Giant Cell-rich Lesions Research Articles

7254 An Unusual Case Of Hypercalcemia

Abstract Disclosure: S. Shushtarian: None. M. Balogun: None. T. Kaur: None. Hypercalcemia varies depending on severity. Higher serum calcium levels and more severe symptoms may indicate primary hyperparathyroidism or a malignant cancer. This is a case of a 32 year old female who presented with recurrent history of nephrolithiasis, found to have hypercalcemia of 13.4 mg/dL and parathyroid hormone of 1928.9 pg/mL, with phosphorus of 1.5 mg/dL. Ultrasound of her thyroid revealed a complex nodule arising from the right parathyroid gland measuring 2.2 X 2.0 cm. CT chest revealed diffuse osseous sclerosis secondary to metabolic disorder. Sestamibi scan did not localize any parathyroid adenoma. MRI of the thoracic and lumbar spine showed multiple small enhancing lesions throughout the pelvis and in the left rib, likely brown tumors related to hyperparathyroidism. X-ray of bony prominence on the patient’s left knee revealed a large lytic lesion of the proximal tibial diaphysis measuring 5.1 X 1.9 cm, concerning for aggressive neoplasm. Subsequent left tibial bone biopsy revealed giant cell rich lesions consistent with brown tumor of hyperparathyroidism. Due to our patient’s high calcium levels and large nodule size, she was referred to a tertiary center as the concern for parathyroid carcinoma and post-op hungry bone syndrome was high. Pre-op PTH level was 1408 pg/mL and post-op PTH was 96 pg/mL. The tumor removed was 2.1 cm. Post surgical pathology was consistent with atypical parathyroid adenoma. Patient was referred for genetic testing. An atypical parathyroid adenoma (APA) only accounts for 1.2 to 1.3% of cases of primary hyperparathyroidism. 80-85% of primary hyperparathyroidism is due to typical adenoma, and 10 to 15% of cases are due to hyperplasia or multiple gland disease. APA can often be confused with parathyroid carcinoma (PC), as they both have a 1:1 male to female ratio, high serum calcium levels, symptomatic hypercalcemia, high PTH levels, and fragility fractures. There are studies showing that both APA and PC have loss of nuclear parafibromin immunoreactivity. In addition, neither APA nor PC have any correlation with menopause, hormones, or gene deletions, unlike typical adenomas. Biopsy is necessary for diagnosis as the histological and immunohistochemical differences can differentiate APA vs PC. Histological features include pseudo-capsular invasion, bands of fibrosis, pronounced trabecular growth, nuclear atypia, and prominent nucleoli. Also, APA has a strong membranous staining pattern of E-cadherin, whereas PC has a loss of membranous staining. These differences are essential as although APA and PC clinically present similarly, APA lacks the invasive growth and possibility for metastatic disease that PC has. The likelihood for relapse of APA is low. Presence of malignancy criteria are indicative that a mass is actually PC and not APA. Despite this, APA is still considered a tumor of uncertain malignant potential and requires follow up. Presentation: 6/3/2024

Role of Denosumab in Spinal Giant Cell Tumour

Abstract Giant cell tumour (GCT) of bone (GCTB) is a type of giant cell-rich bone lesion specified by the presence of numerous multinucleated osteoclast-type giant cells. Giant cells are known to express receptor activator of nuclear factor-kappa B ligand (RANKL) and are responsible for the aggressive osteolytic nature of the tumour. No available treatment option is definitively effective in curing this disease, especially in surgically unsalvageable cases. Denosumab is a fully human monoclonal antibody that targets and binds with high affinity and specificity to RANKL. Results from the studies suggest that denosumab is potentially effective treatment for patients with GCTB of the spine, including the sacrum. This study is a review to highlight role of denosumab in spinal GCT.

Giant cell tumor of bone-an update

In the past few years, numerous new insights have been gained in the field of giant cell tumor of bone (GCTB). On the one hand, the detection of the highly characteristic histone mutation in the H3F3A gene in GCTB is becoming increasingly important in diagnostics in differentiating GCTB from other giant cell-rich lesions of bone as well as for defining rare variants of GCTB without osteoclastic giant cells. On the other hand, the effects of the H3F3A mutation were shown to have an impact on the epigenetic profile of tumor-driving stromal cells, providing new insights into tumorigenesis of GCTB.

