giant cell tumor malignant management.pptx

Malignant giant cell tumor (MGCT) is a rare aggressive variant of conventional giant cell tumor of bone (GCTB), accounting for less than 5% of cases. It may arise as primary MGCT or as secondary malignant transformation after recurrence or radiotherapy. It is characterized by rapid local growth, cortical destruction, soft tissue extension, high recurrence, and metastatic potential, most commonly to the lung. Diagnosis requires careful histopathology to differentiate from high-grade sarcomas such as osteosarcoma or undifferentiated pleomorphic sarcoma. Imaging with MRI and CT defines local extent, while PET/CT is useful for detecting systemic spread. Biopsy planning is crucial to permit definitive en bloc resection. Management is centered on wide surgical excision with negative margins, which offers the best chance of durable local control. Unlike conventional GCTB, curettage is not acceptable due to the high risk of recurrence. Reconstruction after wide excision depends on site and may include prosthesis, allograft, arthrodesis, or vascularized fibular graft. Amputation is reserved for advanced or non-reconstructable disease. Radiotherapy is generally avoided because of its association with malignant transformation in GCTB, but in unresectable or recurrent cases where surgery is not feasible, conformal RT (IMRT, VMAT, proton therapy) may be employed at doses of 60–66 Gy. Systemic therapy is extrapolated from osteosarcoma and other high-grade sarcomas, with regimens including doxorubicin, cisplatin, ifosfamide, and high-dose methotrexate. Although evidence is limited due to rarity, chemotherapy may provide benefit in metastatic or unresectable MGCT. Targeted therapy with denosumab, effective in conventional GCTB, has little role after malignant transformation but may be considered for palliation or to reduce giant-cell components. Experimental options such as immune checkpoint inhibitors and tyrosine kinase inhibitors are under investigation. Pulmonary metastases occur in up to 30–40% of patients. Surgical metastasectomy should be considered in oligometastatic disease, while systemic chemotherapy is indicated in disseminated disease. Prognosis is significantly poorer than conventional GCTB, with 5-year survival rates of 40–60%. Risk factors for poor outcome include inadequate surgical margins, high histological grade, and presence of metastases at diagnosis. Close surveillance is required with MRI or CT of the primary site every 3–6 months for the first 2 years, then annually, and chest CT to monitor for lung metastases. In summary, management of MGCT requires a multimodal approach, with surgery forming the cornerstone. Radiotherapy and chemotherapy are reserved for unresectable, recurrent, or metastatic disease. Despite aggressive treatment, outcomes remain guarded, highlighting the need for early recognition, complete surgical resection, and exploration of novel systemic therapies to improve prognosis.

1. DR SUMIT KUMAR ECMO I Ex SR AIIMS, New Delhi Assistant professor NEIGRIHMS, Shillong ???? Role of denosumab ???? chemothearpy ???Biphasic tumor Primary vs Secondary Malignant GCTB Giant cells—neoplastic or non neoplastic ?????

2. WHO and Clinical Perspectives WHO 2020 classifies GCTB as an intermediate (locally aggressive) bone tumor . In rare cases, GCTB can undergo malignant transformation into high-grade sarcoma. WHO does not formally subclassify malignant GCTB further. CLASSIFICATION This clinical subclassification helps guide treatment and prognosis , despite not being in WHO.

3. The stromal cells are the neoplastic component , capable of high-grade sarcomatous transformation (osteosarcoma, fibrosarcoma, UPS). These stromal cells secrete RANKL , which recruits monocyte precursors to form giant cells via the RANK–RANKL axis . Giant cells are reactive , responsible for bone resorption, but they do not metastasize or undergo malignant change. Histopathology & Cellular Basis Correct interpretation of this histologic architecture is crucial to avoid mistaking malignant GCT for its benign counterpart

4. TP53 mutations , p53 overexpression , and high Ki-67 index are commonly seen and indicate high-grade sarcomatous transformation. While some tumors retain the H3F3A G34W mutation , others lose it due to allelic deletion , reflecting divergent malignant pathways. Feature Benign GCTB Malignant GCTB H3F3A G34W mutation Present in stromal cells Present or lost (due to allelic deletion) TP53 mutation Absent Frequently present p53 expression Low or absent Overexpressed Ki-67 index Low (<10%) High (>30%) GPX-1 expression Low High; correlates with early relapse RANKL expression High May persist Metastatic risk Rare High (especially pulmonary metastasis) 🔬 Comparison Table: Benign vs Malignant GCTB (Molecular Profile) Molecular Markers IHC for p53, Ki-67, and H3F3A helps distinguish malignant GCTB from its benign counterpart.

