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Frequency of Morphologic Prognostic Factors in Surgically Treated Colorectal Cancer

Frequency of Morphologic Prognostic Factors in Surgically Treated Colorectal Cancer 10.2478/chilat-2014-0101 ACTA CHIRURGICA LATVIENSIS • 2014 (14/1) ORIGINAL ARTICLE Frequency of Morphologic Prognostic Factors in Surgically Treated Colorectal Cancer Inese Drike*, Ilze Strumfa*, Andrejs Vanags**, Janis Gardovskis** *Department of Pathology, Riga Stradins University, Latvia **Department of Surgery, Riga Stradins University, Latvia SUMMARY Introduction. Colorectal cancer is one of the most frequent malignant tumours worldwide. In Latvia, the incidence and mortality from colorectal cancer has increased over the past five years. Surgery is the mainstay of colorectal cancer treatment. However, the prognosis of an individual patient after the operation depends on many factors. Here, we report the prognostically important morphologic factors in potentially radically operated colorectal cancer patients in order to create the "morphologic prognostic portrait" - the basic morphologic characteristics of colorectal cancer in Latvian patients. Such data could be helpful in prognostic estimates. Aim of the study was to describe the local tumour spread by pT, to evaluate the occurrence of certain morphologic prognostic factors and to assess lymph node involvement in potentially radically operated colorectal cancer patients. Material and methods. In a retrospective study, 173 consecutive patients who underwent a potentially radical operation in a single university hospital within the year 2012 were identified by archive search. The pathology reports that have been created by protocol approach and diagnostic microscopy slides were reanalysed. Tumour morphology and pTN parameters were assessed according to the World Health Organization and the American Joint Committee on Cancer classifications. Results. The study included 98 women (56.6%) and 75 men (43.4%). The mean age of patients was 68.5 years [95% confidence interval: 66.9 – 70.1]. Only 4.6% [2.4 – 8.9] of patients were younger than 50 years. The most frequent histological tumour types were colorectal adenocarcinoma in 86.7% [80.8 – 90.9] patients and mucinous carcinoma in 9.2% [5.7 – 14.5] of patients. Evaluating the pT parameter, pT3 was found in 43.2% [36.1 – 50.6] and pT4 in 39.8% [32.8 – 47.2] of cases. Lymphatic invasion was found in 35.1% [25.3 – 46.2] of pT3 and 75.4% [64.0 – 84.0] of pT4 cases; p < 0.001. Perineural cancer invasion in pT3 and pT4 tumours was found in 29.9% [20.8 – 40.9] and 69.6% [57.9 – 79.2], respectively; p < 0.001. Conclusions. Colorectal cancer affects both genders with equal frequency. The tumour is mostly diagnosed after the age of 60 years. Adenocarcinoma is the predominant colorectal cancer type in radically operated patients. Perineural and lymphatic invasion in pT4 tumours is statistically significantly more frequent than in less advanced tumours and thus may be pathogenetically linked to wide local tumour spread. Key words: colorectal cancer, morphology, prognostic factors, synchronous colorectal cancer INTRODUCTION Colorectal cancer is one of the most frequent malignant tumours worldwide. In Latvia the incidence and mortality from colorectal cancer has increased (Figure 1) over the past five years. According to the Centre for Disease Prevention and Control of Latvia, there were 1233 new colorectal cancer cases in Latvia in 2012. Among these cases, the largest proportion of patients was diagnosed in the third and fourth stage, characterised by cancer spread beyond the primary tumour (data by the Centre for Disease Prevention and Control of Latvia). For colorectal cancer, the known 2008 2009 2010 2011 2012 unfavorable prognostic factors comprise marked local Year spread of the tumour, metastatic involvement of the New colorectal carcinoma cases, 2008 - 2012 lymph nodes, the development of perforation, presence of residual adenoma, and invasion in the perineural space and blood or lymphatic vessels [Marzouk and Fig. 1. The number of newly diagnosed colorectal Schofield, 2011; Walsh and Carey, 2013]. Presence of carcinoma cases in Latvia per year. synchronous second colorectal carcinoma has been Data: the Centre for Disease Prevention and analysed as a prognostic factor as well [Cunliffe et al., Control of Latvia 1984; Takeuchi et al., 1997]. Count ACTA CHIRURGICA LATVIENSIS • 2014 (14/1) AIM OF THE STUDY SD 10.4 years [67.7 – 71.8] and men estimated as 67.0 ± The aim of this study was to describe the local tumour SD 10.6 [64.5 – 69.4]. The lack of statistical