Bone tumors in children and adolescents

Osseous lesions are rare; however, their incidence is increased in childhood and adolescence. The spectrum of osseous processes in this age group is limited, with benign lesions being much more prevalent than malignant tumors. For the differential diagnosis, it is essential to have in-depth knowledge of the more frequent bone diseases in children and adolescents. The current review presents these diseases based on the morphologic approach of the WHO classification, including giant cell-rich and cystic lesions, chondrogenic and bone-forming lesions [7]. Small round cell sarcomas which are now summarized in aseparate chapter of the WHO classification have been described previously [12, 20].

Cytomorphologic panorama of giant cell tumour of tendon sheath.

Giant Cell Tumour of Tendon Sheath (GCTTS) is a slow growing benign soft tissue tumour arising from synovium of tendon sheath or joint. These tumours occur more frequently in upper limbs, especially hands. In the present study, we aimed to evaluate the cytomorphological spectrum of GCTTS. This retrospective study includes a total of 56 cases of GCTTS diagnosed over a period of 8 years. The clinical and radiological details of these cases were retrieved from the cytopathology records and detailed cytomorphological features were studied and analysed. Histopathological correlation was done in 16/56 cases, where follow-up was available. The mean age of patients at the time of presentation was 32 years and were predominantly females (68%). The most common site of GCTTS was fingers (76%), followed by foot, wrist and toes. The most consistent finding on cytology was stromal cells (100%) of polygonal, spindle and plasmacytoid morphology with interspersed multinucleated osteoclastic giant cells (100%), followed by binucleated stromal cells (75%), xanthoma cells (61%) and hemosiderin laden macrophages (52%). Presence of proteinaceous fluid background was also observed in 50% of the cases. GCTTS can be diagnosed with certainty on FNAC based on characteristic cytomorphological features in an appropriate clinical and radiological setting. FNAC plays a pivotal role in diagnosing GCTTS and differentiating it from other giant cell rich lesions, thus obviating the need of tissue biopsy for diagnosis, which in turn helps the clinician in timely and adequate management of the patient.

DNA methylation profile discriminates sporadic giant cell granulomas of the jaws and cherubism from their giant cell-rich histological mimics.

Sporadic giant cell granulomas (GCGs) of the jaws and cherubism-associated giant cell lesions share histopathological features and microscopic diagnosis alone can be challenging. Additionally, GCG can morphologically closely resemble other giant cell-rich lesions, including non-ossifying fibroma (NOF), aneurysmal bone cyst (ABC), giant cell tumour of bone (GCTB), and chondroblastoma. The epigenetic basis of these giant cell-rich tumours is unclear and DNA methylation profiling has been shown to be clinically useful for the diagnosis of other tumour types. Therefore, we aimed to assess the DNA methylation profile of central and peripheral sporadic GCG and cherubism to test whether DNA methylation patterns can help to distinguish them. Additionally, we compared the DNA methylation profile of these lesions with those of other giant cell-rich mimics to investigate if the microscopic similarities extend to the epigenetic level. DNA methylation analysis was performed for central (n = 10) and peripheral (n = 10) GCG, cherubism (n = 6), NOF (n = 10), ABC (n = 16), GCTB (n = 9), and chondroblastoma (n = 10) using the Infinium Human Methylation EPIC Chip. Central and peripheral sporadic GCG and cherubism share a related DNA methylation pattern, with those of peripheral GCG and cherubism appearing slightly distinct, while central GCG shows overlap with both of the former. NOF, ABC, GCTB, and chondroblastoma, on the other hand, have distinct methylation patterns. The global and enhancer-associated CpG DNA methylation values showed a similar distribution pattern among central and peripheral GCG and cherubism, with cherubism showing the lowest and peripheral GCG having the highest median values. By contrast, promoter regions showed a different methylation distribution pattern, with cherubism showing the highest median values. In conclusion, DNA methylation profiling is currently not capable of clearly distinguishing sporadic and cherubism-associated giant cell lesions. Conversely, it could discriminate sporadic GCG of the jaws from their giant cell-rich mimics (NOF, ABC, GCTB, and chondroblastoma).

