Histopathological Characteristics – Immediate Prognostic Factors for Left Colon Cancer

Introduction: Colorectal cancer represents the second leading cause of cancer mortality in our country, the survival rates being determined by the stage of the disease and the presence of metastases, being of 90% for early stages at 5 years, of 70% for the tumors with local invasion and of 10% in case of distal metastases. The aim of our study is to evaluate the prognosis of left colon cancer according to its histopathological characteristics. Material and methods: A number of 171 patients with left colon cancer (splenic flexure, descending colon, sigmoid colon and rectosigmoidian junction) were included in the study. The patients were admitted to the Surgical Unit of the Emergency Clinical Hospital of Bucharest between January 1 st 2015 – December 31st 2016. The histopathological analysis followed the norms of the Americal College of Pathologists, and the determination of tumor staging was done based on the TNM classi ﬁ cation. Results: Most patients are in the 3rd stage (65.5%) and in the 4th stage (19.3%) of cancer, only 2.3% being diagnosed in the 1st stage. A number of 36 patients present distal metastases, the most frequent location being in the liver (21 patients). 24% of the patients presented postoperative complications, while 2.3% died, without any differences determined by the presence of lymph nodes or distal metastases. Distal metastases are associated with the resistance environment (p=0.048), while the invasion of lymph nodes is signi ﬁ cantly higher (p=0.049) in patients with tubulovillous adenoma. The degree of differentiation of tumors differs signi ﬁ cantly from a statistical point of view (p=0.002), according to the histopathological type. Conclusions: The incidence of lymphatic metastases differs according to the histopathological type of the tumor, the tubulovillous adenoma being more frequently associated with lymphatic metastases; distal metastases are more frequently seen in patients in the rural areas, based on the low addressability and accessibility to medical services. The frequency of postoperative complications and nosocomial death is determined by the advanced stage of the disease (stages 3 and 4), as well as by the late arrival of the patient to the emergency room, especially patients with intestinal occlu-sion.

diff erentiation were defi ned according to the World Health Organization criteria, using the following categories: undiff erentiated, weak, medium and well-diff erentiated 12 . Th e perineural invasion (PNI) was defi ned based on the Betsakis criteria as the presence of tumor cells in any layer of the nervous sheath or groups of tumor cells which occupy more than 33% of the perineural space 13 . Lymphovascular invasion (LVI) was defi ned based on Sato and Washington criteria as the presence of tumor cells in the vascular space or the presence of erythrocytes or elastic lamina around the tumors 14 .

Statistical analysis
Th e results are presented as ranges, averages and standard deviations for the quantitative variables and as absolute frequencies for the qualitative variables. Th e comparison of averages for the continuous quantitative variables was performed using the parametric t test. According to the comparison between the data regarding patients with versus patients without lymph node metastasis, distal metastases respectively, the diff erence between proportions was tested using the chi-square test. In order to assess the correlations between tumor grades, staging and grading of tumors and socio-demographic characteristics, the Pearson or Spearman correlation coeffi cients were used. Th e statistical analysis was performed using SPSS 23.0, p values lower than 0.05 were considered to be signifi cant.

RESULTS
A number of 171 patients was included in the study, patients with left colon cancer with a mean age of 67.2±10.9 years. 58.5% of the patients included in the study are males, and 72.5% of the come from urban areas. Th e presence of lymph node and distal metastases does not signifi cantly diff er according to the age or sex of the patients, not according to the anatomical location of the primary tumor. However, distal metastases are associated with the residence area of the patients (p=0.048) ( Table 1).

INTRODUCTION
Colorectal cancer represents the second leading cause of cancer mortality in Romania, the increasing mortality being constant and thus, constituting an important public health problem. In Romania, colorectal cancer represents the second most frequent location of new cases of cancer registered in 2018, the number of new cases being 6,500 in men and 4,576 in women. Th e incidence is higher among males, increasing with age in both sexes. 1 Th e survival rates for colorectal cancer are determined by the stage of the disease and the presence of metastases, so that the survival rate at 5 years is of 90% for the early stages of localized tumors, of 70% for the tumors with local invasion and of only 10% for the cases of distal metastases 2,3 .
From an anatomical point of view, a distinction can be made between colon cancer and rectal cancer, colon cancer being subdivided into right colon cancer and left colon cancer, the latter including the descending colon and the sigmoid colon. 4,5 Th e clinical and histopathological characteristics are signifi cantly diff erent depending on the location of the colorectal tumor 6,7 . Th e most common histopathological types of left colon tumors are tubular, villous and adenocarcinoma 8 . Th e frequently seen polypoid morphology makes these tumors detectable from early stages during colonoscopy, thus leading to a better prognosis 9 .
Th e aim of the present study is to evaluate the prognosis of left colon cancer according to its main histopathological characteristics.