difference spread by pT, the frequency of certain morphologic was confirmed by p = 0.811. prognostic factors and to assess lymph node involvement in radically operated colorectal cancer patients from Latvia. Women MATERIAL AND METHODS Men In a retrospective study, 173 consecutive patients who underwent potentially radical surgical treatment of colorectal cancer in a single university hospital within st st 2012 (January 1 – December 31 , 2012) were identified by archive search. The corresponding pathology reports 10 and diagnostic microscopy slides were retrieved. Within the present study, potentially radical operations were defined as major colonic and rectal resections, namely, 40-49 50-59 60-69 70-79 80-89 90-99 partial, subtotal or total colectomy, anterior rectal resection, Hartmann operation, rectosigmoidectomy Patie nt age groups in colorectal cancer and rectal extirpation [Bhangu et al., 2013]. The data on neoadjuvant chemotherapy were assessed by medical Fig. 2. The age and gender distribution of the records. The tumour morphology and pTN parameters studied surgically treated colorectal carcinoma were evaluated according to the classifications and cases criteria as defined by World Health Organization and the American Joint Committee on Cancer [Hamilton Colorectal adenocarcinoma was found in 86.7% [80.8 – and Aaltonen, 2010; Edge et al., 2010]. The presence 90.9] of patients with colon cancer. Mucinous carcinoma of perforation and synchronous second colorectal was found in 9.2% [5.7 – 14.5] cases. There were single carcinoma was analysed by pathology reports. Tumour cases of medullary and undifferentiated carcinoma as perforation was defined as a defect in the bowel wall well as few cases of primary signet ring cell carcinoma through the tumour [Swamy, 2010]. The presence of of the large bowel and moderately differentiated (G2) residual adenoma, perineural and intraneural invasion neuroendocrine tumour (Table 1, Figure 3). and involvement of lymphatic vessels and veins in the process were analysed in the retrieved diagnostic Table 1. Histological type of colorectal tumour by pathology slides [Fleming et al., 2012]. As the current gender recomendations highlight the importance of a sufficient Frequency, Tumour type Number Women Men number of lymph nodes found for adequate staging % [95% CI] of colorectal cancer [Compton et al., 2000; Kuijpers Adeno- 150 86.7 84 66 et al., 2013], the total number of retrieved lymph carcinoma [80.8 – 90.9] nodes was also assessed. The slides were routinely Mucinous 16 9.2 97 stained with hematoxylin and eosin. Additional carcinoma [5.7 – 14.5] immunohistochemical investigation was performed upon necessity if the tumour histogenesis was otherwise Signet ring 3 1.7 21 unclear. Descriptive statistical analysis was perfomed. cell carcinoma [0.5 – 4.9] The descriptive data were expressed as mean ± standard Neuro- 2 1.2 20 deviation (SD), median with interquartile range or endocrine [0.3 – 4.1] frequency. To detect statistically significant differences, tumour the 95% confidence interval (CI) was calculated by CIA Medullary 1 0.6 01 software (Altman et al., 2000) and the findings were carcinoma [0.1 – 3.2] further confirmed by the χ2 test regarding frequency Undifferen- 1 0.6 10 and two sample t-test regarding the mean values. tiated [0.1 – 3.2] Differences were considered statistically significant, if p carcinoma value was less than 0.05. Abbreviation in the Table: CI, confidence interval RESULTS The study included 173 patients: 98 women (56.6%) and 75 men (43.4%). The mean age of patients was 68.5 ± SD 10.6 years [95% CI: 66.9 – 70.1], ranging from 41 to 97 years. Only 8 patients were younger than 50 years, comprising 4.6% [2.4 – 8.9] of the study group (Figure 2). No statistically significant difference was found regarding the mean age of women estimated as 69.7 ± Patient count ACTA CHIRURGICA LATVIENSIS • 2014 (14/1) Fig. 3. The histological types of colorectal carcinoma. 3A-B, adenocarcinoma. Note low-grade architecture in 3A and high-grade in 3B; 3C-D, mucinous carcinoma. Note mucus lakes in both 3C and 3D as well as slight fibrosis in 3C; 3E, signet ring cell carcinoma; 3F, undifferentiated carcinoma; 3G-H, neuroendocrine tumour. Note the characteristic architecture in 3G and cytoplasmic expression of synaptophysin in 3H. 3A, B, E, F, G: haematoxylin-eosin; 3C, Masson’s trichrome; 3D, PAS; 3H, immunoperoxidase. Original magnification: 3A, B, C, D, F, G: 100x; 3E and H: 400x. 5 ACTA CHIRURGICA LATVIENSIS • 2014 (14/1) Descen- Evaluating the anatomic localization of the tumour ding 7 00 0 0 0 and the related type of the operations, it was found colon that radical surgery in relation to colorectal cancer Sigmoid was performed mostly on the left part of the bowel, 39 6 0 0 0 0 colon representing 76.9% [70.1 – 82.5] of cases. The most Rectum 62 4 1 0 1 0 frequent single localization of colorectal cancer was the rectum, where the tumour was detected in 39.3% [32.3 – Evaluating the T parameter, pT3 carcinoma represented 46.7] of cases (Table 2). Few patients affected by rectal 43.2% [36.1 – 50.6], and pT4 – 39.8% [32.8 – 47.2] of cancer underwent neoadjuvant treatment: 7.4% [2.8 – all cases (Figure 4). Among the pT3 cases, 77.9% [67.5 – 16.5]. 