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Xanthogranulomatous epithelial tumor (XGET) and HMGA2::NCOR2 fusion keratin-positive giant cell–rich tumor (KPGCT) are recently described morphologically overlapping rare neoplastic entities characterized by HMGA2::NCOR2 fusions, low-grade biological behavior, and a strong predilection for young females. To date, 47 cases have been reported with only four occurring in head and neck anatomic locations. In this study, we describe the clinicopathologic, immunohistochemical, and molecular findings of seven XGET/KPGCTs occurring in the head and neck region. The patients were six females and one male, aged 3.5–59 years old (median, 25 years). The tumors involved the ear, vocal cord, skull, neck soft tissue, and sinonasal cavity. Tumor sizes ranged from 1.5 to 6.7 cm. Histologically, the tumors were characterized by xanthogranulomatous histiocytes, osteoclast-like giant cells, and keratin-positive epithelioid cells. The XGET/KPGCTs involving the ear was remarkable for more cytologic atypia than previously described. Four cases had the HMGA2::NCOR2 fusion identified by NGS and three had HMGA2 gene locus alterations by FISH. Follow-up information was available for 3 of 7 patients (range 6–46 months). The patient with a vocal cord XGET/KPGCTs developed a local recurrence treated with excision. This study illustrates that XGET/KPGCTs involves the head and neck region as well, where it may be unexpected and hence under-recognized, and expands the anatomic locations of involvement to include unreported sites (ear, vocal cord, and sinonasal tract).

Giant Cell Lesions exhibit variable aggressive clinical behavior. Understanding the molecular mechanisms of these lesions can facilitate a more personalized and effective therapeutic approach. The acetylation of Histone H3 at Lysine 9 (H3K9ac) and the expression of Inhibitor of Growth Protein 5 (ING5) were evaluated in 19 cases of Peripheral Giant Cell Granuloma (PGCG), 19 cases of non-aggressive Central Giant Cell Granuloma (CGCG), 19 cases of aggressive CGCG, and 19 cases of Giant Cell Tumor of Bone (GCTB), totaling 76 cases of Giant Cell Lesions. H3K9 hyperacetylation was found in aggressive Giant Cell Lesions compared to non-aggressive lesions (p < 0.05). Aggressive Giant Cell Lesions also show higher ING5 expression in multinucleated giant cells and cannibalistic multinucleated giant cells compared to non-aggressive lesions (p < 0.05). There was no difference in the levels of H3K9ac and ING5 between aggressive Central Giant Cell Granuloma and Giant Cell Tumor of Bone (p > 0.05). H3K9ac and ING5 were associated with aggressive characteristics in the CGCG (p < 0.05). H3K9 hyperacetylation highlights the significance of this epigenetic event in the aggressiveness of Giant Cell Lesions and may indicate their potential for aggressive behavior, thereby providing information to improve treatment strategies, particularly for Central Giant Cell Granuloma. Understanding the CGCG's clinical behavior is essential for determining the therapeutic modality and avoiding long-term post-treatment sequelae.

Abstract We report on the clinicopathologic features of 27 pleomorphic giant cell carcinoma (PGCC) cases of the prostate identified in 20 patients with an age range of 51 to 84 years (68 ± 9; median 71 years). Charlson comorbidity index ranged from 3 to 12. Serum PSA ranged from 4.30 to 662 ng/mL (median 13 ng/mL). On histologic examination, bizarre giant cells with pleomorphic nuclei characterized pleomorphic giant cell carcinoma of the prostate. PGCC component was present in 5% to 100%, with half of the patients presenting with ≥ 20%. Half of the patients initially presented with T4 and 26% with T3 disease. All patients were considered Gleason scores of 9 to 10 (ISUP grade 5). A combination of hormone therapy with chemotherapy with or without radiation therapy was applied in 68% of patients. On follow-up, 14 patients (52%) were alive with disease (1–69 months) or dead of disease (1–38 months). Patients diagnosed earlier with lower TNM stage had longer survival than those diagnosed at a later T-stage or with metastatic disease (p = 0.02). The percentage of PGCC was not related to survival in the current study. Molecular alterations in 3 samples showed a microsatellite-stable disease with low tumor mutation burden and variable PTEN, PTCH1, KDM6A, ARv7, and PIK3CA loss/alteration, TP53 mutation, TMPRSS2-ERG fusion, and MYC, PIK3CB, RICTOR, or IRS2 amplification. Our findings suggest that PGCC is a rare and aggressive subtype of prostate carcinoma whose recognition may steer clinicians to adopt more aggressive treatments and investigate new therapeutic strategies.

