To investigate the relationship between cartilage cap thickness, osteochondroma subtype (pedunculated vs. sessile), patient age, and multiple hereditary exostoses (MHE) diagnosis with malignant transformation of osteochondromas. A single-institution retrospective study of patients who underwent surgical excision of one or more osteochondromas between 1983 and 2025 was conducted. The relationship between cartilage cap thickness, osteochondroma subtype (pedunculated vs. sessile), patient age, and MHE diagnosis with malignant transformation was investigated. Among 1138 pathology-confirmed osteochondromas, 1097 (96.4

Classic adamantinoma, osteofibrous dysplasia (OFD), and OFD-like adamantinoma are rare bone tumors arising primarily in the tibiae. Their distinction can be challenging; data on their molecular pathogenesis remain limited. We searched our pathology files in 2004-2024 for available cases and performed targeted next-generation sequencing along with whole-genome single-nucleotide polymorphism arrays and 3-dimensional genomics/Hi-C sequencing in selected cases. Our cohort included 3 classic adamantinomas (2 females and 1 male; age, 14-56 years), 5 OFDs (3 females and 2 males; age, 9-25 years), and 2 OFD-like adamantinomas (1 female and 1 male; age, 30-41 years). Of the 10 tumors, 9 arose from the tibiae; 1 classic adamantinoma originated from the radius. The 3 classic adamantinomas harbored multiple copy number gains involving chromosome 7, 8, 10, 12, and/or 19. Focal deletion of chromosome 17, intergenic rearrangement involving FGFR1, and NRAS p.G12D were each present in 1 classic adamantinoma. Of the 5 OFDs, KMT2A p.C2441F, KMT2D p.S1040P, PHOX2B p.G213D, and RIF1 deletion were each present in 1 case; no additional copy number/single-nucleotide variants were identified. Of the 2 OFD-like adamantinomas, one case with tumor clusters visible only on cytokeratin immunostain harbored no variants, whereas another case with tumor clusters visible on light microscopy and cytokeratin/p40 immunostains showed gains of chromosome 7, 8, 19, and 20. By Hi-C, 1 classic adamantinoma harbored an approximately 9 Mb tandem duplication on chromosome 12q, 1 OFD harbored a rearrangement with breakpoints near MECOM and HOOK3, and the OFD-like adamantinoma with tumor clusters visible only on cytokeratin immunostain harbored no structural variant. In conclusion, classic adamantinomas and OFD might be genetically distinct. Classic adamantinomas harbored multiple alterations, including chromosome/arm-level copy number gains, the detection of which could aid their distinction from OFDs. Using genomics as the benchmark, OFD-like adamantinomas might be better delineated by light microscopy or p40 than by cytokeratin immunohistochemistry. These data expanded our molecular understanding of these rare bone tumors.

Vulvar smooth muscle tumors have been evaluated using site-specific (1979 and 1996 Vulvar Criteria) or Uterine Criteria. We compared the performance of 3 classification systems for predicting clinical behavior in the largest series of 35 such tumors to date. Follow-up was available for 30 patients (median: 63 mo, 1 to 346). Most presented as a painless mass in premenopausal patients and showed spindled or myxoid morphology. Diagnoses were concordant across all 3 classification systems in most cases (80%, 28/35), including 22 leiomyomas and 6 leiomyosarcomas. Of the 7 discordant tumors, 3 with ≥5 cm, moderate to marked cytologic atypia, 5 mitoses per 10 high-power fields (HPF), and no tumor cell necrosis or infiltrative borders were diagnosed as smooth muscle tumors of uncertain malignant potential (STUMP) by the Uterine Criteria but as leiomyosarcoma/low-grade leiomyosarcoma by the site-specific criteria. Two tumors (≥5 cm, 8 to 9 mitoses per 10 HPF, no cytologic atypia or tumor cell necrosis, and unevaluable borders) were classified as mitotically active leiomyoma by the Uterine Criteria and the 1996 Vulvar Criteria but as low-grade leiomyosarcoma by the 1979 Vulvar Criteria. Two tumors with tumor cell necrosis, moderate atypia, 9 and 66 mitoses per 10 HPF, but <5 cm and well-circumscribed borders were categorized as leiomyosarcoma by the Uterine Criteria but as leiomyoma by both site-specific criteria. Our findings support the validity of the Uterine Criteria relative to the site-specific criteria for vulvar smooth muscle tumors, although the applicability of these criteria to the STUMP category warrants further study.

