and feet are not well-described. Our institutional and consultation archives were searched for all cases of pathologically confirmed osteoid osteomas arising in the hands and feet. Clinical data was obtained and recorded. Seventy-one cases (45 males and 26 females, 7 to 64 years; median 23 years) arose in the hands and feet, representing 12% of institutional and 23% of consultation cases. The clinical impression often included neoplastic and inflammatory etiologies. Radiology studies demonstrated a small lytic lesion in all cases (33/33), the majority of which had a tiny focus of central calcification (26/33). Nearly, all cases demonstrated cortical thickening and/or sclerosis and perilesional edema which almost always had an extent two times greater than the size of the nidus. Histologic examination showed circumscribed osteoblastic lesions with formation of variably mineralized woven bone with single layer of osteoblastic rimming. The most common growth pattern of bone was trabecular (n = 34, 48%) followed by combined trabecular and sheet-like (n = 26, 37%) with only 11 (15%) cases presenting with pure sheet-like growth pattern. The majority (n = 57, 80%) showed intra-trabecular vascular stroma. No case showed significant cytology atypia. Follow up was available for 48 cases (1-432 months), and 4 cases recurred. Osteoid osteomas involving the hands and feet follow a similar age and sex distribution as their non-acral counterparts. These lesions often present with a broad differential diagnosis and may initially be confused with chronic osteomyelitis or a reactive process. While the majority of cases have classic morphologic features on histologic exam, a small subset consists solely of sheet-like sclerotic bone. Awareness that this entity may present in the hands and feet will help pathologists, radiologists, and clinicians accurately diagnose these tumors.

The Incidence and Significance of Calcium Pyrophosphate Dihydrate Deposits in Histologic Examinations of Total Hip, Knee, and Shoulder Joint Arthroplasties.

CONTEXT.­: The incidence, distribution, and significance of calcium pyrophosphate dihydrate deposition (CPPD) disease have not been extensively compared among various total joint resections. OBJECTIVE.­: To investigate and define the clinical and pathologic features of CPPD in hip, shoulder, and knee arthroplasties. DESIGN.­: We retrospectively reviewed consecutive total hip, knee, and shoulder arthroplasty cases (N = 3195) confirmed pathologically between January 1, 2017, and October 10, 2018, comparing clinical and pathologic data. RESULTS.­: Among 2004 hip arthroplasties, 61 (3%) had CPPD on pathologic examination; the majority had a histologic diagnosis of osteoarthritis, followed by fracture and avascular necrosis. Of 1113 knee arthroplasties, 98 (9%) had CPPD; all had a histologic diagnosis of osteoarthritis. Among 78 shoulder arthroplasties, 10 (13%) had CPPD; all but one had a histologic diagnosis of osteoarthritis. Patients with hip and knee CPPD were significantly older than those without CPPD. Of the 169 pathologically detected CPPD cases, only 35 (21%) were documented on preoperative radiologic images or by other clinical means; radiology reports were significantly more likely to document chondrocalcinosis in the knees than in the hips. Histologically, CPPD was noted almost exclusively in the separately submitted soft tissues/joint capsule, concomitantly involving the articular cartilage surface in only 3.0% (5 of 169) of cases. CONCLUSIONS.­: Calcium pyrophosphate dihydrate deposition is more than twice as likely to occur in the knees and shoulders compared with the hips. Patients with CPPD in the knees or hips are usually not recognized preoperatively/radiologically and constitute a significantly older population. Reliably establishing the diagnosis of CPPD requires pathologic examination of the submitted soft tissue/joint capsule.

Osteofibrous Dysplasia and Adamantinoma.

For decades, the diagnosis, treatment, and even pathogenesis of the osteofibrous dysplasia/osteofibrous dysplasia-like adamantinoma/classic adamantinoma spectrum of neoplasms have been controversial. Herein, we discuss and illustrate the radiographic and histologic spectrum, differential diagnoses, unifying chromosomal and molecular abnormalities, and current controversies and treatment recommendations for each entity.

Accurate and Reliable Diagnosis of Avascular Necrosis of the Femoral Head From Total Hip Arthroplasty Specimens Requires Pathologic Examination.

