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.
Giant cell tumor (GCT) of bone is a rare, benign, aggressive bone tumor with an unusual capacity to metastasize to the lung. It was the goal of this study to identify patient and treatment-specific ...variables associated with the development of pulmonary metastases of GCT of bone.
From 1980 to 2009, 291 patients with benign GCT of bone were treated at our institution, and 167 were followed for at least two years. Eleven (6.6%) of these 167 patients developed biopsy-confirmed pulmonary metastasis. All patients were evaluated relative to nine patient, disease, and treatment-specific variables.
We identified four properties of benign GCT of bone associated with an increased risk of metastasis on univariate analysis: age at diagnosis, axial location of the primary GCT, primary Enneking stage-3 disease, and local recurrence. Multivariate analysis showed local recurrence to be an independent risk factor for pulmonary metastasis (adjusted odds ratio, 7.42).
There is an increased risk of pulmonary metastasis of GCT of bone in patients who are younger, present with Enneking stage-3 disease, develop local recurrence, and/or present with axial disease. The mode of treatment was not found to be associated with the development of pulmonary metastasis.
Bone sarcomas are a clinically and molecularly heterogeneous group of malignancies characterized by varying degrees of mesenchymal differentiation. Despite advances in medical and surgical ...management, survival rates for high-grade tumors have remained static at 50% to 70%. Tumor stem cells have been recently implicated in the pathogenesis of other heterogeneous, highly malignant tumors. We demonstrate here the existence of a small subpopulation of self-renewing bone sarcoma cells that are capable of forming suspended spherical, clonal colonies, also called “sarcospheres,” in anchorage-independent, serum-starved conditions. These bone sarcoma cells as well as tissue specimens express activated STAT3 and the marker genes of pluripotent embryonic stem (ES) cells, Oct 3/4 and Nanog. Expression levels of Oct 3/4 and Nanog are greater in sarcospheres than in adherent cultures. A subset of bone sarcoma cells displays several surface markers of mesenchymal stem cells (Stro-1, CD105, and CD44) as well as attributes of mesodermal, ectodermal, and endodermal differentiation. Although previously documented in brain and breast tumors, our results support the extension of the cancer stem cell hypothesis to include tumors of mesenchymal lineage. Furthermore, they suggest the participation of ES cell homeobox proteins in non-germ cell tumorigenesis.
Rosai-Dorfman disease (RDD) is a rare histiocytic proliferative disease of unknown etiology. Typically presenting with cervical adenopathy and constitutional symptoms, RDD involves bone in less than ...10% of cases—and rarely presents as a primary intraosseous lesion. In this report, we describe the presentation of primary, bilateral intraosseous RDD, the first known case in the literature. Asymmetrically involving the lateral femoral condyles of a 59-year-old male, the lesion was discovered incidentally during evaluation and workup for giant cell tumor of bone involving the left tibia. Confirmation of the diagnosis required multiple biopsies and extensive evaluation—reflecting the diagnostic challenge associated with this case. We discuss the clinical, radiological, and pathological findings that allowed us to establish the diagnosis—as well as key differential diagnostic considerations and clinical outcome to date.
Abstract
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.
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.
Immunohistochemical analysis using S100 protein staining was performed to assess the presence of nerve tissue.
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.
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 incidence, distribution, and significance of calcium pyrophosphate dihydrate deposition (CPPD) disease have not been extensively compared among various total joint resections.
To investigate and ...define the clinical and pathologic features of CPPD in hip, shoulder, and knee arthroplasties.
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.
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.
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.
Small molecule inhibitors have proven extremely useful for investigating signal transduction pathways and have the potential for development into therapeutics for inhibiting signal transduction ...pathways whose activities contribute to human diseases. Transforming growth factor beta (TGF-beta) is a member of a large family of pleiotropic cytokines that are involved in many biological processes, including growth control, differentiation, migration, cell survival, adhesion, and specification of developmental fate, in both normal and diseased states. TGF-beta superfamily members signal through a receptor complex comprising a type II and type I receptor, both serine/threonine kinases. Here, we characterize a small molecule inhibitor (SB-431542) that was identified as an inhibitor of activin receptor-like kinase (ALK)5 (the TGF-beta type I receptor). We demonstrate that it inhibits ALK5 and also the activin type I receptor ALK4 and the nodal type I receptor ALK7, which are very highly related to ALK5 in their kinase domains. It has no effect on the other, more divergent ALK family members that recognize bone morphogenetic proteins (BMPs). Consistent with this, we demonstrate that SB-431542 is a selective inhibitor of endogenous activin and TGF-beta signaling but has no effect on BMP signaling. To demonstrate the specificity of SB-431542, we tested its effect on several other signal transduction pathways whose activities depend on the concerted activation of multiple kinases. SB-431542 has no effect on components of the ERK, JNK, or p38 MAP kinase pathways or on components of the signaling pathways activated in response to serum.
* Context.--Bone and soft tissue tumors are heterogeneous, diagnostically challenging, and often defined by gene fusions. Objective.--To present our experience using a custom 34-gene targeted ...sequencing fusion panel. Design.--Total nucleic acid extracted from formalin-fixed, paraffin-embedded (FFPE) tumor specimens was subjected to open-ended, nested anchored multiplex polymerase chain reaction and enrichment of 34 gene targets, thus enabling detection of known and novel fusion partners. Results.--During a 12-month period, 147 patients were tested as part of routine clinical care. Tumor percentage ranged from 10% to 100% and turnaround time ranged from 3 to 15 (median, 7.9) days. The most common diagnostic groups were small round blue cell tumors, tumors of uncertain differentiation, fibroblastic/myofibroblastic tumors, and adipocytic tumors. In-frame fusion transcripts were identified in 64 of 142 cases sequenced (45%): in 62 cases, the detection of a disease-defining fusion confirmed the morphologic impression; in 2 cases, a germline TFG-GPR128 polymorphic fusion variant was detected. Several genes in the panel partnered with multiple fusion partners specific for different diagnoses, for example, EWSR1, NR4A3, FUS, NCOA2, and TFE3. Interesting examples are presented to highlight how fusion detection or lack thereof was instrumental in establishing accurate diagnoses. Novel fusion partners were detected for 2 cases of solid aneurysmal bone cysts (PTBP1-USP6, SLC38A2-USP6). Conclusions.--Multiplex detection of fusions in total nucleic acid purified from FFPE specimens facilitates diagnosis of bone and soft tissue tumors. This technology is particularly useful for morphologically challenging entities and in the absence of prior knowledge of fusion partners, and has the potential to discover novel fusion partners. (Arch Pathol Lab Med. 2021;145:851-863; doi: 10.5858/arpa.2020-0336-OA)
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