Epithelioid malignant peripheral nerve sheath tumor (EMPNST) is recognized as a distinct entity in the 2026 World Health Organization classification, defined by characteristic morphology and frequent SMARCB1 (INI1) loss, which differentiates it from conventional MPNST. Limited data suggest EMPNST may have a more favorable prognosis, but prognostic markers remain undefined. We studied 78 primary EMPNSTs and compared them with 60 conventional MPNSTs. Patients with EMPNST included 41 females and 37 males, with a median age of 45 (range, 6-84) years. Necrosis was observed in 20% of cases, cytologic atypia was mild (25%), moderate (57%), or severe (18%), and mitoses ranged from 0 to 42/10 (median 7/10) high-power fields. SMARCB1 loss was observed in 81% of EMPNSTs and correlated with prominent nucleoli (64%, P < .001). EMPNSTs predominantly arose in the lower extremities, with 32% superficial, whereas conventional MPNSTs were mostly truncal. Targeted sequencing in 34 EMPNSTs identified SMARCB1 inactivation in 77% of cases, which was associated with SMARCB1 loss (P < .001), and recurrent alterations targeting 2q35/XRCC5 in 59% of cases. Among 34 patients with follow-up (median, 43 months; range, 0-225), 9 developed local recurrence, 15 metastases, and 10 died of disease. Compared with conventional MPNST, EMPNST demonstrated longer median progression-free survival (34 vs 19 months, P value for global difference of survival curves = .35); overall survival was not reached in EMPNST (vs 85 months in conventional MPNST, P value for global difference of survival curves = .16). In multivariable analysis, tumor size and mitotic rate were independently associated with poor prognosis (hazard ratio [HR], 5.2; 95% CI, 1.5-17.7; HR, 1.1; 95% CI, 1.01-1.2, respectively). A risk score integrating tumor size > 5 cm, mitoses > 7 of 10 high-power fields, and necrosis predicted poor outcomes (HR, 4.1; 95% CI, 1.4-12). In conclusion, EMPNST tumor size and mitotic activity are key prognostic factors, supporting a simple risk stratification model. SMARCB1 inactivation is the most frequent genomic event, followed by gains at 2q35 potentially targeting XRCC5, highlighting molecular underpinnings for this distinct sarcoma subtype.

In recent years, rare fibrosarcoma-like tumors have been identified in the gynecologic tract characterized by variable CD34 and S-100 positivity and recurrent tyrosine kinase gene fusions in many cases. We identified 17 of these tumors by searching for gynecologic sarcomas expressing S-100 and/or CD34 and supplementing these with cases contributed by collaborating institutions. Tumors involved the uterine cervix (n=11), uterine corpus (n=4), and vagina (n=2). Patients ranged from 28 to 64 (median: 50) years. Fifteen tumors showed overlapping morphologic features including haphazard or fascicular growth of relatively monotonous spindled to ovoid cells with minimal to moderate cytoplasm. Tyrosine kinase gene fusions were identified in 9 tumors, including NTRK fusions in 6 and COL1A1::PDGFB in 3 tumors. Oncogenic variants in ERBB2/ERBB3 were identified in 6 additional tumors. These two subgroups showed distinct immunohistochemical profiles, with all tyrosine kinase fusion-positive tumors being CD34 positive, variably S-100 positive, and SOX10 negative. In contrast, the ERBB-altered tumors were CD34 negative and diffusely positive for S-100 and SOX10. The remaining 2 tumors showed morphologic and immunohistochemical overlap with the tyrosine kinase fusion-positive sarcomas; one was negative for fusion or sequence variants, and sequencing failed in the other. In conclusion, most fibrosarcoma-like tumors of the gynecologic tract are defined by either tyrosine kinase fusions or ERBB2/3 mutations. Immunohistochemistry can be used to predict these subgroups to guide confirmatory genetic testing and targeted therapies.

