Osteoclast-like Multinucleated Giant Cells Research Articles

Recurrent USP6 rearrangement in a subset of atypical myofibroblastic tumours of the soft tissues: low-grade myofibroblastic sarcoma or atypical/malignant nodular fasciitis?

Low-grade myofibroblastic sarcoma (LGMS) is a rarely metastasizing myofibroblastic tumour mostly affecting extremities and the head and neck of adults. Histologically, it shows long infiltrative fascicles of spindle cells with moderate nuclear atypia. By immunohistochemistry, it stains positive for smooth muscle actin (SMA) and sometimes for desmin. To date, no recurrent genetic abnormalities have been described. Ubiquitin-specific peptidase 6 (USP6) gene rearrangement is typically found in some benign bone and soft-tissue tumours including nodular fasciitis (NF), among others. Nevertheless, rare cases of USP6-rearranged tumours resembling NF with atypical features have been reported. One index case of LGMS of the deltoid in a 56-year-old man presented the THBS2::USP6 translocation by RNA sequencing (Archer FusionPlex Sarcoma v2 panel). Further screening of 11 cases of LGMS using fluorescent in situ hybridization (FISH) analysis with a USP6 break-apart probe identified two additional cases. These cases were investigated with RNA-sequencing, and a RRBP1::USP6 translocation was detected in one. The other case was not assessable because of low-quality RNA. Noteworthy, rearranged LGMSs presented distinctive features including variable multinodular/plexiform architecture, prominent vasculature with occasional wall thickening, scattered osteoclast-like multinucleated giant cells, and peripheral lymphoid aggregates. Our findings support the notion that among soft-tissue neoplasms with fibroblastic/myofibroblastic phenotype, USP6 rearrangement is not limited to benign tumours, and warrants further investigation of genetic changes in myofibroblastic sarcomas.

Giant cell tumor of soft tissue involving thyroid gland: a case report and review of the literature

BackgroundGiant cell tumor of soft tissue is a low malignant uncommon neoplasm, with histologic features and immunophenotype similar to its bone counterpart. Primary giant cell tumor of soft tissue in the thyroid gland is considered an exceedingly rare entity.Case presentationWe describe a case of primary thyroid giant cell tumor of soft tissue in a 69-year-old Chinese female patient. Neck ultrasonography showed a 19 mm × 12 mm × 5 mm nodule with heterogeneous echo and clear boundary located within the left thyroid. Histopathological examination revealed that the neoplasm was composed of two morphological components, mononuclear cells admixed with multinucleated osteoclast-like giant cells. Immunohistochemically, the tumor cells were positive for CD68 and vimentin, but were negative for epithelial membrane antigen, cytokeratin, and additional muscle markers. She underwent left unilateral thyroidectomy, and total thyroidectomy was performed for local recurrence 3 months later. The patient remained well without recurrence or metastasis following up for 12 months.ConclusionThe significance of this case lies in its rarity, the challenge of preoperative clinical diagnosis, and the differential diagnosis with other malignancies.

Histological and immunohistochemical analyses of osteoclast maturation in giant cell tumor of bone

IntroductionGiant cell tumor of bone (GCTB) is a benign but locally aggressive tumor characterized by the occurrence of multinucleated osteoclast-like giant cells that play a key role in GCTB pathogenesis. However, little is known about the molecular mechanisms underlying osteoclast differentiation in GCTB. Denosumab, a human monoclonal antibody against RANKL, is used for GCTB treatment. Here, we performed morphological and immunohistochemical examinations of pre- and post-denosumab treatment changes by analyzing each stage of osteoclast differentiation. MethodsWe retrieved 15 archival cases of GCTB with tumor samples from both pre- and post-denosumab treatment. We selected three immunohistochemical markers from the expression data from a previous single-cell RNA study: FOS, a progenitor osteoclast marker, and JDP2 and NFATc1, mature osteoclast markers. ResultsThe mean positivity of the markers decreased after denosumab treatment from 11.1% to 8.9% for FOS, from 10.6% to 7.2% for JDP2, and from 10.0% to 0.2% for NFATc1. Only NFATc1 positivity decreased significantly (P < 0.001) after denosumab treatment. ConclusionsWe identified a new differentiation stage of osteoclast maturation, intermediate cell, by comparing histological findings before and after denosumab treatment. We demonstrated that discrepancies exist between histological and molecular data and highlight the need for establishing an integrated definition of osteoclasts considering morphology and marker expression.