Giant cell rich lesion at distal end radius in a skeletally immature patient

Abstract Giant cell tumor has been reported rarely in pediatric age groups and the reported literature incidence varies from 1.8% to 10.6%. This case study is novel because it reports a rare presentation of giant cell tumor (GCT) as progressive pain and swelling in the wrist in a 12-year-old boy. Radiological workup revealed a lytic lesion and further histopathology revealed the presence of multinucleated giant cells thus confirming the diagnosis of GCT. It was managed by local tumor resection and 2-year follow-up had no signs of recurrence with satisfactory ROM at the elbow wrist and forearm with mild valgus at the wrist.

Brown tumor of the rib associated with primary hyperparathyroidism misdiagnosed as metastatic deposit - A case report

Brown tumor is a rare skeletal manifestation where multiple giant cell rich bony lesions, arise as a direct result of either primary or secondary hyperparathyroidism. It is caused by excess osteoclastic activity and hemosiderin deposition because of uncontrolled parathormone secretion. Brown tumors usually involve mandible, maxilla, clavicle, ribs, and pelvic bones. Our case report describes the case of a 42-year-old lady who consulted our hospital for multiple bony lesions in ribs suspicious of metastasis and summarizes our experience in diagnosis of similar cases that we might come across in the future.

RANKL inhibition for giant cell lesions of the jaw: A retrospective cohort analysis

BackgroundIn all giant-cell-rich lesions (GCRL) occurring in bone, a common underlying excessive RANKL expression is held responsible for the osteolytic activity. Apart from giant cell tumour of bone (GCTB), systematic outcome analysis of RANKL inhibition in other GCRL is unavailable. The aim of this study is to assess the efficacy and safety of a 1-year denosumab protocol in giant cell lesions of the jaw (GCLJ). MethodsA retrospective cohort study was conducted compromising patients treated with a 1-year protocol of monthly subcutaneously administered 120 mg denosumab. Objective tumour response based on histology and imaging was used to calculate objective tumour response rate, progression-free survival (PFS) and time to progression. Type, severity and frequency of adverse events were recorded in a standardised way to assess safety. ResultsTwenty patients, predominantly female (90%), were included. Fifty-five per cent of lesions were located in the mandible; most classified as aggressive lesions (90%). Thirty-five per cent (7/20) of cases were either recurrent after prior treatment or progressive, while on other drug treatment. Objective tumour response rate was 100% after 12 months of treatment. Median PFS was 50.4 months (95% CI 38.0–62.8) with a cumulative PFS rate of 22.6% (95% CI 1.8–43.4) at 5 years follow-up. Median time to progression was 38.4 months (95% CI 26.0–50.8). Treatment was well tolerated, and none of the patients had to interrupt therapy for toxicity. ConclusionHigh-dose denosumab is effective and safe in achieving a complete response in GCLJ within 12 months. The high long-term relapse rate after treatment cessation is the main obstacle for denosumab to become standard treatment for GCLJ.

Imaging features, staging system, and surgical management of giant cell lesions of the temporal bone

Background Giant cell tumors (GCTs) and giant cell granulomas (GCGs) are giant cell-rich lesions that occur extremely rarely in the temporal bone and have similar clinical presentations. Objectives We aimed to analyze the clinical features and introduce our staging system and surgical treatment. Methods Forty-six patients pathologically diagnosed with a giant cell lesion involving the temporal bone between October 2001 and October 2020 were reviewed retrospectively. The clinical characteristics, surgical approaches, and risk factors for recurrence were analyzed. Results GCTs and GCGs presented as masses centered on the temporomandibular joint with similar imaging features, including a thin, calcified shell and central scattered calcifications on a computed tomography scan. Differences were detected on magnetic resonance imaging in 29.6% (4/14) of GCG and 50% (16/32) of GCT cases; the remaining cases were not distinguishable. Based on our staging system and surgical strategy, 31.8% (7/22) of GCT and 10% (1/10) of GCG cases experienced recurrence, which compares to recurrence rates of 60% in GCT cases and 20% in GCG cases in previous studies. Conclusions Specific clinical and preoperative imaging features help to make a diagnosis of temporal giant cell-rich lesions. Our staging system and surgical strategy could help surgeons tailor the surgical strategy.

Update of Key Clinical, Histological and Molecular Features of Malignant Bone Tumours Arising in the Craniofacial Skeleton.