MATERIAL AND METHODS
Patients with tumors located at the level of the left colon (splenic fl exure, descending colon, sigmoid colon and rectosigmoidian junction) were included in the study. Th e patients were admitted to the Surgical Unit of the Emergency Clinical Hospital in Bucharest between January 1 st 2015 -December 31 st 2016. Th e data were collected retrospectively, including all the patients diagnosed with left colon cancer in this period, irrespective of whether they had undergone surgery or not. Th e most relevant demographic data were collected (sex, age, residence area), all postoperative complications were recorded, as well as the postoperative evolution. Th e histopathological analysis was performed according to the norms of the American College of Pathologists 10 , and the determination of tumor staging was done based on the TNM classifi cation (American Joint Committee on Cancer -AJCC) 11 . Th e degrees of DISCUSSIONS Colon cancers are more frequently present in its distal part (from the splenic fl exure to the sigmoid colon) than in its proximal part, and that is why the study of the tumors located at the level of the left colon are of particular importance. In our study, the sigmoid colon (46.2%) represents the most common anatomical location of the tumor, similar to other studies 15 .
Most of the patients included in the study are elderly, without any signifi cant diff erences regarding the age of the patients with lymphatic or distal metastases. A study conducted in 2018 by Murphy and all on a group from 10 European countries states that the advanced age is a good prognostic sign for colorectal cancer 16 . Although in the literature distal colon cancer is more frequently seen among males 17 , in our study there are no signifi cant diff erences regarding the sex of the patients included in the study. Th e signifi cantly higher prevalence of distal metastases in rural area patients can be determined by the low addressability and accessibility of these patients to hospitals.
Most studies do not confi rm the existence of an association between the histopathological type of the tumor and the presence of lymphatic or distal metastases. However, the studies conducted by Newland and Heys reveal that mucinous adenocarcinoma presents a poorer prognosis than other histopathological types 18,19 . In a more recent study from 2017, Kamocki ses does not signifi cantly diff er according to the histological type of the tumor.
Most patients included in the study are in the 3rd stage (65.5%) and in the 4 th stage (19.3%) of cancer, while only 2.3% are diagnosed in the 1st stage. A number of 36 patients present distal metastases, the most common location being in the liver (21 patients), followed by the peritoneum (8 patients). Distal metastases have a signifi cantly higher frequency (p=0.018) in rural area patients (30.3%) than in urban area patients (17.5%).
24% of the patients included in the study presented postoperative complications, while 2.3% died, without any signifi cant diff erences according to the presence of lymph node metastases or distal metastases ( Table 2).
Th e degree of tumor diff erentiation diff ers significantly from a statistical point of view (p=0.002) depending on the histopathological type. All adenomatous polyps are poorly diff erentiated. Th e conventional adenocarcinoma is moderately diff erentiated in 81.8% of the cases and well-diff erentiated in 13.6% of the cases. Mucinous adenocarcinoma is moderately diff erentiated in 60% of the cases and strongly diff erentiated in 40% of the cases (Figure 1). does not show any association between the histological type of cancer and the presence of lymphatic and distal metastases, but this study excluded the mucinous and the signet ring adenocarcinoma from the analysis 15 . In our study, the incidence of lymphatic metastases is signifi cantly diff erent depending on the histopathological type of the tumor, the tubulovillous adenoma being more frequently associated with lymphatic metastases. Th e 3 rd stage tumors are present in 65.5% of the patients included in the study, while 19.3% present 4th stage tumors. Th e increased percentage of patients in advanced stages of the disease can be explained through the symptoms that are not perceived as alarming by the patients at fi rst, so that most of them consult a physician when the emergency intervention becomes necessary, the main complication seen being intestinal occlusion. Because the tumors diagnosed in asympto- Most of the patients (73%) had a favorable evolution. None of the 171 patients included in the current research presented intraoperative complications. Th e average hospitalization period was 11.5±6.53 days.
A part of the patients included in the research (24.0%) presented postoperative complications, while 2.3% of them died. Th e most common postoperative complications were the infection with E. coli and Clostridium diffi cile, followed by hypochromic anemia, postoperative evisceration, hypokalemia, anastomotic fi stula and wound suppuration. 3.2% of the patients who underwent surgery needed another re-intervention. Th e frequency of postoperative complications and nosocomial deaths are determined by the advanced stage of the disease (stages 3 and 4), but also by the late coming of the patients to the emergency room, especially with intestinal occlusion.
Th e main limits of the current study are the lack of data regarding the molecular phenotype of the tumors, which might have permitted the study of the impact of molecular profi le on the characteristics of left colon tumors.
Th e current study is conducted retrospectively in one center, so the conclusions drawn could be limited to it. However, the study is well documented and it included all the patients diagnosed with left colon cancer in the studied period, the patients being studied homogenously.
Th e study of left colon cancer prognosis presents numerous advantages, the main one being a new research on Romanian patients. Th e homogeneity of the data that were the basis of the current study and the wide range of cases represent an advantage, along with the evaluation of the histopathological characteristics according to the international norms and those of a well-documented study.

