What are the presentation, diagnostic work‑up, management, and follow‑up recommendations for a malignant granular‑cell tumor in adults?

Malignant Granular Cell Tumor: Clinical Management

Presentation and Clinical Features

Malignant granular cell tumors (mGCT) typically present as painless, slowly enlarging nodules in subcutaneous or deep soft tissues, most commonly affecting adults in their 40s-50s, with a female predominance (77%). 1

Key Clinical Characteristics:

• Most common locations: Soft tissues (36.3%), ovary/testis (16.8%), skin (11.5%), extremities, breast, and head/neck regions 1, 2
• Median tumor size: 4.0 cm at diagnosis 1
• Age range: 27-73 years (mean 46 years), though rare pediatric cases exist 3, 4
• Presenting symptoms: Painless mass, with occasional peripheral nerve symptoms if neural structures involved 3

Diagnostic Work-Up

The diagnosis requires histopathologic confirmation with immunohistochemistry, and malignancy should be suspected when any mitotic activity, nuclear pleomorphism, or necrosis is present, even without documented metastases. 2, 3

Essential Diagnostic Steps:

Tissue Diagnosis:

• Fine-needle aspiration or core needle biopsy showing large polygonal cells with abundant granular eosinophilic cytoplasm and eccentric nuclei 2
• Immunohistochemistry: S-100 protein (positive in 100%), neuron-specific enolase (positive), CD68 (positive in 78%), and vimentin (positive) 2, 3
• Electron microscopy demonstrates abundant intracytoplasmic autophagic vacuoles/lysosomes 2, 3

Histologic Criteria for Malignancy (≥3 features):

• Nuclear pleomorphism with vesicular nuclei and prominent nucleoli 3
• High nuclear-to-cytoplasmic ratio 3
• Mitotic activity >5 per 50 high-power fields (modified criterion) 3
• Tumor necrosis 2, 3
• Spindling of tumor cells 3
• Multinucleated tumor cells (rare variant) 3

Critical Pitfall: Some tumors appear histologically benign but behave malignantly—diagnosis relies on clinicopathologic correlation including aggressive local recurrence and destruction of neighboring structures. 2, 3

Staging Evaluation:

Preoperative imaging to identify occult metastatic disease:

• MRI and CT scan of the primary site and regional lymph nodes 5
• CT chest/abdomen/pelvis to evaluate for distant metastases 5
• Regional lymph node metastases occur in 12.5% and distant metastases in 11.4% of cases 1
• Metastases most commonly involve lymph nodes and lungs, presenting 3-37 months after initial treatment 5

Management

Wide local excision with regional lymph node dissection is the definitive treatment and the only intervention proven to improve survival. 3, 1

Surgical Approach:

• En bloc wide excision with negative margins is mandatory 5
• Regional lymph node dissection should be performed if nodes appear suspicious on imaging or physical examination 5
• Patients undergoing surgery have dramatically superior survival compared to those who do not (HR = 0.13; 95% CI: 0.05-0.34) 1
• Radical subtotal debulking may be necessary for tumors involving critical structures 2

Adjuvant Therapy:

Radiotherapy may be considered for:

• Incomplete resection margins 2
• Locally advanced disease with invasion of neighboring structures 2

Chemotherapy and radiotherapy have NOT been shown to significantly improve clinical outcomes or survival. 3

Follow-Up Recommendations

Lifelong surveillance is mandatory, as local recurrence occurs in 71% of cases and metastases can develop years after initial treatment. 3, 5

Surveillance Protocol:

First 3 years (highest risk period):

• Clinical examination every 3 months 3
• CT chest/abdomen/pelvis every 6 months 5
• Local recurrence within 1 year is characteristic of malignant behavior 4

Years 3-10:

• Clinical examination every 6 months 3
• CT imaging annually or as clinically indicated 5

Beyond 10 years:

• Annual clinical examination indefinitely, as metastases can present up to 37 months or longer after initial treatment 5

Prognostic Factors:

Poor prognostic indicators:

• Tumor size >5 cm (HR = 34.03; 95% CI: 2.57-450.17) 1
• Presence of metastases (HR = 15.25; 95% CI: 1.19-195.72) 1
• Local recurrence indicates aggressive biology 3

Overall survival:

• 5-year cause-specific survival: 74.3% 1
• 10-year cause-specific survival: 65.2% 1

Critical Management Pitfall:

Do not rely solely on histologic appearance to exclude malignancy—aggressive clinical behavior (persistent local recurrence, destruction of neighboring structures) should prompt treatment as malignant disease regardless of benign-appearing histology. 2, 3