5. Malignant GCTB shows areas of typical GCT architecture adjacent to high-grade sarcomatous regions . A transition zone may be seen, with loss of stromal cell uniformity and a decrease in giant cells. Giant cells remain present but are scattered and non-malignant . Diagnosis is often challenging due to the focal nature of transformation . Histopathology Adequate biopsy sampling from both benign-appearing and aggressive areas is critical for accurate diagnosis.

6. Feature Primary MGCTB Secondary MGCTB Origin De novo (no prior treatment) After prior GCTB treatment (surgery or radiotherapy) Timing At initial diagnosis Appears months to years after initial treatment Histology Mixed benign GCT + high-grade sarcoma in same lesion High-grade sarcoma at previously treated GCT site Common Sarcoma Types Fibrosarcoma, osteosarcoma, undifferentiated sarcoma Osteosarcoma, UPS (often more aggressive) Diagnostic Challenge May be missed on limited biopsy Requires high suspicion in recurrent/aggressive cases Clinical Importance Guides initial treatment planning Indicates need for aggressive salvage management Primary vs Secondary Malignant GCTB

7. Lesion Key Features Distinguishing IHC / Marker Giant cell-rich osteosarcoma Malignant osteoid, atypical cells, lacks benign GCT pattern H3F3A negative Aneurysmal bone cyst (ABC) Blood-filled cystic spaces, no sarcomatous areas USP6 rearrangement (+) Brown tumor (HPT) Multiple lesions, high PTH, osteoclastic giant cells ↑ Serum PTH, Ca++ Chondroblastoma Epiphyseal, chondroid matrix, some giant cells S100+, H3K36M+, H3F3A negative Several tumors mimic malignant GCTB histologically and must be differentiated carefully. Key mimics include giant cell-rich osteosarcoma , aneurysmal bone cyst , brown tumor , and chondroblastoma . 📊 Key Differentials Compared Differential Diagnosis

8. Presents with rapidly enlarging mass , often painful, involving long bones or pelvis. Symptoms include localized pain , swelling, and reduced joint function . Pathologic fractures may occur due to aggressive cortical bone destruction. In secondary MGCTB , symptoms often recur years after curettage or radiotherapy. Systemic symptoms (e.g., weight loss, fever) are rare but may appear in metastatic disease. Clinical Presentation Sudden recurrence or atypical imaging in known GCT cases should raise suspicion of malignancy.

9. Imaging features more aggressive than typical GCT should raise suspicion of malignancy.

10. : Biopsy is often challenging due to mixed benign and malignant areas within the same tumor. Incisional or multiple core biopsies are preferred to avoid missing sarcomatous foci. Radiologic guidance improves accuracy by targeting suspicious zones. Coordination with the surgical team is essential to prevent tumor seeding in resection planes. Biopsy & Sampling Challenges

11. Understanding this helps guide supportive use of Denosumab, not as a curative approach

12. Malignant GCTB – Treatment Overview Non-Metastatic & Resectable wide surgical resection with negative margins Neoadjuvant chemotherapy Adjuvant chemotherapy wide surgical resection with negative margins Non-Metastatic & Unresectable Metastatic Neoadjuvant chemotherapy ± Denosumab Unresectable Resectable definitive radiotherapy Surgery Systemic chemotherapy Resection of metastases Radiotherapy or Denosumab If good response. for palliation, symptom relief, or bone stabilization.

13. Surgery is the cornerstone of curative treatment in non-metastatic malignant GCTB. Aim is wide excision with negative margins (R0) to prevent local recurrence. Surgery is typically performed after neoadjuvant chemotherapy in large or borderline cases, but may be first-line in small, resectable tumors . Limb-sparing surgery is preferred when oncologically safe; Amputation is reserved for cases involving unresectable neurovascular structures or failed salvage. Reconstruction may involve prosthesis, allograft, or arthrodesis, depending on location and extent. In axial skeleton (pelvis, spine, sacrum), surgery is more complex and often combined with adjuvant RT or systemic therapy . Surgery in Malignant GCTB ✅ Key Goals of Surgery: Achieve negative surgical margins Preserve function and structure when possible Minimize risk of local recurrence