Extraskeletal Osteosarcoma with Extensive Gastrointestinal Tract Involvement

Abstract Introduction/Objective Extraskeletal osteosarcoma (ESOS) is a rare aggressive mesenchymal tumor that originates from soft tissues or visceral organs, differentiating it from primary bone osteosarcoma. ESOS represents less than 5% of all osteosarcomas and less than 1% of soft tissue sarcomas. Primary ESOS in the gastrointestinal tract (GIT) is exceedingly uncommon, with a low incidence rate Methods/Case Report A 70 year-old-man with a history of hypertension, Myasthenia Gravis, hypothyroidism (status post total thyroidectomy), and skin cancer presented to the clinic with a chief complaint of abdominal fullness of 4 months duration. Primary work-up revealed anemia (Hemoglobin 7 g/dl) and peripheral blood smear was suggestive of bone marrow infiltration. Evaluation with upper gastrointestinal endoscopy and ultrasound demonstrated regular mucosal folds of the stomach with a solid-cystic lesion between the body of the pancreas and the posterior aspect of the stomach. The patient underwent a fine needle biopsy showing a spindle cell lesion with positive immunohistochemistry (IHC) for Smooth Muscle Actin (SMA), beta-Catenin, CD34, and negative for panCK, DOG-1, and CD117; suggestive of leiomyoma. The patient underwent a total gastrectomy, distal pancreatectomy, and splenectomy. Examination of the specimen confirmed a high-grade malignant spindle cell lesion with numerous associated osteoclast-like multinucleated giant cells, and focal areas consistent with osteoid changes. The IHC was requested and the cells were positive for WT1 and Muscle Specific Actin, SATB2, and Ki-67&amp;gt;90% whereas the cells were negative for SMA, Myo-D1, Myogenin, S100, SOX10, MART1, CD34, CD31, and Calretinin. Also, the genetic analysis for MDM2 was negative. These findings confirmed the diagnosis of ESOS with abdominal visceral involvement (stomach, pancreas, and omentum) Results (if a Case Study enter NA) NA Conclusion ESOS is an extremely rare condition that demands a comprehensive evaluation involving clinical, radiological, histopathological, and immunohistochemical analyses to establish an accurate diagnosis. Distinguishing ESOS from primary bone osteosarcoma is vital due to the different treatment strategies. Additionally, ESOS requires a unique therapeutic approach compared to more prevalent gastrointestinal sarcomas like GIST or leiomyosarcoma. The mainstay of ESOS treatment entails complete surgical resection of the tumor with clear margins, accompanied by adjuvant chemotherapy. Ensuring precise diagnosis is of utmost importance to provide suitable and effective treatment

Aggressive Osteoblastoma of Temporal Bone Causing Facial Palsy in a 9-year-old Child: A Case Report Based on 2020 WHO Classification of Bone Tumors