OBJECTIVES: To evaluate the necessity of pathologic examination for confirming the diagnosis of avascular necrosis (AVN). METHODS: We retrospectively reviewed consecutive nonfractured total hip arthroplasty cases (n = 1,722), comparing operative diagnoses and radiologic data with final histologic diagnoses, focusing specifically on AVN. RESULTS: Among 199 histologically confirmed cases of AVN, 62 (31%) had a preoperative diagnosis of osteoarthritis/degenerative joint disease (OA/DJD); 58 of the latter patients had radiology reports, but only two (3%) documented AVN. Patients with AVN preoperatively diagnosed as OA/DJD were significantly older (mean, 65 years) than patients with AVN correctly diagnosed clinically (mean, 52 years; P < .00001). Among 163 cases with a preoperative diagnosis of AVN, 26 (16%) were confirmed as OA/DJD; the radiology report incorrectly diagnosed AVN in 17 (65%) patients. These latter patients also were significantly older (mean, 60 years) than patients with AVN correctly diagnosed clinically (P = .0008). Patients with a preoperative clinical and/or radiologic diagnosis of AVN were more likely to be younger and have known AVN risk factors. CONCLUSIONS: Accurate and reliable diagnosis of AVN requires pathologic examination, especially among older patients without known risk factors. Prompt diagnosis may lead to behavioral changes in affected patients that reduce the risk of subsequent lesions.

Sclerosing epithelioid fibrosarcoma of bone: morphological, immunophenotypical, and molecular findings of 9 cases.

Primary sclerosing epithelioid fibrosarcoma (SEF) of bone is a rare and scarcely reported neoplasm. We document clinicopathological and molecular features of 9 additional cases. Five males and 4 females had a mean age of 39 years (14-71 years). Most tumors affected flat/irregular bones; only 3 cases involved a long bone. By radiology, it has characteristic radiographic features of a predominantly lytic expansile lesion with a sclerotic rim. Referring diagnoses were SEF (n = 2), low-grade osteosarcoma (n = 2), chondrosarcoma (n = 1), and chondromyxoid fibroma (n = 1). Histologically, five cases revealed classical morphology of SEF of soft tissue. Remaining cases were classified as hybrid SEF/low-grade fibromyxoid sarcoma, characterized by spindle or stellate cells, prominent stroma, and giant hyalinized areas. Various morphological deviations such as prominent vasculature (n = 3), osteoid-like material (n = 4), or parallel bone trabeculae (n = 2) were observed. Immunohistochemically, all cases showed diffuse and strong MUC4 expression. SATB2 was observed in 5/8 cases. Using FISH, EWSR1, and FUS rearrangements were detected in 4 cases and 1 case, respectively. EWSR1-CREB3L1 fusion was identified in 1 additional case by next-generation sequencing. Recurrence and metastasis were observed in 1 case and 2 cases, respectively. All but one patient were alive with disease for a mean interval of 31 months. SEF of bone is a relatively indolent sarcoma of adults, most commonly located in the flat/irregular bones. Due to overlapping histological features, it is often misdiagnosed as osteosarcoma or a chondroid tumor. Most SEF of bone exhibit EWSR1 rearrangements, but rare cases may harbor a FUS gene fusion.

CD34-negative Solitary Fibrous Tumor: A Clinicopathologic Study of 25 Cases and Comparison With Their CD34-positive Counterparts.

CD34-negative solitary fibrous tumors (SFTs) are rare and have not been comprehensively studied. We retrospectively reviewed all cases of SFT confirmed with STAT6 immunohistochemistry and/or STAT6 gene fusion between 2013 and 2020 and collected pertinent clinicopathologic parameters. Of a total of 244 cases, 25 (10%) lacked CD34 expression by immunohistochemistry. Compared with CD34-positive SFT, CD34-negative SFT are more likely to arise in the head and neck area (32% vs. 24%, P=0.02) and present as metastatic disease (28% vs. 1%, P<0.0001). A significantly higher percentage of CD34-negative SFT exhibit high-grade cytologic atypia (hypercellularity, round cell or anaplastic morphology, nuclear pleomorphism, etc.) (48% vs. 22%, P=0.0073). There are no significant differences in the distributions of age, sex, tumor size, mitotic count, tumor necrosis, or risk stratification between CD34-negative and CD34-positive SFT. In addition, only 56% of CD34-negative SFT display a typical hemangiopericytoma-like vascular pattern. Special histologic features among CD34-negative SFT include prominent alternating hypercellular or fibrous and hypocellular myxoid areas with curvilinear vessels mimicking low-grade fibromyxoid sarcoma, pulmonary edema-like microcystic changes, and prominent amianthoid collagen fibers. In conclusion, compared with their CD34-positive counterparts, CD34-negative SFT is more likely to present as metastatic disease, show high-grade nuclear atypia, and lack the characteristic hemangiopericytoma-like vasculature, posing a unique diagnostic challenge. The use of STAT6 immunohistochemistry and/or molecular studies may be prudent in soft tissue tumors that appear CD34 negative and lack conventional SFT histopathologic characteristics.