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.

Radiologic-pathologic correlation is essential for diagnostic accuracy, particularly when dealing with primary bone tumors. This investigation explores the unique radiographic and pathologic features of NFATC2- rearranged bone sarcomas. Inclusion criteria focused on primary bone sarcomas with NFATC2 fusions while excluding soft tissue sarcomas, benign bone cysts, and vascular neoplasms with similar fusions. Our cohort comprised 16 patients (12 males, 4 females) with a mean age of 45.6 years (range: 15 to 77 y). Tumors were located in the femur (n=9), tibia (n=3), humerus (n=2), ulna (n=1), and radius (n=1). Symptoms generally followed a long latency period and several were incidentally discovered for other reasons, with a mean tumor size of 9.7 cm (range: 3.0 to 19.7 cm). Histologic examination revealed typical features of NFATC2 -rearranged sarcomas, including uniform epithelioid, round, or spindle cells growing in cords, chains, clusters, and sheets suspended in a richly vascularized fibromyxoid to variably sclerotic stroma. Mitotic activity varied dramatically between and within tumors (from <5 to >50 per 10 HPF). By immunohistochemistry, positive stains included CD99 (12/14), NKX2.2 (7/7), AGGRECAN (3/3), SMA (6/7), CAM5.2 (3/4), SATB2 (8/9), and ERG (5/8) with more limited expression of CK AE1/AE3 (3/12) and NKX3.1 (2/8). All had an NFATC2 gene fusion, with 9 harboring FUS and 7 EWSR1 as 5' partners. Additional genetic analysis beyond the targeted fusion panel (n=7) demonstrated that all cases harbored a range of secondary genomic alterations in addition to the driver NFATC2 fusion. On radiography and CT imaging, all showed lucent lesions with peripheral sclerosis and narrow transition zones. Expansile cortical remodeling (n=8; 50%) varied from minimal to extensive. Despite generally indolent-appearing radiographic features, 87.5% (14/16) demonstrated soft tissue extension, ranging from focal to extensive. Internal septations were present in 62.5% (10/16). MRI, performed on 15 tumors, revealed hypointensity on T1-weighted images and heterogeneously hyperintense on fluid-sensitive sequences. After contrast administration, avid enhancement was seen in all tumors with perilesional edema and enhancement in 26.7% (4/15). In summary, the imaging of NFATC2 -rearranged bone sarcomas differs significantly from Ewing sarcoma, suggesting a tumor of longer duration characterized by a lytic nature, areas of peripheral sclerosis, expansile cortical remodeling, and frequent extraosseous extension. However, these features may not correlate with prognosis. This study represents the first systematic radiologic evaluation of NFATC2 -rearranged bone sarcomas, highlighting distinctive characteristics that may aid pathologists in their initial diagnostic assessments.

Pediatric bone tumors are increasingly sampled through image-guided biopsies. Evolution of molecular and diagnostic adjuncts have enabled diagnosis of these challenging lesions with limited diagnostic tissue. Radiologic correlation remains critical in the evaluation of these lesions and sampling quality can affect diagnostic interpretation. Our understanding of giant-cell lesions has expanded with the identification of highly specific histone mutations in giant cell tumors and chondroblastoma. Meanwhile, molecular testing has allowed validation of newer entities such as Xanthogranulomatous Epithelial tumor/Keratin-Positive Giant cell tumor while clarifying the well-defined lesions such as aneurysmal cyst. Tissue preservation and avoidance of harsh acid decalcification techniques is the mainstay to allow preservation of nucleic acids and application of newer ancillary studies. In this review, we provide an overview of the current diagnostic approach in pediatric bone tumors with key updates.

BACKGROUND:Incidental skull lesions are increasingly detected due to the widespread use of brain imaging. We have encountered an unusual cohort of unclassifiable calvarial spindle cell lesions showing phenotypic overlap with perineurioma and meningioma, which we sought to further characterize. MATERIAL AND METHODS:Cases of unclassifiable low-grade spindle cell lesions arising in the calvarium were collected. Clinical, radiological and pathological findings were reviewed. All cases were uniformly stained for a panel of meningothelial and perineurial immunomarkers. RESULTS:Eight cases were identified (6 females, 2 males; 51-81 years), arising in the parietal (n = 4), frontal (n = 3), parietal-occipital (n = 1) bones. Radiologically, the lesions appeared as lytic with non-aggressive features, but progressive enlargement was documented in cases with serial imaging. Histologically, all cases were composed of uniform, bland spindle cells with elongated, tapered cytoplasm and inconspicuous nuclei arranged in short fascicles and whorls. Immunohistochemically, all cases were positive for EMA (8/8) and Collagen IV (3/3). The lesions showed consistent but limited staining for SSTR2a (2 cases, 6%-50%; 4 cases, 1%-5%). The lesional spindle cells were negative for PR (0/7), GLUT1 (0/6), S100 (0/6), CD34 (0/5), SOX10 (0/4) and claudin 1 (0/3). Follow-up (available in 6 patients; range 6-61 months, median 15.5 months) showed no evidence of recurrence after curettage or excision. CONCLUSION:Perineurioma-like, EMA-positive calvarial neoplasms are a rare group of spindle cell tumours for which no local recurrence or distant metastasis has been documented to date, although they do show a propensity for progressive growth. Recognition of their distinctive clinicopathological and radiological features is important for accurate diagnostic classification and appropriate patient management.

