pleomorphic carcinoma is an aggressive tumour initially described in the lung by nash and stout . in the 4th edition of the world health organization
( who ) classification of tumours of the lung , pleomorphic carcinoma is defined as a poorly differentiated ( squamous cell carcinoma or adenocarcinoma ) or undifferentiated carcinoma in which at least 10% spindle and/or giant cells are identified , or as a carcinoma constituted purely of spindle and giant cells .
primary sites of occurrence of extrapulmonary pleomorphic carcinomas have been described in other organs such as the stomach , thyroid , gallbladder , pancreas , kidney , liver , bladder , and colon . to the best of our knowledge , only one report described a case of giant cell carcinoma of the colon resembling that observed in the lung .
based on the recommendations of the nomenclature committee on cell death , mitotic catastrophe is defined as a tumour - suppressive mechanism occurring during or after aberrant mitosis leading to cell death or cell senescence .
histological patterns of micro- and multinucleation have been used as morphological markers for the detection of mitotic catastrophe [ 5 , 6 ] . a high frequency of multinucleated giant cells is characteristically found in pleomorphic carcinomas . in this report , we present an additional case of primary pleomorphic carcinoma of the colon , and we underline similarities to and differences from pulmonary pleomorphic carcinoma .
the possibility of the pleomorphic component as morphological expression of mitotic catastrophe is finally discussed .
a 65-year - old caucasian woman with a medical history of hypercholesterolaemia , chronic obstructive pulmonary disease , and paroxysmal tachycardia was admitted to the surgery unit of the university hospital  g. martino ( messina , italy ) in 2013 for abdominal obstructive symptoms ( colicky pain to the right iliac fossa as well as borborygmi ) , change in bowel habits ( diarrhoea ) , asthenia , and severe weight loss since 6 months .
there was no nausea or vomiting . on physical examination , a globular and tympanic abdomen , painless at superficial and deep palpation , was evident .
she reported a history of adequate food intake with regular bowel habits , alcohol consumption ( < 20/30 g daily ) , and smoking .
there was no family history of gastrointestinal malignancy , although familiality for bladder carcinoma was reported .
abdominal ultrasonography highlighted an exophytic / stenosing mass at the level of the ascending colon .
afterwards , colonoscopy also revealed an exophytic / stenosing malignant neoplastic mass in the caecum , subsequently confirmed through histological evaluation of biopsy .
carcinoembryonic antigen ( value for smokers < 10.0 ng / ml ) and carbohydrate antigen 19 - 9 ( value < 35 iu / ml ) were within normal limits .
a contrast - enhanced computed tomography scan showed no evidence of liver or distant metastases .
routine haematoxylin - eosin sections were made from formalin - fixed , paraffin - embedded tissue .
sections were also stained with periodic acid - schiff and alcian blue at ph 2.5 .
additional sections  collected on silanized , coated slides  were used for the immunohistochemical stains , using the dako envisiontm flex , high ph detection system together with autostainer instruments .
the commercial source , clone , and dilution of the primary antibodies are detailed in table 1 .
macroscopic examination of the resected colon revealed an endophytic / ulcerative lesion measuring 7 cm in its greatest dimension , invading the caecum nearly to the ileocaecal valve .
microscopically , the tumour was a poorly differentiated adenocarcinoma with a grade 4 pleomorphic component that occupied up to 10% of the whole tumour section .
the pleomorphic component showed trabeculae and nests of neoplastic cells possessing eosinophilic cytoplasm , as well as irregularly shaped vesicular nuclei with a single large eosinophilic nucleolus .
giant cells containing multiple nuclei , micronuclei , and prominent eosinophil nucleoli were also found ( fig . 
the micronuclei appeared as round chromatin fragments with a diameter less than one third of the diameter of the nucleus .
1b ) and large geographical necrotic areas with sharp boundaries with respect to the viable tumour tissue ( fig . 
only 1 out of the 44 harvested perivisceral lymph nodes presented carcinomatous metastasis ( pt3 , pn1 , clinical stage in accordance to the 2009 ptnm system ) .
the histochemical stains were negative for periodic acid - schiff and alcian blue in all of the pleomorphic neoplastic cells .
on the immunohistochemical stains , these cells were diffusely and strongly positive for ceap , ckae1/ae3 , ck7 , and vimentin , but they were negative for ck20 , smooth muscle actin , desmin , synaptophysin , and -human chorionic gonadotropin .