CONCLUSIONS
Th e incidence of lymphatic metastases diff ers according to the histopathological type of the tumor, the tubulovillous adenoma being more frequently associated with lymphatic metastases; distal metastases are more frequently seen in patients in the rural areas, based on the low addressability and accessibility to medical services. Th e frequency of postoperative complications and nosocomial death is determined by the advanced stage of the disease (stages 3 and 4), as well as by the matic patients have a signifi cantly better prognosis, it would be ideal if elderly patients and those with a family history of colon cancer underwent some regular check-ups. Th e presence of rectalgia is associated with a good prognosis because it alarms the patient and determines an early diagnosis and thus, an adequate treatment in the early stages of the disease.
Regarding the degree of diff erentiation, 12.9% of the tumors are poorly diff erentiated (G1), 67.8% are moderately diff erentiated (G2) and 19.3% are well diff erentiated (G3). We noticed lymph node metastases in 33.3% of the patients with tumors with a G3 degree of diff erentiation. Distal metastases were seen in 33.3% of the tumors with a G1 diff erentiation degree and in 31.2% of those with a G2 diff erentiation degree. None of the patients with a G3 diff erentiation degree tumor presented distant detectable metastases. Although none of these diff erences was statistically signifi cant, this thing might result from a too small number of patients with G1 and G3 diff erentiation degree tumors.
Ueno and co. used the same cellular pleomorphism scale to analyze the incidence of lymph node metastases in patients with colorectal cancer 20 . Th e study they conducted revealed the presence of lymph node metastases in 3.7% and 37% of the patients with G1/G2 and G3 diff erentiation degree, respectively. In 2017, Kamocki noticed the presence of lymph node metastases in 51% of the G2 tumors and in 53% of G3 tumors. He also reported hepatic metastases in 45% of G2 tumors and 33% of G3 tumors 15 .
Because of the low number of poorly diff erentiated tumors (G1) and well diff erentiated tumors (G3), the results did not reveal statistically signifi cant diff erences and the aggressiveness of the tumor could not be determined depending on the degree of diff erentiation, nor the metastatic potential. However, according to most authors, the G1 tumor diff erentiation degree is a favorable prognostic factor in cancer patients.
An important part of the patients (69.9%) presents lymphatic metastases and 21.1% present distal metastases, thus having an unfavorable prognosis. Th e extension to the lymph nodes correlates signifi cantly with the degree of the tumor extension (p<0.001) and with the distal extension of the tumor (p=0.014).
Regarding the localization of metastasis, 79.2% of the 36 patients with metastases present hepatic metastases, 29.1% present peritoneal metastases, 12.5% pulmonary metastases and 4.2% cerebral metastases. Th e distal extension of the tumor correlates with the resi-late arrival of the patient to the emergency room, especially patients with intestinal occlusion.
In conclusion, our research confi rms that there are certain diff erences in the prognosis of left colon cancer according to the histopathological characteristics of the tumor. Th ese diff erences will have to be taken into consideration especially in the advanced stages of the disease, i.e. stages 3 and 4, associated with high incidence of immediate complication. In addition, the