BACKGROUND:To determine if dose escalation improves outcomes for chondrosarcomas (CHS) of the base of the skull (BOS) and the cervical spine (CS). METHODS:A prospective, randomized, dose-escalation trial was designed for patients with CHS of the BOS and CS. Patients were randomly assigned to 70 Gy (RBE) or 76 Gy (RBE). The primary endpoint was local failure (LF). Secondary endpoints included overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), and treatment-related toxicities. RESULTS:Between 1987 and 2007, 105 patients were randomized, median follow-up was 29.2 years (IQR, 26.7-32.4). Forty-six patients were assigned to 70 Gy (RBE) and 59 were assigned to 76 Gy (RBE). LF at 5-, 10-, and 20 years were 7%, 9%, and 11% for 70 Gy (RBE), and 10%, 15%, and 19% for 76 Gy (RBE) (P = .16). Like LF rates, there was no benefit in dose escalation for OS (P = .28) and CSS (P = .22). Progression-free survival at 5-, 10-, and 20 years was 93%, 89%, and 77% for the low-dose group and 83%, 71%, and 59% for the high-dose group (P = .069). Late RT injury ≥ grade 3 was reported in a total of 19 (18%) patients across both dose levels, with 11% in the low-dose group and 24% in the high-dose group (P = .13). CONCLUSIONS:This is the first and largest trial of patients with grade I/II BOS and CS CHS evaluating dose escalation for tumor control. Proton-based RT is effective and safe for these tumors, but there is no apparent benefit in dose escalation. CLINICAL TRIAL INFORMATION:NCT00592748.

INTRODUCTION:Dedifferentiated liposarcoma (DDLPS) is a typically non-lipogenic malignant neoplasm that arises from progression of an underlying atypical lipomatous tumour/well-differentiated liposarcoma (ALT/WDLPS) and is classically defined by amplification of chromosome 12q15, including MDM2 and frequently cyclin-dependent kinase 4 (CDK4). Detection of MDM2 amplification by fluorescence in situ hybridization (FISH) and/or MDM2 protein expression immunohistochemistry (IHC) has, therefore, become central to the diagnosis of DDLPS, particularly in small biopsies from the retroperitoneum. Rare exceptions to this paradigm have been described, but the clinicopathologic and molecular spectrum of MDM2 non-amplified DDLPS remains poorly characterized. We report a series of MDM2 non-amplified DDLPS to better define their diagnostic features, genomic alterations and clinical behaviour. METHODS:Pathology archives from 2010 to 2025 were queried for cases diagnosed as DDLPS. Inclusion criteria required a high-grade sarcoma arising in a histologically confirmed ALT/WDLPS background, absence of MDM2 overexpression by IHC and lack of MDM2 amplification by FISH and/or single nucleotide polymorphism array. Clinicopathologic features, immunophenotype, treatment and outcomes were reviewed. RESULTS:Among 253 cases of DDLPS identified during the study period, four (1.6%) fulfilled criteria for MDM2-negative DDLPS. All tumours arose in the retroperitoneum or intra-abdominal soft tissues and demonstrated high-grade sarcoma morphology with an associated WDLPS component on resection. Despite the absence of MDM2 amplification, all cases showed strong CDK4 expression by IHC. Molecular analysis revealed recurrent alterations involving cell-cycle regulation, including CDK4 copy number gain in all cases and loss of CDKN2A in three. Two cases harboured TP53 alterations. Clinically, outcomes were heterogeneous, ranging from aggressive disease with rapid recurrence and death within months to prolonged disease-free survival exceeding 5 years. CONCLUSION:MDM2 non-amplified DDLPS represents a rare subset of DDLPS that appear to be driven by alternative mechanisms of cell-cycle dysregulation, most commonly involving CDK4 gain and CDKN2A loss, with occasional TP53 alterations. Awareness of this variant is critical to avoid misclassification as other high-grade sarcomas, particularly on limited biopsies, and underscores the importance of integrating morphology, IHC and broad genomic profiling in diagnostically challenging retroperitoneal sarcomas.

Clear cell sarcoma overlaps histologically and immunophenotypically with melanoma. Molecular testing for EWSR1 rearrangement aids in their distinction but may not be readily available. We aim to construct machine learning-based classifiers using supervised and deep learning. We digitized hematoxylin-and-eosin-stained slides from clear cell sarcomas and melanomas with confirmatory testing, constructed nuclear morphometric-based and deep learning-based classifiers (using CLAM/ResNet-50, CTransPath, and UNI models), and evaluated their performance using an independent external validation set. Morphometric analysis of 1,954,194 nuclei (1,308,124 from clear cell sarcomas, 646,070 from melanomas; 8700-70,726 [median 32,472] nuclei per slide) yielded two optimal classifiers using single-node decision tree models; both pertained to nuclear perimeter and included interquartile/interdecile range normalized to median. Factors associated with inaccurate predictions included < 10,000 nuclei/sample and altered morphology in clear cell sarcoma due to therapy. In the external validation set, comparable to the prediction accuracies by four pathologists (median 80%; range 60%-100%), the two nuclear morphometric-based classifiers achieved accuracies of 80%-90%, and the optimal deep learning-based classifier CLAM/CTransPath showed an accuracy of 90%. In conclusion, we have derived interpretable nuclear morphometric- and deep learning-based classifiers to distinguish clear cell sarcoma from melanoma. Quantitative morphometric analysis with machine learning holds the potential as a diagnostic adjunct.