Although clinical signs and symptoms of giant cell arteritis improve promptly after starting glucocorticoid therapy, reports have suggested that the vascular inflammation may persist. To assess the duration and quality of histopathologic changes in treated patients, we prospectively obtained second temporal artery biopsies in patients treated for 3 to 12 months after their first diagnostic biopsy. Forty patients (28 women, 12 men, median age 77 years) agreed to have a second temporal artery biopsy randomly assigned to 3, 6, 9, or 12 months subsequent to the first. Clinical and laboratory evaluation of the patient cohort revealed a typical rapid response and continued suppression of clinical manifestations as a result of glucocorticoid treatment. Histopathologic findings, evaluated in a blinded manner by a cardiovascular pathologist, showed unequivocal findings of vasculitis in 7/10 patients with second temporal artery biopsy at 3 months, 9/12 at 6 months, 4/9 at 9 months, and 4/9 at 12 months. Lymphocytes were present in all positive initial biopsies and remained the dominant cell population in chronically treated patients. Granulomatous inflammation decreased in a time-dependent manner from 78 to 100% at initial biopsy to 50% at 9 months and 25% at 12 months. The increased medial fibrosis noted in the second biopsies (60 vs 33% in primary temporal artery biopsies) suggested that the finding may represent a chronic finding in arteritis. In summary, the response to glucocorticoids in giant cell arteritis was frequently discordant. Clinical manifestations were readily suppressed, but vascular changes were gradual and often incomplete.

Background: Multinucleated giant cells (MNCs) form an integral part of numerous bone and soft tissue tumors, tumor-like lesions and are often associated with granulomas of immunological and nonimmunological origin. The presence of various types of giant cells depends on the lesions in which they are present which are difficult to be diagnosed under routine histological techniques. Immunohistochemistry can be used for a better diagnosis and understanding of the origin of various giant cells using various markers of immune response like human leukocyte antigen-DR (HLA-DR) and those expressed on monocytes and macrophages like CD 68 and leukocyte common antigen (LCA).Materials and Methods: The study group consisted of 10 cases of giant cell tumor (GCT) of long bones, tuberculous granuloma, and giant cell granuloma to evaluate and analyze the expression pattern of LCA, CD 68, and HLA-DR in various giant cell lesions. Results: Strong expression of CD 68 was observed in 80% of the lesions, strong and moderate expression of CD 45 observed in 70% of the lesions among and within the groups. In contrast, HLA-DR demonstrated negative expression in 80% of cases except for tuberculous granuloma where all the 10 cases showed moderate to strong immunoreactivity. Conclusion: CD 68 and CD 45 expression was found in central giant cell granuloma, peripheral giant cell granuloma and GCT, suggesting the origin from mononuclear phagocyte system and considering their clinical behavior of osteoclast type. High expressivity of HLA-DR in tuberculous granulomas which is an essential factor for presentation of the microbial antigen to CD 4 helper cells thus reassuring the fact that they are up-regulated in response to infection.

p63 contributes to skeletal development and tumor formation; however, little is known regarding its activity in the context of bone and soft tissue neoplasms. The purpose of this study was to investigate p63 expression in giant cell tumor of bone and to determine whether it can be used to discriminate between other giant cell-rich tumors. Seventeen cases of giant cell tumor of bone were examined to determine the cell type expressing p63 and identify the isoforms present. Total RNA or cell protein was extracted from mononuclear- or giant cell-enriched fractions or intact giant cell tumor of bone and examined by RT-PCR or western blot, respectively. Immunohistochemistry was used to evaluate p63 expression in paraffin embedded sections of giant cell tumor of bone and in tumors containing multinucleated giant cells, including: giant cell tumor of tendon sheath, pigmented villonodular synovitis, aneurysmal bone cyst, chondroblastoma, and central giant cell granuloma. The mononuclear cell component in all cases of giant cell tumor of bone was found to express all forms of TAp63 (α, β, and γ), whereas only low levels of the TAp63 α and β isoforms were detected in multinucleated cells; ΔNp63 was not detected in these tumors. Western blot analysis identified p63 protein as being predominately localized to mononuclear cells compared to giant cells. This was confirmed by immunohistochemical staining of paraffin-embedded tumor sections, with expression identified in all cases of giant cell tumor of bone. Only a proportion of cases of aneurysmal bone cyst and chondroblastoma showed p63 immunoreactivity whereas it was not detected in central giant cell granuloma, giant cell tumor of tendon sheath, or pigmented villonodular synovitis. The differential expression of p63 in giant cell tumor of bone and central giant cell granuloma suggest that these two tumors may have a different pathogenesis. Moreover, p63 may be a useful biomarker to differentiate giant cell tumor of bone from central giant cell granuloma and other giant cell-rich tumors, such as giant cell tumor of tendon sheath and pigmented villonodular synovitis.