The craniofacial skeleton is a highly complex and specialized anatomic region containing and protecting the brain and sensory organs. Bone sarcomas arising here comprise a heterogeneous group of tumours, some of which differ in their biological behaviour compared to their peripheral counterparts. The reasons for this seem to lie, at least partially, in the embryonal development of the craniofacial bones. For reaching the correct diagnosis as the cornerstone of optimal personalised treatment planning, a multidisciplinary team of specialists, including pathologists, radiologists, oncologists, and head and neck surgeons needs to be involved. The most common tumours arising in the craniofacial bones are bone-forming tumours, cartilage-forming tumours, fibro-osseous lesions, giant cell-rich lesions, and notochordal tumours. While morphology remains the backbone for the diagnosis, the last decade has witnessed tremendous advances in the molecular characterization of tumours, and molecular testing is increasingly becoming a part of the diagnostic process. The integration of these new molecular markers into the diagnostic approach has undoubtedly increased the diagnostic accuracy and objectivity, and holds great promise to also identify new therapeutic targets for precision medicine in the future. Examples include HEY1-NCOA2 in mesenchymal chondrosarcoma, IDH1/2 mutations in chondrosarcoma and TFCP2 rearrangements in rhabdomyosarcoma. In this article, key clinical, histological and molecular features of malignant bone tumours arising in the craniofacial region are discussed, with a special focus on the differential diagnosis and prognostic considerations.

Epigenetic lockdown of CDKN1A (p21) and CDKN2A (p16) characterises the neoplastic spindle cell component of giant cell tumours of bone.

Giant cell tumour of bone (GCTB) comprises the eponymous osteoclastic multinucleated giant cells eliciting bone lysis, an H3F3A-mutated neoplastic mononucleated fibroblast-like cell population, and H3F3A wild-type mononucleated stromal cells. In this study, we characterised four new cell lines from GCTB. Furthermore, we compared the genome-wide DNA methylation profile of 13 such tumours and three further cell lines with giant cell-rich lesions comprising three H3F3B-mutated chondroblastomas, three USP6-rearranged aneurysmal bone cysts, three non-ossifying fibromas, two hyperparathyroidism-associated brown tumours as well as mesenchymal stem cells, osteoblasts, and osteoclasts. In an unsupervised analysis, we delineated GCTB and chondroblastomas from the other analysed tumour entities. Using comparative methylation analysis, we demonstrated that the methylation pattern of the cell lines approximately equals that of H3F3A-mutated stromal cells in tissue. These patterns more resemble that of osteoblasts than that of mesenchymal stem cells, which argues for the osteoblast as the cell of origin of giant cell tumours of bone. Using enrichment analysis, we detected distinct hypermethylated clusters containing histone and collagen genes as well as target genes of the tumour suppressor p53. We found that the promotor regions of CDKN1A, CDKN2A, and IGFBP3 are methylated more strongly in GCTB than in the other giant cell-containing lesions, mesenchymal stem cells, osteoblasts, and osteoclasts (p < 0.001). This hypermethylation correlates with the lower gene expression at the mRNA level for these three genes in the cell lines, the lack of p16 and p21 in these cell lines, and the lower expression of p16 and p21 in GCTB. Overall, our analysis reveals characteristic DNA methylation patterns of giant cell tumours of bone and chondroblastomas and shows that cell lines of giant cell tumours of bone are a valid model for further analysis of H3F3A-mutated tumour cells. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Distinct H3F3A Driver Mutation Defines Giant Cell Tumor of Bone: A Necessary Adjunct in the Diagnosis of Such a Lesion in the Hyoid Bone, Presenting as a Base of Tongue Mass