This phase 1 trial using intensity modulated photon pre-operative radiotherapy for patients with retroperitoneal sarcoma demonstrated that the dose can be safely escalated to 63.0 Gy to a select tumor volume deemed at high risk for positive margins. Thus, this approach is worthy of further prospective study with larger cohorts.

Giant cell tumors of bone are locally aggressive, frequently harbor H3F3A p.G34W mutations, and rarely undergo malignant transformation. The pathogenesis of malignant transformation remains incompletely characterized. Herein, we present 28 malignant giant cell tumors of bone from 14 males and 14 females, aged 16 to 65 (median 39) years. Primary sites included long bones (n=20), pelvis (n=3), vertebrae (n=2), and rarely rib, phalanx, and cuneiform (n=1 each). Sixteen (62%) of 26 tumors with available history represented malignant transformation or recurrence of conventional giant cell tumors of bone, at intervals of 1.3 to 35 (median 7.3) years before malignant transformation. Eight of 15 patients with available treatment history received denosumab before a diagnosis of malignancy. Ten (38%) of 26 tumors with available history likely arose de novo, including 7 with conventional areas and 3 H3F3A -mutant sarcomas lacking conventional giant cell tumor of bone. Of 28 malignant giant cell tumors of bone, 18 (64%) and 10 (36%) harbored osteoblastic and chondroblastic elements, respectively. Among 23 tumors with available genetic testing or surrogate immunohistochemistry, 17 (74%) were p.G34W-mutant, whereas other tumors carried H3F3A p.G34L (n=2), p.G34V (n=2), and p.G34R (n=1) alterations; 1 tumor harbored H3F3B p.K116E and p.R117S in cis. Seven (70%) of 10 malignant giant cell tumors of bone showed complex copy number alterations by single nucleotide polymorphism (SNP) array, DNA next-generation sequencing (NGS), and/or karyotype analysis. In contrast, complex chromosomal alterations were lacking in 32 conventional giant cell tumors of bone tested (24 by karyotype, 7 by SNP array, 1 by DNA NGS), 3 atypical giant cell tumors of bone with isolated marked nuclear atypia (2 by karyotype, 1 by SNP array) and 3 metastasizing conventional giant cell tumors of bone (2 by DNA NGS, 1 by karyotype). Clinical follow-up was available for 20 patients (71%), and one additional patient had metastases at presentation. Overall, 14 of 21 patients (67%) developed metastases, and 10 of 20 patients with follow-up (50%) died of disease at 2 months to 9.6 years (median 7 mo). Most patients were treated with chemotherapy; 1 patient (PD-L1 TPS >95%) was treated with pembrolizumab, with complete clinical response of metastatic disease at 2.5 years. In conclusion, malignant giant cell tumors of bone typically arise from long bones, harbor osteosarcomatous and/or chondrosarcomatous differentiation, and show significant risk for distant metastasis and demise. Our data suggest that copy number analysis may be useful in distinguishing malignant giant cell tumors of bone from their conventional, atypical, and metastasizing conventional counterparts.

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.

PURPOSE:To report the first cohort of children with spinal and sacrococcygeal chordomas (CH) and chondrosarcomas (CHS) treated with proton-based radiation therapy (PRT). MATERIALS AND METHODS:Between 1989 and 2019, 52 pediatric patients ≤22 years old with spinal CH (n = 43) or CHS (n = 9) were treated with PRT at a single institution. The primary tumor originated in the C-spine (n = 37, 71%), T-spine (n = 6, 12%), L-spine (n = 7, 14%), or sacrum (n = 2, 3%). The CH group included 33 conventional and 10 atypical/poorly differentiated CH. The CHS group included 5 conventional and 4 mesenchymal CHS. Pre-RT chemotherapy was administered to 13 (25%) patients. Salvage radiation was delivered to 13 (25%) patients with progressive disease. The median total dose was 74.5 Gy (RBE) [IQR, 69.8-76 Gy (RBE)], delivered in 1.8 to 2.5 Gy (RBE) daily fractions. Primary endpoints were overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS). A univariate and multivariable Cox regression analysis was performed to identify prognostic and predictive factors. RESULTS:At a median follow-up of 11.4 years (IQR, 5.7-19.8) from the date of diagnosis, 17 (32.7%) patients recurred (8 local, 7 distant, and 2 iatrogenic). Fifteen of these patients died of disease. The 5-, 10-, and 20-year OS were 82.7%, 72.3% and 72.3%, respectively. The 5-, 10-, and 20-year DSS were 86.1%, 77.5%, and 77.5%, respectively. The 5-, 10-, and 20-year PFS were 72.3%, 70.1% and 70.1%, respectively. The 20-year OS, DSS, and PFS for conventional CH were 93.9%, 97%, and 87.9%, respectively. Factors significantly associated with worse outcomes were poorly differentiated CH subtype, pre-RT chemo, and low KPS (P < .05). Pre-RT tumor progression was found to be a significant prognostic factor for PFS (P = .02). Two patients developed late grade 3 toxicities. CONCLUSIONS:This is the largest study of pediatric spinal and sacrococcygeal CH/CHS to date. High-dose PRT following surgical resection offers high disease control rates for conventional CH/CHS.

