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Ultrastruct Pathol, 35(2), 66–71, 2011
Copyright © 2011 Informa Healthcare USA, Inc.
ISSN: 0191-3123 print/ 1521-0758 online
DOI: 10.3109/01913123.2010.543753
Original Article
Mitotic Catastrophe in Malignant Epithelial Tumors:The
Pathologist’s Viewpoint
Rosario Caruso, MD1, Francesco Fedele, MD1, Roberta Lucianò, MD1, Giovanni Branca, MD1,
Claudia Parisi, MD1, Domenica Paparo, MD2, and Antonino Parisi, MD2
Department of Human Pathology, University of Messina, Messina, Italy, and 2Department of Surgical Sciences,
University of Messina, Messina, Italy
1
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Abstract
Mitotic catastrophe is a common phenomenon occurring in tumor cells with impaired p53 function exposed to
various cytotoxic and genotoxic agents. The defective p53 checkpoint causes improper segregation of chromosomes, resulting in aberrant mitosis, multiple micronuclei, multinucleate giant cells, and eventual necrosis-like
death and centrosome aberration. Although various descriptions explaining mitotic catastrophe exist, there is
still no generally accepted definition of this phenomenon. However, the syndrome of mitotic catastrophe may
be a unifying morphological concept of particular interest to cancer research, as it integrally links cell death
to checkpoints of the cell cycle. Morphological findings compatible with mitotic catastrophe may be found in
pleomorphic, giant cell carcinomas—neoplasms characterized by a poor prognosis. The inclusion of mitotic
catastrophe as part of the microscopic evaluation of tumors will add further insight to the pathobiology of
tumor progression and in novel therapeutic designs. Finally, the possibility of assimilating mitotic catastrophe
into a prognostic score is discussed.
Keywords: Electron microscopy, Human carcinomas, Immunohistochemistry, Mitotic catastrophe
inflammation [3]. Unlike in apoptosis, chromatin is
not packed into discrete membrane-bound particles,
but forms many unevenly textured and irregularly
shaped clumps, a feature that is being used for differentiating between the two modes of cell death [3].
The mitochondria undergo inner membrane swelling,
cristeolysis, and disintegration. Dilation and fragmentation of the cisterns of rough endoplasmic reticulum
and Golgi apparatus are frequently observed. From
a histological viewpoint, various morphological
forms of tissue necrosis exist. In coagulative necrosis,
denaturation of intracytoplasmic protein is the dominant process. In hematoxylin–eosin-stained sections,
coagulative necrosis appears acellular and stains
homogeneously with red eosin. Careful examination,
however, shows retention of the general architectural
pattern of the tissue, despite the death of its constituent elements. Coagulative necrosis is also characterized by abrupt transition from viable cells to necrotic
cells without an interposed zone of granulation tissue or hyalinized tissue between viable and necrotic
cells. After a period of time, this pattern is replaced by
colliquative necrosis, in which the cellular structures
The number of ways in which cells die is broadly
characterized into apoptosis and necrosis. The term
“apoptosis” has been coined by Kerr et al. [1] to
describe a specific morphological aspect of cell death.
Apoptosis is accompanied by rounding-up of the
cell, retraction of pseudopods, reduction of cellular
volume (pyknosis), chromatin condensation, nuclear
fragmentation (karyorrhexis), classically little or no
ultrastructural modifications of cytoplasmic organelles, plasma membrane blebbing (but maintenance
of integrity until the final stages of the process), and
engulfment by resident phagocytes (in vivo) [1,2].
Factors contributing to necrosis are mostly extrinsic
in nature, such as osmotic, thermal, toxic, hypoxic–
ischemic, and traumatic insults. The morphology of a
necrotic cell is very distinct from that of a cell undergoing classic apoptosis, with ultrastructural changes
occurring in both the cytoplasm and the nucleus. The
main characteristic features are chromatin flocculation,
swelling and degeneration of the entire cytoplasm
and the mitochondrial matrix, blebbing of the plasma
membrane, and eventual shedding of the cytoplasmic
contents into the extracellular space with subsequent
Received 16 November 2010; accepted 23 November 2010
Correspondence: R. A. Caruso, MD, Dipartimento di Patologia Umana, Policlinico Universitario, I-98125 Messina, Italy. E-mail: rosariocaruso@
tin.it
66
67 R. Caruso et al.
are broken down by proteolytic enzymes released from
ruptured lysosomes and similar enzymes released by
infiltrating inflammatory cells [4].