<h3>Introduction</h3> Giant cell tumor of bone (GCTB) is a rare benign tumor mostly affecting the epiphyses of long bones in skeletally mature patients that is rarely described in the head and neck. Conventionally, diagnosis is based on microscopic features, exclusion of mimics, and clinico-radiologic correlation. Morphologic overlap with numerous giant cell-containing lesions of bone and soft tissue complicates the diagnosis. GCTB is characterized by the <i>H3F3A</i> mutation, which can be detected immunohistochemically using H3.3 G34W, a monoclonal antibody specific for this mutation. <h3>Case Findings</h3> A 57-year-old male presented with dysphagia, dysarthria, and right base of tongue (BOT) mass suspicious for carcinoma. Imaging revealed a heterogeneous parapharyngeal lesion extending from BOT to the hyoid bone. A BOT biopsy demonstrated giant cell-rich granulation tissue and non-endothelial lined blood lakes, suggestive of aneurysmal bone cyst (ABC). Fluorescent in situ hybridization (FISH) analysis did not identify <i>USP6</i> rearrangement, effectively eliminating primary ABC and favoring secondary ABC. Base of tongue resection, partial pharyngectomy and hyoid bone resection followed. <h3>Results</h3> Microscopically, the resection revealed a giant cell-rich lesion emanating from the hyoid bone, suggestive of GCTB and thus unlikely soft tissue giant cell tumor. Cellular pleomorphism and atypical mitoses were absent. Stromal cells expressed H3.3 G34W, confirming the diagnosis of GCTB. Zonal features of secondary ABC were juxtaposed to the dominant GCTB. <h3>Conclusions</h3> Hyoid GCTB is exceedingly rare, and such a diagnosis presents a conundrum. H3.3 G34W nuclear staining is an indicator of <i>H3F3A</i>mutation in GCTB that can help distinguish GCTB from other mimics. Prior reports of hyoid GCTB did not employ ancillary studies to identify <i>H3F3A</i> mutation or <i>USP6</i> rearrangements, as these have only been recently available. Our case fulfills current diagnostic criteria for GCTB, and excludes other giant cell-rich lesions. Accurate diagnosis of GCTB in this atypical location allows for appropriate surveillance algorithms.

Diagnostic Utility of Genetic and Immunohistochemical H3-3A Mutation Analysis in Giant Cell Tumour of Bone.

To validate the reliability and implementation of an objective diagnostic method for giant cell tumour of bone (GCTB). H3-3A gene mutation testing was performed using two different methods, Sanger sequencing and immunohistochemical (IHC) assays. A total of 214 patients, including 120 with GCTB and 94 with other giant cell-rich bone lesions, participated in the study. Sanger sequencing and IHC with anti-histone H3.3 G34W and G34V antibodies were performed on formalin-fixed, paraffin-embedded tissues, which were previously decalcified in EDTA if needed. The sensitivity and specificity of the molecular method was 100% (95% CI: 96.97–100%) and 100% (95% CI: 96.15–100%), respectively. The sensitivity and specificity of IHC was 94.32% (95% CI: 87.24–98.13%) and 100% (95% CI: 93.94–100.0%), respectively. P.G35 mutations were discovered in 2/9 (22.2%) secondary malignant GCTBs and 9/13 (69.2%) GCTB after denosumab treatment. We confirmed in a large series of patients that evaluation of H3-3A mutational status using direct sequencing is a reliable tool for diagnosing GCTB, and it should be incorporated into the diagnostic algorithm. Additionally, we discovered IHC can be used as a screening tool. Proper tissue processing and decalcification are necessary. The presence of the H3-3A mutation did not exclude malignant GCTB. Denosumab did not eradicate the neoplastic cell population of GCTB.

Utility of p63 in Giant Cell Lesions of Bone- A Case Series

Giant cell lesions of bone include a relatively large group of biologically and morphologically diverse bone lesions which shows presence of numerous multinucleate osteoclast like giant cells. Recently, p63 has been found to be a sensitive marker in the diagnosis of giant cell tumor. The aim of this case series is to assess the role of p63 in diagnostically difficult giant cell lesions of bone. This study has been conducted in a tertiary care center in North Kerala. Giant cell rich lesions of bone in hematoxylin and eosin staining, in which an accurate diagnosis is not possible with the available clinical and radiological data are included in this study. The tissue was stained with hematoxylin and eosin and immunohistochemical staining with p63 was done. Though the specificity of the marker was found to be less, it was concluded that, p63 can be used as an ancillary aid along with histomorphological and radiological data in arriving at a diagnosis.

'I Can't Keep Up!': an update on advances in soft tissue pathology occurring after the publication of the 2020 World Health Organization classification of soft tissue and bone tumours.