Dermatofibroma/fibrous histiocytoma is a common tumor of the dermis, composed of myofibroblasts, dendrocytes, and macrophages with characteristic entrapment of dermal collagen fibers at the periphery of the tumor. Various subtypes of dermatofibroma, including cellular, aneurysmal, and atypical dermatofibroma, are associated with an increased risk of recurrence, especially with incomplete excision. Two cases of benign fibrous histiocytoma with recurrence and metastasis are described. Patient 1 had a cellular fibrous histiocytoma with KIRREL1::PRKCD fusion presenting as a superficial and deep soft tissue mass involving the scapula and lateral clavicle. Patient 1 subsequently developed metastasis to the chest wall and thigh. Patient 2 had a recurrent aneurysmal fibrous histiocytoma with LAMTOR1::PRKCD fusion presenting as a large shoulder mass with invasion of the clavicle and lymph node metastasis. Patient 2 developed rapid local recurrence and PET-avid pulmonary nodules, radiologically consistent with metastasis. Fibrous histiocytoma is typically a morphologically benign neoplasm that only rarely exhibits clinically aggressive behavior with multiple recurrences and metastases. Although uncommon, recognition of this entity is important so that pathologists and sarcoma oncologists can ensure accurate diagnosis, multidisciplinary management, and appropriate clinical surveillance. In addition, complex chromosomal abnormalities may serve as useful indicators of fibrous histiocytoma with the risk of aggressive clinical behavior.

Non-neoplastic bone lesions represent a heterogeneous group of conditions that stem from reactive, genetic, or metabolic processes. These lesions can sometimes closely mimic malignant tumors, posing diagnostic challenges. This article focuses on a few non-neoplastic bone lesions and their differential diagnoses, including florid reactive periostitis, Paget disease of bone, fractures (including compression/stress fractures), and melorheostosis, each of which exhibits distinct clinical, radiological, and pathologic features. Unlike neoplastic processes of bone, no specific immunohistochemical features or molecular studies are helpful in diagnosing these lesions. In many cases, the diagnosis is based primarily on the radiographic findings, often eliminating the need for a biopsy.

The synovium is an integral component of synovial joints, as well as extra-articular structures such as the tenosynovium and bursae. This article reviews normal histology and the immunohistochemical profile of the synovium. It also discusses several common and distinctive intra-articular and extra-articular tumors arising in synovium-lined structures, such as tenosynovial giant cell tumor, synovial chondromatosis, and the recently described chondroid synoviocytic neoplasm. Among these, tenosynovial giant cell tumor and chondroid synoviocytic neoplasm are the only true neoplasms of synoviocytes. An emerging entity, calcified chondroid mesenchymal neoplasm, will also be mentioned. The clinical, radiologic, morphologic, and molecular genetics features of these tumors are discussed, along with their differential diagnoses. In addition, the article addresses other rare lesions, such as lipoma arborescens, a nonneoplastic condition, and synovial hemangioma, which often present as an intra-articular mass. Finally, a brief overview of selected primary intra-articular sarcomas is provided.