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.

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.

Osteosarcoma is the most common primary malignant neoplasm of bone. Despite recent advances in the management of the disease, the overall survival of patients has failed to improve in the past 30 years due to the biological and genetic complexities of the disease and the lack of reliable prognostic and predictive markers to guide the treatments. Histologic tumor necrosis in response to chemotherapy has served as the most reliable predictor of disease outcome for years. Patients with a good histologic response (greater than 90% tumor necrosis) to chemotherapy had better disease outcomes compared with patients with a poor histologic response (less than 90% tumor necrosis). With the changes in the intensity of chemotherapeutic regimens, the prognostic value of histologic measurement of tumor necrosis has been questioned in recent studies. Purpose In this study, we used a series of immunohistochemical measurements of 2 cell cycle regulators, p16 and p21, to evaluate their prognostic value, separately and in combination, for the disease outcomes. Method A total of 101 patients with high-grade osteosarcoma were included in this study. Clinicopathologic data were collected, and immunohistochemistry for p16 and p21 was performed and interpreted by 3 independent pathologists. Statistical analysis was performed to assess the strength of each of these markers relative to disease outcome. Results Our results indicate that more than 90% expression (high) of p16 by immunohistochemistry on the initial biopsy has a strong predictive value for good histologic response to chemotherapy. The patients are also more likely to survive the past 5 years and less likely to develop metastasis than patients with less than 90% p16 (low) expression. The results for p21, on the other hand, show a unique pattern of relationship to the clinicopathologic outcomes of the disease. Patients with less than 1% (low) or more than 50% (high) expression of p21 by immunohistochemistry show a higher chance of metastasis, poor necrotic response to chemotherapy, and an overall decreased survival rate when compared with p21 expression between 1% and 50% (moderate). Our results also showed that the expression of p16 and combined p16 and p21 demonstrates a stronger predictive relationship to 5-year survival than tumor histologic necrosis and p21 alone. Discussion The results of this study, once proven to be reproducible by a larger number of patients, will be valuable in the initial assessment and risk stratification of the patients for treatment and possibly the clinical trials.

Historically, the diagnosis of giant cell-rich neoplasms arising in bone has been challenging owing to overlapping clinical and radiographic findings resulting in the difficult separation of several neoplasms, particularly when biopsy material is limited. However, with the discovery of the driver histone mutations in giant cell tumor of bone (GCTB) and chondroblastoma, as well as USP6 rearrangements in aneurysmal bone cyst, pathologists now have objective ancillary tools to aid in the separation of several histologically similar giant cell-rich neoplasms. Furthermore, the recognition of histone mutations has allowed pathologists to revisit several entities, such as “malignant chondroblastoma,” and furthered our understanding of phenomena such as “aneurysmal bone cyst-like change,” formerly recognized as “secondary aneurysmal bone cyst.” Herein, the evolution of testing for histone mutations in bone tumors is considered; the sensitivity and specificity of the histone antibodies is reviewed; and a practical guide for the use of these ancillary tests is offered.

Jaw osteosarcoma (JOS) is a rare, distinct variant that differ from long bone osteosarcoma (LBOS) in several aspects. JOS typically appears about twenty years later than LBOS, displays a lower propensity for metastasis to other organs, and exhibits better survival rates. The dissimilarities in clinical and biological behavior between JOS and LBOS are likely due, at least in part, to variations in their respective microenvironments. In this report, we present a case of OS affecting the mandible in a young patient. This case displayed classic radiographic features but a unique histopathological presentation, posing a diagnostic challenge for pathologists, especially if encountered in small biopsies.

BACKGROUND: Bertolotti syndrome (BS) is characterized by chronic pain and functional impairment associated with lumbosacral transitional vertebrae (LSTVs). The study aimed to investigate the histologic characteristics of the pseudoarticulation between the enlarged transverse process and sacrum seen in Castellvi 2a LSTV and explore the involvement of nervous tissue in pain generation. METHODS: Immunohistochemical analysis using S100 protein staining was performed to assess the presence of nerve tissue. RESULTS: These changes included fibrillation, chondrocyte cloning, alterations in the proteoglycan matrix, and focal chondrocyte necrosis. Notably, no nerve tissue was observed in any of the specimens, as confirmed by negative S100 protein staining. CONCLUSIONS: The study findings suggest that nerve tissue is not involved in the nociceptive mechanisms underlying pain in BS. The histologic similarities between the pseudoarticulation and osteoarthritic joints indicate that pseudoarticulation itself may be a significant source of pain in BS. These insights contribute to our understanding of the pathophysiology of BS and support treatment paradigms prioritizing pain control with medications such as NSAIDs before considering surgical intervention. Future studies with larger sample sizes and in vivo models are needed to further validate these findings and explore the changes in joint histology under biomechanical forces in LSTVs.