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Epithelial Neoplasias
Characterized by Coagulative
Necrosis
Tumor necrosis has garnered increased attention over
the last few years, in part because a number of studies
have now shown that tumor necrotic tissue represents
a significant prognostic marker with an independent
influence on metastasis-free survival in patients with
neoplasm. Tumor necrosis has been extensively studied in kidney [5–7], breast [8–12], lung [13], thyroid
[14], gastric [15], and colorectal carcinomas [16]. Recent
studies suggest that surgical pathologic evaluation of
tumor necrosis should routinely record its presence
or absence [5–7,12,16]. Such an assessment is easily
performed through routine histologic evaluation
with reasonably high rates of reproducibility among
pathologists.
In invasive carcinoma of the breast, necrosis has
been shown to correlate with increased tumor size,
high-grade disease, microvessel density, macrophage
infiltrates, high proliferative fraction, decreased relapsefree survival, and a poor prognosis. More recently,
extensive central necrosis has been reported as a common morphological feature of the tumors belonging to
the molecular class of basal-like breast cancers [8,9,12].
Recent studies suggest that the presence of tumor
necrosis provides information, in addition to routinely
reported prognostic factors [11]. Tumor necrosis is
associated with a poorer outcome irrespective of histologic grade, and, indeed, all grades had similarly poor
outcomes in the presence of tumor necrosis. Instead,
in the absence of tumor necrosis, patients with grade
3 tumors had poorer outcome than those with grade
1–2 tumors [11]. These results suggest that the presence of tumor necrosis identifies a biologically distinct
subgroup within breast cancer and that the difference
is important in determining the efficacy of standard
chemotherapy and endocrine therapy [11].
Nonapoptotic Tumor Cell Death
In addition to apoptosis and necrosis, various models
of tumor cell death have been proposed, including
paraptosis, autophagy, and mitotic catastrophe. Thus,
tumor cells can die by manifesting massive autophagy
(sequestration of large parts of the cytoplasm in
autophagic vacuoles, often before the cells undergo
apoptosis) [3], as a result of paraptosis (a process of
swelling and vacuolization that begins with physical
enlargement of the endoplasmic reticulum and the
mitochondria) [17] or by mitotic catastrophe.
Definition of Mitotic Catastrophe
It should be noted that there is still no consensus definition
of mitotic catastrophe. Due to this, there are disagreements
and uncertainties about the precise causes, mechanisms,
and outcomes of mitotic catastrophe. Some authors have
considered mitotic catastrophe as a state generally, but not
necessarily, associated with cell death as an outcome [18].
Alternatively, mitotic catastrophe has been classified not
as a mode of cell death but as a special example of apoptosis [19]. Other groups have presented evidence indicating that death-associated mitotic catastrophe is not a
separate mode of cell death, rather a process (“prestage”)
preceding cell death, which can occur through necrosis or
apoptosis [20]. Mitotic catastrophe has also been depicted
as the main form of cell death induced by ionizing radiation [21,22]. As pathologists, we prefer a morphological
definition of mitotic catastrophe [23]. Therefore, in this
review, mitotic catastrophe is defined as a cell death mode
occurring after a dysregulated/failed mitosis, which can
be accompanied by morphological alterations, including
micronucleation (which often results from chromosomes
and/or chromosome fragments not being distributed
evenly between daughter nuclei) and multinucleation (the
presence of two or more nuclei with similar or heterogeneous sizes, deriving from a deficient separation during
cytokinesis) [3,23]. Multinucleated, bizarre giant cells
can be seen in benign (e.g., symplastic leiomyoma of the
uterus) or malignant conditions, including carcinomas,
sarcomas, and lymphomas [24]. In this review, however,
we focus only on the relationship between mitotic catastrophe and malignant epithelial tumors.
