• Point mutations in the glycine 34 position in H3F3A have been reported in up to 96% of giant cell tumors of bone
• The most common mutation in these tumors, by far, is G34W (J Pathol Clin Res 2015;1:113, Nat Genet 2013;45:1479)
• These mutations affect histone methylation

Contributed by Jose G. Mantilla, M.D.

A radiolucent lesion in the mandible of a 38 year old man was biopsied and is shown in the image above. An H3.3 G34W immunohistochemical stain is negative. What is the correct diagnosis?

1. Central giant cell granuloma
2. Chondroblastoma
3. Conventional type osteosarcoma
4. Giant cell tumor of bone
5. Solid aneurysmal bone cyst

A. Central giant cell granuloma. Although this lesion has similar morphologic features to those of giant cell tumor of bone, it is an indolent lesion with different biological features. Its characteristic location and absence of G34W reactivity help support this diagnosis (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;118:583). Answer B is incorrect because the histologic features in the image are not representative of chondroblastoma, which is composed of cytologically bland, clear to epithelioid cells and may have a characteristic pattern of pericellular calcification. Giant cells are common. Answer C is incorrect because no features of malignancy are present in the image. Answer D is incorrect because giant cell tumor of bone has similar histologic features; however, most cases express G34W and typically arise in the epiphysis of long bones. Answer E is incorrect because although aneurysmal bone cysts may have prominent giant cells, the lesion lacks histologic features diagnostic of an aneurysmal bone cyst (e.g., aneurysmal spaces, characteristic myofibroblastic population).

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Reference: H3.3 G34W (H3F3A)

Which of the following diseases has been reported to harbor point mutations in the histone 3.3 genes?

1. Conventional type osteosarcoma
2. Epithelioid sarcoma, proximal type
3. Giant cell tumor of bone
4. Malignant peripheral nerve sheath tumor
5. Undifferentiated SMARCA4 deficient thoracic malignant neoplasm

C. Giant cell tumor of bone. Point mutations in H3.3 have been described in the majority of cases of giant cell tumor of bone and chondroblastoma (Nat Genet 2013;45:1479). Answers D, B and E are incorrect because although alterations in the polycomb repressive complex 2 (PRC2) complex genes (as seen in malignant peripheral nerve sheath tumor) and switch / sucrose nonfermenting complex (SWI / SNF) (seen in both epithelioid sarcoma and undifferentiated SMARCA4 deficient thoracic neoplasm) lead to alterations in histone methylation, these are not due to intrinsic mutations in the histone genes. Answer A is incorrect because conventional type osteosarcoma lacks recurrent genetic alterations.

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Reference: H3.3 G34W (H3F3A)