AbstractAggressive osteoblastoma (AO) is an uncommon bone tumor that represents a borderline lesion between osteoblastoma and osteosarcoma. The vertebral column, the sacrum, the pelvis, and jaw/craniofacial bones are primarily affected. Aggressive osteoblastoma does not metastasize and is treated by surgical resection. The authors report a case of AO in a 9-year-old female patient presenting with 5th and 7th cranial nerve palsy. Prior pathological history included resection of an expansile nodule in the left temporal bone. Conventional radiological examination and computed tomography (CT) of the skull revealed an osteoblastic lesion arising in the petrous portion of the left temporal bone, measuring 5.2 cm in the largest dimension. The patient was subjected to partial surgical resection of the process. Microscopy revealed a primary neoplastic bone composed of numerous epithelioid round osteoblasts disposed in solid sheets and with mild atypia, large eosinophilic cytoplasm, and an eccentric, ovoid nucleus. The process exhibited loose stroma, low mitotic index, osteoid formation, and a few osteoclast-like multinucleated giant cells. The diagnosis of AO was thus established. After 5 months of clinical follow-up, the patient is asymptomatic, without evidence of tumoral growth on CT scans.

Cutaneous Atypical Fibroxanthoma With Osteoclast-Like Giant Cell: A Rare but Diagnostic Pitfall.

Atypical fibroxanthoma (AFX) is a dermal-based, low-grade neoplasm with no specific lineage of differentiation. The occurrence of AFX with osteoclast-like giant cells is exceptionally rare. Less than 20 cases have been reported in the literature. A 77-year-old man with a medical history of multiple basal and squamous cell carcinomas of the skin, presented with a progressively growing erythematous nodule on the sun-damaged right central parietal scalp. A shave biopsy showed a dermal spindle cell proliferation accompanied by numerous osteoclast-like multinucleated giant cells and predominant atypical mitotic figures. The immunohistochemical staining showed a diffuse positive staining for CD68 and SMA, patchy staining for CD10, and negative staining for SOX-10, pan-cytokeratin, CK5/6, S100, CD34, and desmin. The tumor was completely excised with negative margins. A subsequent follow-up over a period of 13 months showed no recurrence. Distinguishing AFX with osteoclast-like giant cells from both malignant and benign skin lesions with osteoclast-like giant cells is crucial. Although AFX tumors display worrisome malignant histologic features, most cases have a favorable prognosis with a local recurrence rate below 5% and exceedingly rare metastasis.

Undifferentiated carcinoma with osteoclast-like giant cells – a case report

Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells is an exceptionally rare malignancy, with fewer than 100 cases reported to date. While the histological features of this entity have been well described, cytological diagnosis can present a challenge. This case report describes the cytological features of a fine needle aspirate from a heterogenous pancreatic mass in a 75-year-old man. The smears revealed singularly dispersed and clustered cells with marked atypia in a background of histiocytes and osteoclast-like multinucleated giant cells.

Clinical manifestations and imaging and pathological features of giant cell angioblastoma: Report of four cases and literature review.

Giant cell angioblastoma is a relatively rare vasogenic tumour. To date, studies on its clinical manifestations, imaging characteristics, pathological features, and prognosis are extremely limited and unknown, with only a few cases recorded. In this study, four cases of giant cell angioblastoma confirmed by pathological examination were reported to improve our understanding and deep exploration of the tumour spectrum. All cases in our study were male, including two adults and two boys. The lesions were located in the lower segment of the femur, medial condyle of the femur, knee joint, and popliteal fossa. Regarding the imaging characteristics, two patients with lesions in bone showed bone destruction, while the other two had lesions that invaded soft tissues, showing irregular, abnormal signal shadows and obvious enhancement. Histopathological analysis revealed that the nodular tumour tissue was mainly composed of oval and spindle cells, with varying numbers of osteoclast-like multinucleated giant cells, and the interstitial tissues were often filled with blood vessels of different sizes. The immunophenotype demonstrates that endothelial cells of small vessels in nodules expressed CD31, SMA, and ERG, while osteoclast-like multinucleated giant cells and histiocytes expressed CD68 and CD163, and the surrounding cells expressed SMA. All four patients were treated with surgical resection. One of them relapsed 1 month after surgery and received a second surgical resection. No distant metastasis or death occurred during the follow-up period. This study indicates that giant cell angioblastoma is a local invasive vascular tumour that can develop both in children and adults with skin, mucous membrane, soft tissue, and bone involvement. Imaging characteristics show bone destruction and irregular, abnormal signal shadows; in addition, obvious pathological morphological features can be observed. Currently, the treatment is mainly surgical resection, and interferons may be used as adjuvant chemotherapy.

