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1. Introduction
Recent studies have shown that tumor necrosis (TN) influences metastasis-free survival in patients exhibiting neoplasms (1,2). In particular, TN has been reported to indicate poor prognosis in lung (3), breast (4,5), thyroid (6), colorectal (7,8), pancreatic (9) and renal (10–16) malignancies. Therefore, it has been proposed that the presence/absence of TN must be indicated in any histopathological report (12,14), as this type of assessment has a high rate of reproducibility among pathologists (9,12).
It is generally accepted that TN is a result of chronic ischemic injury due to rapid tumor growth. Jain and Carmeliet (17) suggested that intratumoral mechanical stresses, resulting from tumor cell proliferation, cause focal large-vessel obstruction, leading to ischemic intratumoral infarcts. The compression, exerted by surrounding neoplastic cells on the microvasculature, is considered to be spatially and temporally heterogeneous (18) and this may explain the uneven distribution of TN. However, whether insufficient tumor vascularization and inadequate tumor cell oxygenation are the only factors causing TN remains controversial. We hypothesize that hypoxia may indirectly induce coagulative necrosis in tumor cells harboring p53 mutations via mitotic catastrophe. Mitotic catastrophe is a cell death mechanism, which occurs as a result of dysregulated/failed mitosis that may be accompanied by morphological alterations, including micronucleation, multinucleation and abnormal mitoses.
In this review, the morphologic features of TN in malignant epithelial tumors are investigated. In addition, the associations between hypoxia, mitotic catastrophe and TN are briefly reviewed within the framework of our hypothesis.
2. Definition of apoptosis and TN
Depending on the lethal stimulus, tumor cells may die as a result of distinct cellular death mechanisms, including apoptosis and necrosis. The term ‘apoptosis’ was coined by Kerr et al (19) to distinguish the phenomenon as a mechanism of cell death that is morphologically separate from coagulative necrosis. Ultrastructural features of apoptosis include margination and condensation of chromatin, nuclear fragmentation in apoptotic bodies (corresponding to the histological terms, pyknosis and karyorrhexis), and ruffling of the plasma membrane, which maintains integrity until the final stages of the process (19–21). Phagocytosis of apoptotic bodies is carried out by professional phagocytes, including macrophages and dendritic cells, and non-professional ‘neighboring’ phagocytes, including epithelial cells, endothelial cells, smooth muscle cells and fibroblasts. By contrast, necrosis is characterized by cellular swelling, which is...