Giant cell tumors of bone are locally aggressive, frequently harbor H3F3A p.G34W mutations, and rarely undergo malignant transformation. The pathogenesis of malignant transformation remains incompletely characterized. Herein, we present 28 malignant giant cell tumors of bone from 14 males and 14 females, aged 16 to 65 (median 39) years. Primary sites included long bones (n=20), pelvis (n=3), vertebrae (n=2), and rarely rib, phalanx, and cuneiform (n=1 each). Sixteen (62%) of 26 tumors with available history represented malignant transformation or recurrence of conventional giant cell tumors of bone, at intervals of 1.3 to 35 (median 7.3) years before malignant transformation. Eight of 15 patients with available treatment history received denosumab before a diagnosis of malignancy. Ten (38%) of 26 tumors with available history likely arose de novo, including 7 with conventional areas and 3 H3F3A -mutant sarcomas lacking conventional giant cell tumor of bone. Of 28 malignant giant cell tumors of bone, 18 (64%) and 10 (36%) harbored osteoblastic and chondroblastic elements, respectively. Among 23 tumors with available genetic testing or surrogate immunohistochemistry, 17 (74%) were p.G34W-mutant, whereas other tumors carried H3F3A p.G34L (n=2), p.G34V (n=2), and p.G34R (n=1) alterations; 1 tumor harbored H3F3B p.K116E and p.R117S in cis. Seven (70%) of 10 malignant giant cell tumors of bone showed complex copy number alterations by single nucleotide polymorphism (SNP) array, DNA next-generation sequencing (NGS), and/or karyotype analysis. In contrast, complex chromosomal alterations were lacking in 32 conventional giant cell tumors of bone tested (24 by karyotype, 7 by SNP array, 1 by DNA NGS), 3 atypical giant cell tumors of bone with isolated marked nuclear atypia (2 by karyotype, 1 by SNP array) and 3 metastasizing conventional giant cell tumors of bone (2 by DNA NGS, 1 by karyotype). Clinical follow-up was available for 20 patients (71%), and one additional patient had metastases at presentation. Overall, 14 of 21 patients (67%) developed metastases, and 10 of 20 patients with follow-up (50%) died of disease at 2 months to 9.6 years (median 7 mo). Most patients were treated with chemotherapy; 1 patient (PD-L1 TPS >95%) was treated with pembrolizumab, with complete clinical response of metastatic disease at 2.5 years. In conclusion, malignant giant cell tumors of bone typically arise from long bones, harbor osteosarcomatous and/or chondrosarcomatous differentiation, and show significant risk for distant metastasis and demise. Our data suggest that copy number analysis may be useful in distinguishing malignant giant cell tumors of bone from their conventional, atypical, and metastasizing conventional counterparts.

Background Idiopathic condylar resorption (ICR) is a rare condition of unknown etiology characterized by progressive decrease in volume and pathologic remodeling of a previously normal mandibular condyle. Juvenile idiopathic arthritis (JIA) affecting only the temporomandibular joint (TMJ-only JIA) is characterized by synovitis and destruction of TMJ tissues without involvement of other joints. It is often difficult to differentiate the 2 conditions because they exhibit similar phenotypes. Purpose To compare histology of resected condylar specimens from patients with ICR and TMJ-only JIA. Specific aims were as follows: 1) to correlate longitudinal clinical data with histopathology of resected condyle specimens and 2) to compare resorption patterns between the 2 disease processes. Study Design, Setting, Sample This was a retrospective cohort study of patients treated at the Massachusetts General Hospital from 1999 through 2023. Predictor/Exposure/Independent Variable Primary predictor variable was the diagnosis (ICR or JIA). Secondary predictor variables included age, gender, race, putative contributing factors, and laboratory studies. Main Outcome Variable(s) Primary outcome variable was presence or absence of inflammatory infiltrates in bone and synovial specimens. Secondary outcome variables were structural integrity and morphologic characteristics of the condylar cartilage and bone. Analyses Spearman correlation was used to assess the relationship between histological scores and age, gender, and possible associated contributing factors. A P value < .05 was considered statistically significant. Results Thirty-five subjects (67 specimens) were included in group 1 (ICR). Eight subjects (15 specimens) were included in group 2 (TMJ-only JIA). The histopathologic findings in ICR consisted of severe and irregular cartilage surface disruption, fibrocartilage degeneration, and subchondral bone with no inflammatory infiltrate. Degeneration was observed to begin at the anterior pole of the condyle and progress eventually to total resorption to the sigmoid notch. TMJ-only JIA was notable for more severe condylar degeneration and inflammation in the bone and synovia. There was no specific pattern of degeneration. For both groups, the subject’s age, gender, or putative contributing factors did not correlate with the histopathologic scores. Conclusion and Relevance These results support the hypothesis that “ICR” and TMJ-only JIA are distinct clinical entities and can be distinguished by histopathologic findings in the mandibular condyles and synovia.