The osteoclast-type giant cell rich carcinoma of urinary bladder: A case series.

Osteoclast-type giant cell-rich carcinomas (OGCRCs) of urinary bladder are extremely rare, aggressive tumors that are often diagnosed as undifferentiated carcinomas. The morphology overlaps with other giant cell-rich benign and malignant bladder lesions. Little is known about the pathogenesis and clinical management of this aggressive variant. The aim of this study was to review clinico-pathologic features, and survival characteristics in a series of OGCRCs. Five cases of OGCRCs of bladder were retrospectively reviewed. Clinical presentation, histomorphology, ancillary tests, treatment and follow-up data were retrieved and analyzed. All patients were adult males (age range 63-86 years) and presented with painless gross hematuria. All cases showed biphasic morphology with polygonal to epithelioid to spindle mononuclear cells (MCs) and scattered multinucleated osteoclast-like giant cells (OGCs). Background urothelium showed urothelial carcinoma in-situ (CIS) (4/5) and/or invasive urothelial carcinoma (UC) (2/5) and invasive high-grade papillary urothelial carcinoma (PUC) (2/5). MCs showed focal expression of at least one epithelial marker and focal/diffuse expression of urothelial markers. OGCs were positive only for histiocytic markers. Oncomine test showed presence of p53 mutation (p.R282W) in case 3. Pathologic stage was T1 (n=3), T2b (n=1) and T3a (n=1). 2/5 patients died of disease within 3 years of diagnosis. OGCRC is an extremely rare and potentially aggressive malignant neoplasm of bladder. Most cases have associated conventional in-situ or invasive UC supporting undifferentiated or de-differentiated nature of this neoplasm. Surgery should be considered given the potential for aggressive behavior. However optimal treatment for OGCRCs remains unknown.

OSTEOBLASTOMA OF THE MANDIBLE: A CASE REPORT

A 19-year-old White female patient presented with the chief complaint of pain in the left region of the mandible, without extra- or intraoral clinical alteration. Radiographic exams and cone beam computed tomography revealed a mixed-density lesion, with poorly defined borders, promoting dental displacement, and cortical expansion by lingual. Teeth 31 to 35 showed thickening of the periodontal ligament. The provisional diagnosis was osteoblastoma. An incisional biopsy revealed the presence of thin, anastomosed irregular bone trabeculae, lined by a rim of osteoblasts and occasional osteoclast-like multinucleated giant cells, permeated by fibrovascular stroma, confirming the clinical hypothesis of osteoblastoma. The lesion was surgically removed, and the final diagnosis was osteoblastoma. Osteoblastoma is a rare benign neoplasm in the jaw, and diagnosis is based on the correlation between clinicopathologic findings. Because of its varied clinical behavior, early diagnosis is an important strategy for the establishment of an effective treatment.

Primary Giant Cell Tumor of Soft Tissue in The Female Breast

A giant cell tumor of soft tissue (GCT-ST) is a rare tumor composed of mononuclear and osteoclast-like multinucleated giant cells. It is a low-grade malignant potential tumor morphologically analog to a giant cell tumor of bone. The superficial and deep soft tissue of extremities is the most frequent site of this tumor which is cured by complete or radical resection. GCT-ST as a primary tumor in the female Breast is exceedingly rare. Presentation of osteoclast-like multinucleated giant cells in the breast tumor has been described in association with the variant of breast carcinoma. We report a case of primary GCT-ST arising in the female Breast without a relationship with the epithelial component. To the best of our knowledge, this is the fifth such case report, and only the second one occurred in a female under 50 years.

