Endometrial Biopsy with Spindle Cells and Multinucleated Giant Cells
The finding of spindle cells and large multinucleated giant cells on endometrial biopsy requires immediate exclusion of endometrial giant cell carcinoma (EGCC), a rare but aggressive malignancy, followed by consideration of benign reactive processes if malignancy is ruled out.
Immediate Diagnostic Priorities
Rule Out Malignancy First
Endometrial giant cell carcinoma must be excluded as the primary concern, as this rare entity consists of poorly cohesive nests of bizarre multinucleated giant cells with mononuclear tumor cells and carries significant malignant potential 1, 2.
EGCC often contains a conventional carcinomatous component (most commonly endometrioid adenocarcinoma in 50-70% of tumor volume) alongside the giant cell component, making complete histologic evaluation essential 1, 2.
The giant cells in EGCC show focal positivity for epithelial markers (AE1/AE3, CAM 5.2, EMA), partial loss of epithelial markers, hormone receptor positivity (focal/multifocal), and are negative for CD68, muscle markers, and specific differentiation markers 1, 2.
A striking peritumoral and intratumoral inflammatory infiltrate composed of lymphocytes, plasma cells, and focal eosinophils/neutrophils is characteristic of EGCC, with emperipolesis noted in 80% of cases 1.
Essential Immunohistochemical Panel
Request the following stains immediately to characterize the cells:
- Epithelial markers: AE1/AE3, CAM 5.2, EMA to identify carcinomatous differentiation 1, 2
- CD68: Positive in benign osteoclast-like giant cells, negative in EGCC 2, 3
- Vimentin: Typically positive in both malignant giant cells and reactive stromal cells 2, 3
- Hormone receptors (ER/PR): Focal positivity suggests EGCC 2
- p16: Diffuse positivity seen in EGCC 2
- Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2): EGCC is typically mismatch repair-proficient 2
Differential Diagnosis Algorithm
If Epithelial Markers Are Positive (Focal or Multifocal)
Endometrial giant cell carcinoma is the diagnosis until proven otherwise 1, 2.
EGCC should be managed similarly to undifferentiated/dedifferentiated carcinoma and carcinosarcoma given its aggressive behavior 2.
Stage the disease appropriately: most present as stage IA-IB, but advanced stage (IIIC2) occurs and lung metastases have been reported 4 years post-diagnosis 1.
Prognosis varies: one patient remained disease-free for 14 years, while another developed metastatic disease, indicating the uncertain prognostic significance of the giant cell component extent 1.
If CD68 Positive in Giant Cells
Endometrial carcinosarcoma with osteoclast-like giant cells should be considered, where the osteoclast-like giant cells are strongly CD68-positive and represent a reactive histiocytic component rather than neoplastic cells 3.
The epithelial component will be EMA and cytokeratin-positive, while spindle cells show vimentin positivity 3.
This diagnosis still represents an aggressive malignancy requiring comprehensive staging and treatment.
If Epithelial Markers Are Negative and Clinical Context Is Benign
Atypical endometrial stromal cells may occur adjacent to benign lesions such as polypoid leiomyomas with bizarre nuclei 4.
These atypical cells can be mistaken for malignant cells, especially in small endometrial samples, but their association with benign smooth muscle tumors and lack of epithelial marker expression helps distinguish them from carcinoma 4.
The etiology of these multinucleated giant cells and atypical stromal cells in benign contexts remains unclear, but recognition prevents unnecessary radical surgery 4.
Critical Clinical Pitfalls to Avoid
Never diagnose benign reactive changes without comprehensive immunohistochemical workup, as EGCC can be missed in small biopsy samples where only the giant cell component is sampled 1, 4.
Do not assume all multinucleated giant cells are reactive or inflammatory without excluding epithelial differentiation through immunostains 1, 2.
Avoid underestimating the malignant potential based on limited sampling—request deeper levels and additional tissue if the initial biopsy shows only spindle cells and giant cells without definitive conventional carcinoma 1.
Recognize that EGCC may be exclusively composed of giant cells (20% of cases) without an identifiable conventional carcinomatous component, making immunohistochemistry absolutely essential 1.
Management Based on Final Diagnosis
If EGCC Is Confirmed
Proceed with comprehensive surgical staging including total hysterectomy, bilateral salpingo-oophorectomy, and lymph node assessment 1.
Manage as high-grade endometrial carcinoma with consideration for adjuvant therapy based on stage and risk factors 2.
Close surveillance for recurrence is warranted given reports of late metastases 1.