Background To investigate the effect of baseline clinical characteristics and glucocorticoid treatment on temporal artery biopsy (TAB) findings in patients with giant cell arteritis (GCA). Methods Individuals who developed GCA after inclusion in two population-based health surveys were identified through linkage to the local and the national patient registers. In addition, other patients diagnosed with GCA at the Departments of Internal Medicine and Rheumatology at an area hospital were included. A structured review of medical records and TAB pathology reports was performed. The presence or absence of giant cells, granuloma, fragmented internal elastic lamina, fibrosis and grade of inflammatory infiltrates were recorded. Results In 183 cases with a confirmed clinical diagnosis of GCA, 139 were biopsied after start of glucocorticoids (median treatment duration 3 days; interquartile range 2–5). Patients with a positive TAB (77 %) had significantly higher C-reactive protein (CRP; p  = 0.007) and erythrocyte sedimentation rate (ESR; p  = 0.03) at the time of clinical diagnosis. A positive TAB tended to more common in women, but there was no difference in the proportion of patients with polymyalgia rheumatica or visual symptoms. Patients biopsied before or on the same day as initial treatment where more likely than those biopsied 1–3 days after treatment start to have positive biopsy [odds ratio (OR) 2.86; 95 % CI 1.06–7.70] as well as inflammatory infiltrates (OR 3.30; 95 % CI 1.15–9.49). There was no significant difference in the proportions of a fragmented internal lamina ( p  = 0.86), giant cells ( p  = 0.10), granuloma ( p  = 0.19), minor inflammatory infiltrates ( p  = 0.47), major inflammatory infiltrates ( p  = 0.09), or overall positive biopsy ( p  = 0.17) report by treatment duration comparing: ≤ 0 days, 1–3 days, 4–6 days, 7–28 days. Among those biopsied 7–28 days after start of treatment, 80 % of TABs were positive, and histopathology features were not substantially different from those biopsied after shorter glucocorticoid treatment. Conclusion Biopsies were more likely to be positive and have characteristic histopathologic features in patients with high CRP and ESR, and prior to start of corticosteroid treatment TABs taken 1–4 weeks after initiation of glucocorticoid treatment reveal changes consistent with GCA and therefore still yields clinically useful information for the diagnosis.

Giant cell tumor of bone (GCTB) is an aggressive osteolytic bone tumor characterized by the within-tumor presence of osteoclast-like multinucleated giant cells (MGCs), which are induced by the neoplastic stromal cells and lead to extensive bone destruction. However, the underlying mechanism of the pathological process of osteoclastogenesis in GCTB is poorly understood. Here we show that the proteoglycan Serglycin (SRGN) secreted by neoplastic stromal cells plays a crucial role in the formation of MGCs and tumorigenesis in GCTB. Upregulated SRGN expression and secretion are observed in GCTB tumor cells and patients. Stromal-derived SRGN promotes osteoclast differentiation from monocytes. SRGN knockdown in stromal cells inhibits tumor growth and bone destruction in a patient-derived orthotopic xenograft model of mice. Mechanistically SRGN interacts with CD44 on the cell surface of monocytes and thus activates focal adhesion kinase (FAK), leading to osteoclast differentiation. Importantly, blocking CD44 with a neutralizing antibody reduces the number of MGCs and suppresses tumorigenesis in vivo. Overall, our data reveal a mechanism of MGC induction in GCTB and support CD44-targeting approaches for GCTB treatment.

Our recent perplexing findings that polyploid giant cancer cells (PGCCs) acquired embryonic-like stemness and were capable of tumor initiation raised two important unanswered questions: how do PGCCs acquire such stemness, and to which stage of normal development do PGCCs correspond. Intriguingly, formation of giant cells due to failed mitosis/cytokinesis is common in the blastomere stage of the preimplantation embryo. However, the relationship between PGCCs and giant blastomeres has never been studied. Here, we tracked the fate of single PGCCs following paclitaxel-induced mitotic failure. Morphologically, early spheroids derived from PGCCs were indistinguishable from human embryos at the blastomere, polyploid blastomere, compaction, morula and blastocyst-like stages by light, scanning electron or three-dimensional confocal scanning microscopy. Formation of PGCCs was associated with activation of senescence, while budding of daughter cells was associated with senescence escape. PGCCs showed time- and space-dependent activation of expression of the embryonic stem cell markers OCT4, NANOG, SOX2 and SSEA1 and lacked expression of Xist. PGCCs acquired mesenchymal phenotype and were capable of differentiation into all three germ layers in vitro . The embryonic-like stemness of PGCCs was associated with nuclear accumulation of YAP, a key mediator of the Hippo pathway. Spheroids derived from single PGCCs grew into a wide spectrum of human neoplasms, including germ cell tumors, high-grade and low-grade carcinomas and benign tissues. Daughter cells derived from PGCCs showed attenuated capacity for invasion and increased resistance to paclitaxel. We also observed formation of PGCCs and dedifferentiation in ovarian cancer specimens from patients treated with chemotherapy. Taken together, our findings demonstrate that PGCCs represent somatic equivalents of blastomeres, the most primitive cancer stem cells reported to date. Thus, our studies reveal an evolutionarily conserved archaic embryonic program in somatic cells that can be de-repressed for oncogenesis. Our work offers a new paradigm for cancer origin and disease relapse.

Destructive lesions in the craniofacial region especially in the jawbones, if associated with giant cells, include a spectrum of lesions that pose difficulty in diagnosis. The nature of such a lesion in the jawbones is questionable about whether it is a reactive/benign lesion or aggressive/non-aggressive. Clinical, radiological and histopathological correlation may be a reliable indicator to differentiate between the qualities of the lesion, which directly accounts for effective and individual planning of the treatment. Here we present a case of a woman in her late 20s with an unusual destructive lesion of the mandible.