The calcified chondroid mesenchymal neoplasm (CCMN) represents a recently recognized tumor type with only 50 well-documented cases in the English-language literature. Herein we report an additional case of CCMN presenting as a large mass in the temporomandibular joint region of a 41-year-old female. A review of previously reported cases and the current case of CCMN shows the following features: 1) average age 52 years (range 14-87 years) and an approximately even sex distribution; 2) most frequently involved sites: distal extremities (including foot, hand, wrist, forearm) (n=41) and temporomandibular joint/temporal/parotid region (n=9); 3) multilobular soft tissue tumor with chondroid to cartilaginous matrix, often grungy or lace-like calcifications, and variable cytologic atypia; 4) frequently detected FN1 rearrangement (n=15), including FN1 fusion with FGFR2 (n=7) or other receptor tyrosine kinases; 5) 2 reported local recurrences (after incomplete excision); 6) no reports of malignant biologic behavior.

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.

Introduction This investigation assessed whether the following factors were associated with radiographic local progression in bone metastases from renal cell carcinoma (RCC): (1) high-risk histologic features (2) lesional surgery (3) biologically effective dose (BED) of radiation therapy. Methods and materials A single-institution database identified all patients who underwent surgery and radiation therapy for bone metastases from RCC to the appendicular skeleton and pelvis from 2006 to 2016. Thirty-six patients underwent radiotherapy for 80 metastases. While all patients had surgical stabilization, 17/36 also had lesional surgery to address the metastatic lesion. Progression of each individual lesion was determined using the application of RECIST criteria to imaging at last follow-up. Results The rate of progressive disease was 8/25 (32%) in the high-risk group versus 5/55 (9%) in the standard-risk group (p = 0.019). The rate of progression among high-risk metastases undergoing lesional surgery was 0/9 versus 8/16 (50%) having non-lesional surgery (p = 0.0218). The rate of progression among standard-risk metastases undergoing lesional surgery was 1/16 (6%) versus 4/39 (10%) with non-lesional surgery (p = 1.00). High-risk histologic features (OR: 10.592, 95% confidence interval: 1.347–83.271, p = 0.025) and as well as a reduction in risk with every additional Gray of BED (OR: 0.902, 95% confidence interval: 0.827–0.984, p = 0.021) were found to predict progressive disease. Conclusions Bone metastases from renal cell carcinoma with high-risk histologic features are associated with less favorable response to radiotherapy than those with standard-risk histology. Delivery of a higher BED was associated with lower odds of progression.

Aneurysmal bone cyst (ABC) is a benign locally destructive bone neoplasm composed of multi-loculated blood-filled cystic spaces. The most common sites of involvement are the meta-diaphysis of the long bones and posterior elements of the vertebrae. Secondary, ABC-like changes can complicate a variety of other benign and malignant primary bone neoplasms, including giant cell tumor, fibrous dysplasia, and osteosarcoma. About two-third of primary ABCs have a rearrangement of the USP6 gene, which is not present in the ABC-like changes that occur secondary to other primary bone tumors (i.e., secondary ABC). Primary ABC of bone carries a variable but generally high rate of local recurrence. This paper provides an overview of the pathophysiology, clinical presentation, radiographic and pathologic findings, treatment, and prognosis of ABC.

Background:Time to treatment initiation (TTI) is a quality metric in cancer care. The purpose of this study is to determine the accuracy of TTI data from a single cancer center registry that reports to the National Cancer Database (NCDB) for sarcoma diagnoses. Methods:A retrospective analysis of a single Commission on Cancer (CoC)-accredited cancer center's tumor registry between 2006 and 2016 identified 402 patients who underwent treatment of a musculoskeletal soft tissue sarcoma and had TTI data available. Registry-reported TTI was extracted from the tumor registry. Effective TTI was manually calculated by medical record review as the number of days from the date of tissue diagnosis to initiation of first effective treatment. Effective treatment was defined as oncologic surgical excision or initiation of radiation therapy or chemotherapy. Registry-reported TTI and effective TTI values were compared for concordance in all patients. Results:In the entire cohort, 25% (99/402) of patients had TTI data discordance, all related to surgical treatment definition. For patients with a registry-reported value of TTI = 0 days, 74% (87/118) had a diagnostic surgical procedure coded as their first treatment event, with 73 unplanned incomplete excision procedures and 14 incisional biopsies. In these patients, effective TTI was on average 59 days (P < 0.001). For patients with a registry-reported value of TTI >0 days, only 4% (12/284) had discordant TTI values. Conclusions:Nearly three-fourths of patients with a registry-reported value of TTI = 0 days in a large, CoC-accredited cancer center registry had a diagnostic procedure coded as their first treatment event, though their effective treatment had not yet started. These data suggest that TTI is likely longer than what is reported to the NCDB. Redefinition of what constitutes surgical treatment should be considered to improve the accuracy of data used in measuring TTI in sarcoma.

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.