14. Chemotherapy in Malignant GCTB 🔸 Adjuvant Chemotherapy Indications : No prior neoadjuvant chemo High-grade sarcoma, large tumor size Positive/close margins or poor response (<90% necrosis 🔹 Neoadjuvant Chemotherapy Indications : Large, borderline resectable tumors Pelvic, sacral, or spinal location Anticipated close margins High-grade histology on biopsy Regimens : MAP : Methotrexate (HDMTX), Doxorubicin, Cisplatin AP : Doxorubicin + Cisplatin (if MTX not feasible)

15. Role of Radiotherapy in Malignant GCTB ⚠️ Key Points RT is adjunctive, not a primary curative modality in resectable cases Consider combining with chemotherapy in high-risk unresectable tumors Radical RT Adjuvant RT Palliative RT 🔹 Indications Positive or close surgical margins where re-excision isn’t feasible 🔹 Indications Unresectable tumors (e.g., spine, sacrum, pelvis) Medically inoperable or unfit for chemotherapy 🔹 Indications symptomatic bone lesions or local recurrence 🔸 Technique & Dose Dose: 55–66 Gy in 1.8–2 Gy fractions Technique: IMRT or VMAT for precision targeting No elective lymph node irradiation — nodal involvement is extremely rare

16. 🧠 Key Message: Multimodal therapy is needed in metastatic MGCTB: chemo is foundational , surgery is selective, and RT/Denosumab provide palliation and local control . Metastatic Malignant GCTB- Treatment Overview 🔹 Systemic Chemotherapy (Mainstay ) Regimens similar to osteosarcoma: MAP OR AP Consider Ifosfamide or second-line regimens in resistant cases Used upfront for pulmonary or extrapulmonary metastases 🔸 Surgical Resection of Metastases Lung metastasectomy in select patients with good chemo response May improve survival in oligometastatic disease Best done after systemic disease is controlled 🔹 Radiotherapy (Palliative Role) For pain relief , bleeding, or unresectable metastatic lesions Especially useful for spine or pelvic bone metastases 🔸 Denosumab (Supportive Use) May reduce bone destruction and pain Not curative — used in symptom control or in chemo-ineligible patients MAP : Methotrexate, Doxorubicin, Cisplatin AP : Doxorubicin + Cisplatin

17. Feature Primary MGCTB Secondary MGCTB Incidence 1.6% (range 0–9.5%) 2.4% (range 1.1–5.1%) Histology Sarcoma adjacent to benign GCTB Sarcoma at site of prior treated GCTB Differentials Giant cell-rich sarcomas, benign GCTB Same (osteosarcoma, UPS, leiomyosarcoma) Cause De novo sarcomatous transformation Mostly post-radiation (75%) or surgery (25%) Prognosis Better: 5-year OS ~87% Worse: 5-year DFS ~32% Technol Cancer Res Treat 2019 Apr 1 Primary vs Secondary Malignant GCTB ( Palmerini et al., 2019)

18. Group Treatment Given Outcome Summary Primary MGCTB (n = 5) Surgery ± Chemotherapy 3 long-term survivors, 2 with lung mets Secondary MGCTB – Post-RT (n = 6) Amputation or Surgery ± Chemo All died of metastatic disease Secondary MGCTB – Post-Surgery (n = 6) Mixed: Surgery, Chemo, or Palliative Care 3 alive NED, 2 early deaths, 1 unrelated death

19. Patient Type Initial Treatment Denosumab Response Subsequent Therapy Outcome Timeline 1 Secondary MGCTB ( mets to lung & kidney) Denosumab Partial response at 2 months Doxorubicin + Cisplatin → Ifosfamide + Etoposide → RT → Trofosfamide Alive, on oral chemo Progression at ~6 months 2 Primary MGCTB (sacral, UPS histology) Radiotherapy (60 Gy ) Complete lung response Doxorubicin + Ifosfamide → Docetaxel + Gemcitabine Died after disease progression Progression after initial CR

20. Common Sites Distal femur, proximal tibia Histologies in Secondary MGCTB Osteosarcoma (15), UPS (4), Fibrosarcoma (1) Mean Latent Period (Secondary MGCTB) 7.9 years 5-year OS Primary MGCTB: 56.2% / Secondary MGCTB: 40% (p = 0.188) Pulmonary Metastasis 69% of patients Local Recurrence Reduced with wide margins (p = 0.006) Chemo Impact on Lung Mets Delayed progression (13 vs 6 months, p = 0.002) Chemo Impact on Survival No OS benefit (57.0% vs 33.3%, p = 0.167) Retrospective analysis of 1365 GCTB patients (1998–2016) 32 patients (2.3%) had malignant GCTB ( Primary : 12 cases, Secondary : 20 cases) Mean age: 33.7 years , mean follow-up: 9.5 years Journal of Bone Oncology 26 (2021) 🧠 Conclusion: Wide resection remains the most critical factor. Chemotherapy may delay lung metastasis, but long-term survival remains poor.