Cutaneous Fibrous Histiocytomas, Ossifying-Variant with Osteoclast-like Giant Cells and Granular Cell-Variant: A Series of Two Unusual Cases with Emphasis on the Differential Diagnosis

The ossifying variant and the granular cell variant are rare subtypes of cutaneous fibrous histiocytoma (CFH), characterized by islands of mature metaplastic bone tissue rimmed by multinucleated osteoclast-like giant cells and by large-sized cells with granular cytoplasm and mildly hyperchromatic nuclei with inconspicuous nucleoli, respectively. We herein present two cases of these unusual CFH variants in a 37-year-old woman and in a 38-year-old man, respectively. The main differential diagnoses, including both benign and malignant lesions, are also discussed.

Giant Cell Tumor of Bone Versus Tenosynovial Giant Cell Tumor - Similarities and Differences.

Giant cell tumor of bone (GCTB) and tenosynovial giant cell tumor (TGCT) share misleadingly similar names, soft texture and brown color macroscopically, osteoclast-like multinucleated giant cells microscopically and localisation in the musculoskeletal system. However, these two tumor types are biologically and clinically two distinct entities with different natural courses of progression and considerably different modes of surgical and medical treatment. In this article, we provide a detailed update on the similarities and the differences between both tumor types.GCTB is a locally aggressive osteolytic bone tumor, commonly seen in patients in their third decade of life. It usually occurs as a solitary lesion in the meta-epiphyseal region of long bones. It can be diagnosed using plain radiographic imaging, CT radiography or MRI to estimate the tumor extent, soft tissue and joint involvement. GCTB is usually treated with intralesional excision by curettage. Systemically, it can be treated with bisphosphonates and denosumab or radiotherapy.TGCT is a rare, slowly progressing tumor of synovial tissue, affecting the joint, tendon sheath or bursa, mostly seen in middle-aged patients. TGCT is usually not visible on radiographs and MRI is mostly used to enable assessment of potential bone involvement and distinguishing between two TGCT types. Localised TGCT is mostly treated with marginal surgical resection, while diffuse TGCT is optimally treated with total synovectomy and is more difficult to remove. Additionally, radiotherapy, intraarticular injection of radioactive isotopes, anti-TNF-α antibodies and targeted medications may be used.

Serglycin induces osteoclastogenesis and promotes tumor growth in giant cell tumor of bone

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.

Utility of Cyclin D1 Immunostaining in Cutaneous Xanthogranuloma.

Mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase pathway activation has recently been found to be associated with almost all Langerhans cell histiocytosis cases. In BRAF V600E mutation-positive cases, this activation is seen as a downstream activation. In addition, cyclin D1 is a downstream target of the MAPK pathway. Recent studies have argued in favor of using cyclin D1 as a potential neoplastic marker to differentiate Langerhans cell histiocytosis from other reactive Langerhans cell proliferations in the skin and lymph nodes. Therefore, we chose to study the immunohistochemical expression of cyclin D1 in cutaneous xanthogranuloma (XG) cases. Fifteen XG cases were retrieved and stained for cyclin D1, BRAF (v-raf murine sarcoma viral oncogene homolog B1), CD1a, and langerin (CD207). Twelve cases showed strong and diffuse nuclear positivity for cyclin D1, both in the XG cells and in the multinucleated osteoclast-like giant cells. Three cases showed focal weak nuclear staining for cyclin D1. All 15 cases showed negative immunoreactivity for BRAF, CD1a, and CD207. Although limited by small sample size, we conclude that most cases of cutaneous XG should show at least weak nuclear staining with cyclin D1. The histogenesis of XG is still largely unknown, and the finding of cyclin D1 positivity in a majority of cases may indicate a role for the MAPK/extracellular signal-regulated kinase pathway in cutaneous XG.

