Benign Tumors That Metastasize

1. Giant Cell Tumor (GCT) of Bone

• Histologically benign (osteoclast-type giant cells, no significant atypia)
• Can metastasize to the lungs in ~2-3% of cases, even after histologically confirmed benign primary tumor
• Pulmonary metastases are typically well-circumscribed nodules and can occasionally undergo spontaneous regression
• Behavior is locally aggressive (cortical destruction, soft tissue extension) but pulmonary mets usually follow benign clinical course
• Risk factors for pulmonary metastasis include local recurrence and distal radius location

2. Benign Metastasizing Leiomyoma (BML)

• A rare disease of premenopausal women with prior uterine leiomyomas (most have had myomectomy or hysterectomy)
• Characterized by noninvasive, well-circumscribed smooth muscle tumors at extrauterine sites - identical histology to ordinary uterine leiomyoma
• Most common sites: lungs (most frequently), lymph nodes, mediastinum, retroperitoneum, bone, heart, spine, pancreas, skeletal muscle
• Pulmonary BML: usually asymptomatic, found incidentally as single or multiple lung nodules on CT/CXR
• First described in 1939; >100 cases reported worldwide
• Pathogenesis debated - likely hematogenous spread from uterine leiomyoma, possibly facilitated by surgical disruption
• Estrogen-sensitive: treatment is estrogen deprivation - oophorectomy or GnRH agonists (e.g., leuprolide acetate); tumors regress post-menopause
• PET-FDG is low-uptake (low glycolytic activity), unlike leiomyosarcoma - useful in differential

3. Metastasizing Pleomorphic Adenoma (MPA) of Salivary Gland

• The rarest form of "malignant mixed tumor" (along with carcinoma ex pleomorphic adenoma and carcinosarcoma)
• Histologically identical to benign pleomorphic adenoma - bland myoepithelial and ductal cells in myxoid/chondroid matrix, NO cytologic atypia, NO significant mitoses
• Despite this, metastasizes to:
  • Local lymph nodes (30%)
  • Bone (50%)
  • Lung (30%)
• Usually preceded by multiple local recurrences at the primary (parotid) site
• Mean time from primary tumor to metastasis detection: ~12 years
• Prognosis: approximately 40% of patients die of disease
• The 2017 WHO classification grouped MPA with benign pleomorphic adenoma - this should NOT be taken to mean it is truly benign
• Clinical lesson: complete surgical excision of pleomorphic adenoma at first presentation is essential

4. Malignant Ameloblastoma

• Ameloblastomas that retain classic benign histopathologic features (no cytologic atypia, no increased mitoses) but metastasize to distant locations
• Distinguished from "ameloblastic carcinoma" which DOES show cytologic malignant features
• Metastases typically long delayed, sometimes appearing years after initial treatment
• Most common metastatic site: lungs; cervical lymph nodes also involved
• Treatment of metastases: surgical excision preferred; radiotherapy if surgery not feasible

5. Pheochromocytoma / Paraganglioma

• Histologically "benign"-appearing pheochromocytomas can metastasize - the only absolute criterion of malignancy is presence of tumor at sites where chromaffin tissue is normally absent (liver, lung, bone, lymph nodes)
• Histologic features (pleomorphism, mitoses, necrosis) are unreliable predictors
• Spindle cell morphology and confluent tumor necrosis are associated with aggressive behavior but not definitive
• ~10% of pheochromocytomas are malignant by this criterion
• Robbins: "Tumors with 'benign' histologic features may metastasize, while bizarrely pleomorphic tumors may remain confined to the adrenal gland"

6. Vascular Tumors (Hemangiomas - Epithelioid Subtype)

• Most hemangiomas are purely benign
• Epithelioid hemangioendothelioma represents a "locally aggressive neoplasm that rarely metastasizes" - occupying the gray zone between benign hemangioma and frank angiosarcoma
• The spectrum: hemangioma → epithelioid hemangioendothelioma → angiosarcoma

Summary Table