2b ) , whereas p53 labelling was shown in more than 90% of the tumoural nuclei ( fig . 
we described a rare case of pleomorphic carcinoma of the right colon showing opposing clinicopathological features . although it was classified as a grade 4 tumour , it was characterized by a pushing growth pattern and presented only one lymph node with metastasis .
these data confirm that classic grading of colorectal carcinoma is insufficient to predict a prognosis , and that further parameters such as growth patterns are needed .
accordingly , several recent studies have shown that colorectal carcinomas with pushing margins are associated with superior disease - free survival rates when compared with tumours with infiltrative margins .
the present tumour had some of the morphological features described in giant cell carcinoma of the lung , such as pleomorphic tumour cells , malignant giant cells , atypical mitoses , and coagulative necrosis .
however , pleomorphic carcinoma of the lung has been reported to have a poor prognosis , whereas in our case , the patient has been well without evidence of recurrence or metastases 2 years after the operation .
many studies suggested that pleomorphic tumours are a heterogeneous group of neoplasms arising in different anatomical sites ( e.g. lung , uterus , breast , central nervous system ) characterized by variable morphological features and prognoses [ 8 , 9 , 10 , 11 ] .
in particular , a certain percentage of patients affected by them were found to be long - term survivors despite the anaplastic morphology of their primary neoplasms [ 8 , 10 , 11 ] .
the differential diagnosis of pleomorphic carcinoma includes adenocarcinoma with a choriocarcinomatous component as well as mixed adenoneuroendocrine carcinoma [ 7 , 12 , 13 ] .
a choriocarcinomatous component usually is characterized by immunoreactivity to -human chorionic gonadotropin , which was not found in our case , while the latter was excluded by the lack of expression of neuroendocrine markers such as synaptophysin and chromogranin [ 12 , 13 ] . in our case , multinucleated tumour cells contained not only abnormally large giant nuclei but also those that are abnormally small , in the form of micronuclei .
the presence of micronuclei is usually overlooked in the reports of pleomorphic carcinoma in the current literature .
micronuclei derive from chromosomes and/or chromosome fragments that have been irregularly distributed between daughter nuclei after abnormal mitosis . besides micronucleation and multinucleation ,
we interpret these findings as a morphological expression of mitotic catastrophe , a particular type of cell death occurring in tumour cells after aberrant mitosis [ 5 , 6 , 14 ] .
after mitotic catastrophe , tumour cells may continue to divide and thus develop polyploidy and/or aneuploidy .
ki-67 is an antigen of cell proliferation frequently used in routine histopathological diagnostics as a prognostic factor in more malignancies .
specifically , it is an epitope of a nuclear and nucleolar protein of 360 kda only expressed in nuclei of cells in active proliferation , i.e. during cell cycle phases g1 , s , g2 , and m , but not in the quiescent phase , i.e. in cell cycle phase g0 [ 17 , 18 ]
. normally , p53 acts as a guardian of the genome , protecting cells against cancer via two main ways : by determining cell cycle arrest at g1 and g2/m and by inducing cellular apoptosis [ 19 , 20 ] .
nuclear p53 immunohistochemical positivity in tumour cells suggests mutation in the p53 gene [ 21 , 22 ] .
thus , immunohistochemical overexpression of p53 and ki-67 constitutes further evidence of mitotic catastrophe in the pleomorphic component of our case of colonic neoplasm .
ionizing radiation and different classes of cytotoxic agents induce cell death through mitotic catastrophe [ 15 , 18 ] .
histological recognition of mitotic catastrophe could be useful to predict an eventual pharmacological modulation ( induction or inhibition ) of tumour cell death .
therefore , mitotic catastrophe has recently gained attention as a potential therapeutic target in neoplasms [ 23 , 24 , 25 ] . in summary , we reported a case of colorectal carcinoma with clinicopathological features partially similar to pleomorphic cell carcinoma of the lung , a neoplasm associated with a bad prognosis . in particular , this tumour presented only one lymph node with metastasis , and the patient is still well 2 years after the operation .
this case presented morphological and immunohistochemical features compatible with mitotic catastrophe , a form of non - apoptotic cell death due to aberrant mitosis .
the inclusion of mitotic catastrophe as part of a microscopic evaluation may be useful for understanding the pathogenesis of this rare entity and for new cancer treatment modalities .
no further ethical approval was necessary to perform histology and immunohistochemistry in the case included in this report .
 pleomorphic carcinoma is an aggressive neoplasm defined by the world health organization ( who ) as a poorly differentiated ( squamous cell carcinoma or adenocarcinoma ) or undifferentiated carcinoma in which at least 10% spindle and/or giant cells are identified , or as a carcinoma constituted purely of spindle and giant cells . 
 although this entity has initially been shown in the lung , it has been described also in extrapulmonary locations , with only one report for a colonic site . a 65-year - old woman developed a caecal tumour . 
 gross examination revealed an endophytic / ulcerative mass 7 cm in length . 
 microscopically , the tumour was a poorly differentiated adenocarcinoma with a pleomorphic component that occupied more than 10% of the specimen . 
 the tumour shared these histopathological findings with pulmonary giant cell carcinoma but differed in other clinicopathological features such as a pushing growth pattern , stage pt3n1 , and an uneventful outcome 24 months after operation . 
 the pleomorphic component showed morphological and immunohistochemical features compatible with mitotic catastrophe , a non - apoptotic cell death occurring in cycling cells after aberrant mitosis . 
 these features included multinucleation , micronucleation , atypical mitoses , foci of geographic necrosis , as well as immunohistochemical overexpression of p53 and ki-67 . 
 the interpretation of the pleomorphic component as morphological expression of mitotic catastrophe may be useful in comprehending the pathogenesis of this rare neoplasm , and it may have practical implications as a potential cancer therapeutic target . 
Introduction
Case Report
Materials and Methods
Gross Pathology and Histopathology
Discussion
Statement of Ethics
Disclosure Statement