Osteoclastic giant cell tumor of the pancreas with osteoid and bone formation: a case report

Background: Extraosseous giant cell tumors involving visceral organs (pancreas, kidneys, bladder, etc.) and soft tissues present similar histological features to those occurring in the bones. Rarely, they may affect pancreas and their origin remains still controversial, with some authors supporting the epithelial and some others the mesenchymal origin. Case Presentation: We report the case of a pancreatic giant cell tumor with osteoclast-like cells, negative for epithelial markers. A 64-year-old man presented with a 2-month history of progressively worsening abdominal pain, radiating to the lumbar region. He reported no other symptoms. The abdominal clinical examination was unremarkable and there was no associated jaundice. Liver function tests remained within normal limits. His past medical history had nil of note. He underwent an outpatient abdominal computed tomography which revealed a large cystic lesion at the body of the pancreas measuring 10 × 7 × 6.5 cm. We proceeded with a limited excision of the pancreatic mass alone, avoiding major dissections that would unnecessarily increase morbidity and mortality and the postoperative course was good. The histological morphological and immunohistochemical assessment revealed two tumor cell types: osteoclast-like multinucleated giant cells and pleomorphic mononuclear cells, with bone formation and without important cellular and nuclear atypia. Conclusion: Pancreatic giant cell tumors with osteoclast-like giant cells are rare tumors of the pancreas with various clinical characteristics and controversial origin. En bloc resection has prevailed as the only beneficial treatment so far.

Characterization of novel USP6 gene rearrangements in a subset of so-called cellular fibroma of tendon sheath

Fibroma of tendon sheath (FTS) is an uncommon benign fibroblastic/myofibroblastic neoplasm that typically arises in the tenosynovial tissue of the distal extremities. Histologically, it is a well-circumscribed proliferation of spindle cells within collagenous stroma with peripheral slit-like vessels. Most examples are relatively hypocellular and more densely collagenous than nodular fasciitis; however, a cellular variant has been described, which has considerable morphologic overlap with nodular fasciitis and has been shown to harbor USP6 translocations in a subset of cases. The incidence of these rearrangements and the identity of the USP6 fusion partners have not been described in detail. In this study we evaluate 13 cases of cellular fibroma of tendon sheath by anchored multiplex PCR/next generation sequencing in order to detect potential gene fusions. Nucleic acids of adequate quality were obtained in 11 cases, demonstrating gene fusions in 7/11 (64%), all of which involve USP6 with a variety of partners, including PKM, RCC1, ASPN, COL1A1, COL3A1, and MYH9. Some unusual histomorphologic findings were present in a subset of cases including palisading growth pattern, epithelioid cells, and osteoclast-like multinucleated giant cells, particularly in the tumors with PKM and ASPN gene partners. Overall, the findings support a biologic relationship between cellular fibroma of tendon sheath and other lesions within the spectrum of USP6-rearranged neoplasms, particularly nodular fasciitis.

English

BACKGROUND Giant Cell Tumour (GCT) is a locally aggressive benign bone neoplasm characterized by proliferation of mononuclear stromal cells and many osteoclastlike multinucleated large giant cells affecting the epiphyseal segments of long bones mostly in females of 20 - 40 years age group. Distal radius is the third most common site of occurrence of GCT next to distal femur and proximal tibia. Resection or extended curettage remain the main modalities of treatment in Campanacci Grade I and II while en-bloc excision with reconstructive procedures, arthrodesis or amputation are the treatments of choice in Grade III with the latter two procedures leading to loss of joint function. Fibula being a non-weight transmitting bone of the lower limb, can be harvested in its proximal 1 / 3 rd and used for the reconstruction of the distal radius. In this study, we evaluate the functional and clinical results of resection and reconstruction using a nonvascularized fibula graft in the distal radius GCT. METHODS This is a prospective study of 20 patients diagnosed with GCT of distal radius either treated primarily at our institution or reviewed here after having been treated elsewhere. After confirmation of diagnosis, the patients underwent resection of the tumour and reconstruction of the distal radius using ipsilateral non vascularized fibula graft, fixed with dynamic compression plate. Follow-ups were done at regular intervals and radiological signs of graft healing, recurrence of tumour, wrist range of motion, and revised Musculoskeletal Tumour Rating Scale (MSTS) was used for assessing the functional outcome. RESULTS In our study, it was found that mostly females 13 (66.6 %) of the age group 30 - 35 yrs. were affected. The average grip strength achieved was 71 % (42 - 86 %) &amp; average combined movements of 64 % (29 - 78 %) of contralateral normal side. Mean duration of union was 24 weeks (14 - 42 weeks). One case of non-union was seen which eventually achieved union with bone grafting. There was one case of soft tissue recurrence but the patient refused any further procedure. Complications were seen in 8 cases (41.6 %). We achieved excellent results in 15 (75 %), good in 2 (10 %), satisfactory in 2 (10 %) and poor in 1 (5 %) case. CONCLUSIONS We found that in GCT resection of the distal radius and reconstruction arthroplasty using autologous non-vascularized proximal fibular graft is useful in preserving the functional status as well as achieving satisfactory range of movement and grip strength with lesser chances of tumour recurrence. KEYWORDS Distal Radius, Giant Cell Tumour, Resection Reconstruction, Fibula