21. © United States & Canadian Academy of Pathology 2018 Case Type Treatment Given Outcome Summary Primary MTGCT (n=8) Resection ± Denosumab, RT 4 ANED, 1 AWD, 2 DOD, 1 recent/unclear Secondary MTGCT (n=2) Amputation or surgery + RT/chemo Both developed lung ± lymph node metastases; DOD Denosumab use 1 patient with unresectable pelvic tumor Helped stabilize disease, not curative RT use 2 patients received postoperative radiation Role was palliative or for local control Chemotherapy 1 patient: Ifosfamide, Doxorubicin, Cisplatin Used adjuvantly in one advanced case 10 well-characterized cases from Mayo Clinic and consulting centers Tumors arose in small joints and pelvis , median age: 60 years 8 primary , 2 secondary MTGCT Follow-up available for 9 patients (mean: 20 months)

22. ESMO Open March 2025 Feature Result / Observation Sex & Age 90% male; median age: 36.5 years (range: 23–50) Common Sites Fibula (3), Femur (2), Tibia (2) Histology 2 osteosarcoma-like; 4 undifferentiated sarcoma without giant cells H3F3A Mutation (IHC) All 10 cases positive for H3F3A G34W Misdiagnosis Risk 2 cases would’ve been labeled osteosarcoma without H3F3A Outcome (18-month f/u) 1 death, 2 cases with metastasis Treatment Insight Surgery alone had lower mortality vs chemo (from systemic review) Prospective series of 10 cases of primary malignant GCTB All tumors were H3F3A G34W-positive on IHC Goal: Improve diagnostic accuracy and define therapeutic strategy 🧠 Clinical Insight: H3F3A IHC is essential for accurate PMGCTB diagnosis Prevents misclassification as osteosarcoma (which alters management) PMGCTB shows better prognosis; upfront surgical resection is preferred High male predominance and unusual predilection for fibula

23. Researcher / Institution Original or Direct Definition Hutter et al. / Dahlin et al. "Primary malignant GCTB is a high-grade sarcoma arising side by side with a benign giant cell tumor of bone. Secondary malignant GCTB is a sarcoma that occurs at the site of previously treated GCTB." Mondal et al. (India) "Primary malignant GCTB is composed of sarcomatous growth juxtaposed to zones of typical benign GCTB. Secondary malignant GCTB is a sarcoma at the site of a previously documented GCTB." Bertoni et al. (Rizzoli, Italy) "Primary malignant GCTB is a high-grade sarcoma arising adjacent to benign GCTB tissue. Secondary malignant GCTB occurs at the site of a previously treated GCTB, often post-radiation." Unni et al. / Mayo Clinic "Primary malignant GCTB is a malignant tumor of bone composed of sarcomatous growth next to benign GCTB. Secondary is a sarcoma arising at a previously documented GCTB site." Domovitov et al. (MSKCC) "Primary malignant GCTB shows giant cells and stromal cells in which the stromal cells demonstrate a clearly sarcomatous appearance. Mitoses or collagen alone are not sufficient for diagnosis." Definitions of Malignant GCTB (Researcher-Based)

24. Treatment Overview – Non-Metastatic Malignant GCTB 🟢 1. Resectable Tumors Primary wide resection is the cornerstone of treatment. Neoadjuvant chemotherapy may be used in large or borderline cases but is not mandatory in all. Adjuvant chemotherapy is recommended if no neoadjuvant was given or if histologic grade is high. Denosumab may be used pre-op to reduce vascularity but is not curative. Adjuvant radiotherapy considered only if margins are close/positive and re-excision isn’t feasible. 🔵 2. Unresectable Tumors (e.g., pelvis, spine) Start with neoadjuvant chemotherapy ± Denosumab to attempt downstaging. If still unresectable → proceed to definitive radiotherapy (e.g., IMRT 60–66 Gy ). Surgery may be reconsidered if significant tumor shrinkage occurs. If chemotherapy is contraindicated, RT becomes the main modality for local control. 🔁 Key Goals in Non-Metastatic Disease: Achieve margin-negative resection when possible. Use chemo to control micrometastasis and improve local response. Consider radiotherapy only in select, high-risk, or unresectable cases .