Detection Methods of Mitotic
Catastrophe
According to the recommendations of the Nomenclature
Committee on Cell Death [25], the definition of cell death
must be based on precise terms of the parameters that
describe the presumed cell death pathway involved.
Electron microscopy is the gold standard for detection
of these types of cell death [25]. It is now agreed that a
rational combination of at least two techniques should
be utilized, one to visualize morphological changes and
the second to determine biochemical changes, when the
modes of cell death are asserted [25]. Therefore, at present morphological detection methods of mitotic catastrophe include light and electron microscopy as well as
immunohistochemical markers (p53, Ki-67, pericentrin,
gamma-tubulin).
p53
In response to a range of stresses, including DNA damage, hypoxia, or proliferative signals, p53 stabilizes, causing cells to undergo either cell-cycle arrest or apoptosis
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Mitotic Catastrophe in Malignant Epithelial Tumors 68
[26]. Thus, p53 acts as a “guardian of the genome” in
protecting cells against cancer [26]. Following severe
genotoxic damage, many p53-mutated tumors undergo
mitotic catastrophe. This type of delayed cell death is
thought to represent an alternative to immediate, interphase death through apoptosis [20]. Cell death with an
apoptotic phenotype occurs in p53 wild-type cells and
is deregulated in many cancers [26]. Although the gene
encoding p53 is found mutated in more than 50% of all
types of human cancers, mitotic catastrophe has been
overlooked until now. Cells lacking p53 function also
lack G2 checkpoint function [26]. This is an important
fact for cancer treatment outcome as >50% of human
tumors (especially solid tumors) are p53 nonfunctional
and, thus, lack G2 checkpoint surveillance and are often
resistant to cytotoxic and genotoxic treatments. Thus,
the ultimate goal of eradicating cancer by subjecting
patients to surgical intervention and rounds of radiation and/or chemotherapeutic agent treatments might
be compromised by the tumor response to these later
treatments. Basically, alterations in p53 can be analyzed
by mutation analysis or immunohistochemical staining.
Mutations in the TP53 gene can result in either the production of a stable p53 protein, which can be detected
immunohistochemically, or production of truncated
p53 protein. The latter type of mutations (null mutations) will result in false-negative immunohistochemical
staining for the p53 protein and lead to the erroneous
conclusion that no mutation is present [27]. Therefore,
immunohistochemical staining of p53 suffers both falsenegative and false-positive results, compared with p53
gene sequencing, so introduction of additional immunohistochemical parameters can be expected to increase
precision.
Ki-67 Immunohistochemistry
Ki-67 is a nuclear protein that has demonstrable utility
as a prognostic marker for several malignancies [28].
Ki-67 is an enormous protein (nearly 360 kDa), encompassing one of the most uniformly and tightly regulated
proteins expressed within proliferating eukaryotic cells
(cell cycles G1, S, G2, and M), but not quiescent cells
(cell cycle G0). Ki-67 is widely accepted as a reliable
indicator of cell proliferation within various human tissues, including various forms of cancer. Consequently,
Ki-67 has been routinely exploited to assess tumor cell
proliferation to gauge the aggressiveness as well as
responsiveness to therapy of multiple human malignancies [28].
Role of Centrosomes in Mitotic
Catastrophe
The centrosome is a fascinating organelle that resides
near the cell center—hence, its name. The interphase
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centrosome consists of a pair of orthogonally oriented
centrioles surrounded by a pericentriolar matrix.