Malignant gastrointestinal neuroectodermal tumor: clinicopathological analyses of four cases

Objective: To investigate the clinicopathological features, diagnosis, differential diagnosis, and molecular alterations of malignant gastrointestinal neuroectodermal tumor (MGNET). Methods: Four cases of MGNET were collected at Fujian Provincial Hospital, from July 2013 to January 2019. H&E and immunohistochemical staining were retrospectively evaluated, together with genetic mutation analysis of EWSR1. The relevant literature was systematically reviewed. Results: There were two male and two female patients, with an age range of 34-81 (median 57) years. Tumor sizes ranged from 5-9 (median 6.8) cm. Microscopy showed diffuse and flaky growth of tumor cells, some of which were small and round. The tumor cells were arranged in solid, flaky, nested or pseudoadenoid patterns. The tumor cells were epithelioid, oval, short spindled, or small, with round or oval nuclei. The cytoplasm was eosinophilic or clear. Osteoclast-like multinucleated giant cells were scattered focally. Mitosis was about (2-10)/10 HPF. Immunohistochemically, the tumor cells were positive for S-100 protein (4/4), SOX10 (4/4), Syn (2/4), INI1 (4/4), H3K27Me3 (4/4) and vimentin (4/4). Ki-67 index was 15%-90%. Gene mutation detection confirmed EWSR1 mutation in all four cases, and C-KIT/PDGFRα genes were not mutated in two cases. Conclusions: MGNET is a rare high grade malignant soft tissue tumor. The diagnosis is based on clinicopathological, immunophenotypic, and molecular pathology features. The primary treatment for MGNET is complete surgical excision and chemotherapy; the prognosis is poor.

The two faces of giant cell tumor of bone.

Giant cell tumor (GCT) is a bone-destructive benign neoplasm characterized by distinctive multinucleated osteoclast-like giant cells with osteolytic properties distributed among neoplastic stromal cells. GCT is locally aggressive with progressive invasion of adjacent tissues and occasionally displays malignant characteristics including lung metastasis. GCT is characterized genetically by highly recurrent somatic mutations at the G34 position of the H3F3A gene, encoding the histone variant H3.3, in stromal cells. This leads to deregulated gene expression and increased proliferation of mutation-bearing cells. However, when GCT complicates Paget disease of bone (GCT/PDB) it behaves differently, showing a more malignant phenotype with 5-year survival less than 50%. GCT/PDB is caused by a germline mutation in the ZNF687 gene, which encodes a transcription factor involved in the repression of genes surrounding DNA double-strand breaks to promote repair by homologous recombination. Identification of these driver mutations led to novel diagnostic tools for distinguishing between these two tumors and other osteoclast-rich neoplasms. Herein, we review the clinical, histological, and molecular features of GCT in different contexts focusing also on pharmacological treatments.