Progress in our understanding of the pathogenesis and diagnosis of soft tissue neoplasia is exceptionally rapid. Although the most recent World Health Organization classification of soft tissue tumours contains many new entities and refinements of older ones, even this comprehensive document is by now incomplete or in need of modification. This review will attempt to summarise the developments in soft tissue pathology that have occurred since 2020, emphasising lesions for which morphology and genetics intersect in a complementary fashion. Novel entities discussed include KMT2A-rearranged sarcoma, PRRX::NCOAx fibroblastic tumours, EWSR1::PATZ1 sarcomas, BRAF-altered infantile fibrosarcoma-like lesions, NUTM1-rearranged colorectal sarcomas, and a variety of interesting giant cell-rich and matrix-producing lesions. In addition, recently described mimics of atypical lipomatous tumour/well-differentiated liposarcoma are covered, as is a wholly new, morphologically defined and genetically confirmed entity, pseudoendocrine sarcoma. Finally, exciting new developments in the use of immunohistochemistry as a surrogate for molecular genetic techniques are discussed.

Giant cell-rich lesions of bone

Giant cell-rich lesions of bone

De novo TRPV4 Leu619Pro variant causes a new channelopathy characterised by giant cell lesions of the jaws and skull, skeletal abnormalities and polyneuropathy

BackgroundPathogenic germline variants in Transient Receptor Potential Vanilloid 4 Cation Channel (TRPV4) lead to channelopathies, which are phenotypically diverse and heterogeneous disorders grossly divided in neuromuscular disorders and skeletal dysplasia....

Chondroblastoma Expresses RANKL by RNA In Situ Hybridization and May Respond to Denosumab Therapy.

Lesions of bone featuring osteoclast-like giant cells comprise a diverse group of entities, including giant cell tumor (GCT) of bone, chondroblastoma, and aneurysmal bone cyst, among others. The receptor activator of nuclear factor-κB ligand (RANKL) has been implicated in the pathogenesis of GCT of bone and may play a role in the pathogenesis of other giant cell-rich lesions as well. In addition, RANKL inhibitors (denosumab) have also been shown to have some efficacy in treating some giant cell-rich lesions. Herein, we examine RANKL expression by RNA in situ hybridization in a total of 84 osseous lesions with a focus on chondroblastoma, GCT, fibrous dysplasia, and aneurysmal bone cyst. The lesions were tested for RANKL expression using a chromogenic RNA in situ hybridization assay. RANKL expression was identified in 24/25 (96%) GCT, 24/26 (92%) chondroblastomas, 6/7 (86%) aneurysmal bone cysts, and 3/16 (19%) patients with fibrous dysplasia. RANKL expression was statistically lower in chondroblastoma and aneurysmal bone cyst compared with GCT. RANKL reactivity in fibrous dysplasia was exclusively seen in the 3 cases with osteoclast-type giant cells. Our results indicate a high proportion of chondroblastomas, GCTs, and aneurysmal bone cysts express RANKL while reactivity in fibrous dysplasia is dependent on the presence of osteoclast-type giant cells. On the basis of the success of denosumab therapy for GCTs, our results indicate that it may be a potential therapeutic option in other primary osseous tumors.

KRAS mutations in brown tumor of the jaws in hyperparathyroidism.

Brown tumors are giant cell-rich lesions that result from abnormal bone metabolism in hyperparathyroidism, one of the most common endocrine disorders worldwide. Brown tumors occasionally affect the jaws and, despite well-known clinical and microscopic features, their molecular pathogenesis remains unclear. We investigated the presence of pathogenic activating mutations in TRPV4, FGFR1, and KRAS in a cohort of brown tumors since these have recently been reported in giant-cell lesions of the jaws and non-ossifying fibromas of the bones (FGFR1 and KRAS), which are histologic mimics of brown tumors. We target sequenced 13 brown tumors of the jaws associated with primary or secondary hyperparathyroidism. As mutations in these genes are known to activate the MAPK/ERK signaling pathway, we also assessed the immunostaining of the phosphorylated form of ERK1/2 (pERK1/2) in these lesions. KRAS pathogenic mutations were detected in seven cases (p.G12V n=4, p.G12D n=1, p.G13D n=1, p.A146T n=1). KRAS variants of unknown significance (VUS), p.A134T and p.E37K, were also detected. All samples showed wild-type sequences for FGFR1 and TRPV4 genes. The activation of the MAPK/ERK signaling pathway was demonstrated by pERK1/2 immunohistochemical positivity of the brown tumors´ mononuclear cells. Mutations in KRAS and activation of the MAPK/ERK signaling pathway were detected in brown tumors of hyperparathyroidism of the jaws, expanding the spectrum of giant cell lesions whose molecular pathogenesis involve RAS signaling.