Although pericentriolar material contains hundreds of
proteins, gamma-tubulin and pericentrin are the two
classical markers of the centrosome where they have
specific localizations [29]. The role of centrosomes in a
wide range of tumor types has been investigated and
centrosome aberration (supernumerary and structurally
altered centrosomes) may play a potentially causative
role in malignant progression. Some researchers have
found centrosome defects in a significant fraction of
precursor lesions, including in situ carcinomas of the
uterine cervix, prostate, and female breast, by detecting
centrosomes proteins, pericentrin, and gamma-tubulin
using immunohistochemistry [30–32]. Lingle et al. [33]
reported detailed morphological abnormalities in cancer cells, such as supernumerary centrioles, excess pericentriolar material, disrupted centriole barrel structure,
unincorporated microtubule complexes, centrioles of
unusual length, and mispositioned centrosome. Lingle
et al. [33] suggested that differentiated tumors have
centrosomes that may be mislocated, as in tumors with
inverted cell polarity. Centrosome abnormalities are
characteristic of poorly differentiated anaplastic tumors
[33]. The presence of excess pericentriolar material was
associated with the highest frequency of abnormal
mitoses as assessed by Ki-67 immunolabeled paraffin
sections of the same tumors [33]. Centrosome abnormalities may result in multipolar spindles, which cause
abnormal chromosome segregation and may generate
cells with micronuclei and multinucleated giant cells,
which are characteristically found in mitotic catastrophe
[34,35]. Thus, the study of mitotic catastrophe in human
carcinomas should also include electron microscopy
and immunohistochemistry (pericentrin and gammatubulin) of centrosomes.
Ultrastructural Definition of
Micronuclei, Nuclear Blebs, and
Strings
The nuclei of the cells of most solid tumors in histopathologic preparations vary in size, shape, and chromatin pattern, both from normal nuclei and from each
other. Nevertheless, only a few attempts have been
made to classify abnormalities in the morphology of
interphase nuclei. The study of Gisselsson et al. [36,37],
on primary cultures of solid tumors, suggested a rough
classification into three types: nuclear strings, nuclear
blebs, and micronuclei. In that study, a nuclear string
was defined as a chromatin thread connected to the
membrane(s) of one or two nuclei, a nuclear bleb as
a round or oval protrusion of the nuclear membrane
connected to the main part of the nucleus by a thinner
chromatin segment, and a micronucleus as a rounded
chromatin located adjacent to a nucleus, with a diameter
not exceeding one-third of the diameter of that nucleus
69 R. Caruso et al.
[37]. Nuclear heterogeneity has been documented by
Fenech et al. [38] in normal and folate-deprived cultures
of human lymphocytes. In addition to micronuclei, they
describe nuclear buds and nucleoplasmic bridges, which
are synonymous with the nuclear blebs and strings
of Gisselsson’s study [37], respectively. Some studies
suggest that nuclear blebs might be converted into
micronuclei during interphase [39]. According to Utani
et al. [40], micronuclei and nuclear buds are important
indicators for genome instability.
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Pleomorphic, Giant Cell
Carcinoma
Morphologic features compatible with mitotic catastrophe can be seen in pleomorphic, giant cell carcinoma:
a tumor lacking any identifiable glandular, squamous,
or any other type of differentiation. In fact, it consists
of sheets of highly undifferentiated pleomorphic cells,
often with areas of necrosis. There may be numerous bizarre/multinucleated cells. Mitotic figures are
numerous with many being abnormal. Areas of more
differentiated carcinoma can be seen in association with
anaplastic areas. Pleomorphic, giant cell carcinomas are
usually highly aggressive malignant tumors that are
widely found, but most commonly in the lungs, breast
[41,42], pancreas, and thyroid [24].
blebs and strings. Pale, swollen nuclei could be seen
in some multinucleated giant cells, suggesting an
association with nonapoptotic necrosis-like features
(Figure 1b).
We also reported a case of pleomorphic, giant cell
carcinoma of the stomach (Figure 2) that showed a
pleomorphic population of tumor cells with multinucleated giant cells and focal areas of tissue necrosis
(less than 5% of the tumor) [44]. Multipolar, atypical
mitoses were frequent (Figure 2). There was p53 and
Ki-67 immunohistochemical overexpression. In 3 other
cases, we have studied gastric neoplasms consisting of
uniform tumor cells arranged in a trabecular or solid
pattern with extensive tissue necrosis (more than 40%
of tumor area) (Figures 3a, 3b) [15]. Bizarre, giant cells
were often observed singly or in small groups among
the trabecular areas. p53 and Ki-67 were overexpressed
(Figure 3c), and multipolar mitoses were also seen
(Figure 3b). These preliminary data suggest a variable
expression of necrotic phenomena in gastric carcinomas,
emphasizing the need for further research.
Our Experience
Recently, we reported a case of a 70-year-old woman
with an anaplastic giant cell thyroid carcinoma, along
with immunohistochemical and electron microscopic
findings [43]. In addition to coagulative necrosis as well
as nuclear overexpression of p53 and Ki-67, the tumor
was characterized by atypical mitoses and mononucleated and multinucleated giant cells (Figure 1a).
Tumor cell nuclei showed heterogeneous size ranging from micronuclei to large-size (giant) nuclei.
Micronuclei were confirmed by electron microscopy
(Figure 1b) that also showed the presence of nuclear
A
B
Figure 2 Anaplastic giant cell carcinoma of the stomach.
Solid sheet of poorly cohesive mononucleated and multinucleated giant cells. Note the presence of mitotic multipolarity.
Semithin section, Giemsa ×400.
C
FIGURE 1 Anaplastic giant cell carcinoma of the thyroid. (a) Some multinucleated giant tumor cells contain a pale
swollen nucleus. Semithin section, Giemsa ×400. (b) Anaplastic carcinoma cell showing multiple nuclei and micronuclei
(curved arrow). Note the presence of a pale, swollen nucleus with necrosis-like features (arrow). ×10,000. (c) Anaplastic
carcinoma cell characterized by nuclear blebs (arrows) and a micronucleus (double arrow). ×10,000.
Ultrastruct Pathol
Mitotic Catastrophe in Malignant Epithelial Tumors 70
A
B
C
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Figure 3 Gastric carcinoma with a solid growth pattern. (a) Peritheliomatous pattern of necrosis characterized by sheath
of viable tumor cells surrounding a centrally disposed blood vessel. H & E ×100. (b) Uniform large tumor cells arranged
in solid pattern. Note the presence of tripolar mitosis. H & E ×400. (c) Abnormal mitotic figures decored by Ki-67 immunostaining (arrows). Coagulative necrosis is associated with a large population of Ki-67 immunoreactive cycling tumor
cells. ×200.
They also reflect the uncertainties about the precise
causes and mechanisms of mitotic catastrophe. In fact,
as reported above, mitotic catastrophe has also been considered as a state generally, but not necessarily, associated with cell death as an outcome. Moreover, there are
several problems in the identification of mitotic catastrophe in carcinoma tissue samples. One of these is the percentage of pleomorphic giant cells in tumor tissue. For
example, breast carcinomas are classified according to
WHO as pleomorphic, if characterized by proliferation
of pleomorphic and bizarre tumor giant cells comprising more than 50% of the total neoplastic proliferation
in a background of adenocarcinoma with spindle and
squamous differentiation [43,44]. If a breast carcinoma
shows less than 50% of pleomorphic giant cells, can it
still be considered a morphological expression of mitotic
catastrophe? Thus, the application of the mitotic catastrophe concept in histopathology could be considered a
work in progress, and, in addition, efforts to improve the
existing schemes are obviously necessary. In particular,
it is important to define the cutoff values of percentage
of pleomorphic giant cells and tumor necrosis.
Implications and Perspective
The term mitotic catastrophe refers to a syndrome characterized by a constellation of morphologic features,
including multinucleation, micronucleation, abnormal
mitoses, centrosome aberration, tissue necrosis, as well
as p53 and Ki-67 overexpression. Features compatible
with mitotic catastrophe may be found in pleomorphic
giant cell carcinoma of the thyroid, lung, pancreas, and
stomach. Probably, they may also be demonstrated in
aggressive, high-grade breast carcinomas (basal-like carcinomas) and in grade 4 undifferentiated carcinomas. We
think that mitotic catastrophe may be a unifying concept
useful for studying the extreme end of the morphological spectrum of grades in infiltrating carcinomas in order
to identify a distinct, although rare, subgroup within
carcinomas, characterized by unfavorable prognosis.
Therefore, we suggest that the presence or absence of
© 2011 Informa Healthcare USA, Inc.
mitotic catastrophe, as defined in previous reports and
in the current paper, becomes assimilated into a score
that gives more precise prognostic information.
ACKNOWLEDGMENT
Declaration of interest: The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of the paper.
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