85.7] were localised in left side, but among pT4 – 75.4% [64.0 – 84.0] cases were left-sided paralleling the general Table 2. The anatomic localisation of surgically distribution of colorectal carcinoma (Table 4). treated colorectal carcinoma Number Frequency, 95% CI of the Table 4. pT parameter distribution of colorectal Site of cases % frequency carcinoma by the affected side of large bowel Caecum 11 6.3 3.6 – 11.0 Number of cases Ascending 22 12.7 8.5 – 18.5 Right side Left side colon pT Transverse 20 11.6 7.6 – 17.2 Frequ- 95% Frequ- 95% Count Count colon ency, % CI ency, % CI Descending 7 4.1 1.9 – 8.1 colon 1. 9 – 0.9 – pT1 3 7.5 4 3.0 Sigmoid 45 26.0 20.1 – 33.0 20.6 7.7 colon 1. 9 – 8.0 – pT2 3 7.5 17 12.8 20.6 19.6 Rectum 68 39.3 32.3 – 46.7 28.5 – 36.9 – pT3 17 42.5 60 45.1 Abbreviation in the Table: CI, confidence interval 57.8 53.6 28.5 – 31.2 – pT4 17 42.5 52 39.1 Left-sided colorectal adenocarcinoma accounted for 57.8 47.6 117 cases or 87.9% [81.3 – 92.5] of left side operations. Total 40 133 Mucinous colorectal carcinoma was found in 9.0% [5.2 – 15.1] of all left side operations. There were 62 Abbreviation in the Table: CI, confidence interval of the cases of rectal adenocarcinoma, corresponding to 41.3% frequency [33.8 – 49.3] of the total number of adenocarcinomas. In sigmoid colon, adenocarcinomas were found in 26.0% [19.6 – 33.6] of cases. Mucinous carcinoma of the sigmoid colon represented 37.5% [18.5 – 61.4] of all mucinous cancer cases (Table 3). Table 3. Histological type of tumour by anatomic localisation site Number of cases Signet Undif- Muci- Medul- Neuro- Localisa- Adeno- ring feren- nous lary endo- tion carci- cell tiated carci- carci- crine T1 T2 T3 T4 noma carci- carci- noma noma tumour pT distribution in colorectal cancer noma noma Caecum 8 2 0 0 1 0 Fig. 4. pT distribution in surgically treated colorec- Ascen- tal carcinoma ding 19 2 0 0 0 1 colon The number of identified lymph nodes ranged from 1 Trans- to 33. The median value was 11, interquartile range verse 15 2 2 1 0 0 8. The mean number of investigated lymph nodes per colon patient was 11.8 ± SD 6.4 [10.8 – 12.8]. In 80 cases (46.2%), the number of identified lymph nodes reached or exceeded 12 while in 45 (26.0%) cases the number of Count ACTA CHIRURGICA LATVIENSIS • 2014 (14/1) retrieved lymph nodes found was 8 to 11. No metastasis of patients. There was no lymphatic invasion in pT1 in regional lymph nodes (pN0) was detected in 49.1% tumours: 0% [0 –35.4]. Regarding pT2 carcinomas, such [41.8 – 56.5] of cases. The pN1 spread (1 – 3 metastases invasion was found in 3 cases, corresponding to 15.0% in regional lymph nodes) was identified in 27.8% [21.6 – [5.2 – 36.0] of pT2 cases. Evaluating the lymphatic 34.8] patients. If more than 12 lymph nodes were invasion in pT3 and pT4 tumors, it was present in retrieved, pN1 was detected in 28.7% [19.9 – 39.5] 35.1% [25.3 – 46.2] of pT3 and 75.4% [64.0 – 84.0] of cases and pN2 in 22.5% [14.7 – 32.8] of cases. In of pT4 cases. The statistical significance of the observed patients with 8 to 11 identified lymph nodes, pN1 was difference was confirmed by p < 0.001. Invasion into found in 24.4% [14.2 – 38.7] and pN2 in 20.0% [10.9 – veins was observed in 29.0% [19.6 – 40.6] of pT4 cases, 33.8] of cases. Comparing the pN distribution (pN0 versus but intraneural growth – in 47.8% [36.5 – 59.4] of pN1 versus pN2) between the patients with less than 8 pT4 carcinomas. Both findings were significantly more retrieved lymph nodes, 8 – 11 or at least 12 identified frequent than in pT3, p = 0.002. Perineural cancer lymph nodes, there were no statistically significant invasion in pT3 and pT4 tumours were found in 29.9% difference as shown by χ2 test, resulting in p = 0.917. [20.8 – 40.9] and 69.6% [57.9 – 79.2], respectively Perforation, defined as a complete defect in bowel (Table 7). The statistical significance of the observed wall through the tumour, was observed in 11 cases, difference was again confirmed by p < 0.001. corresponding to 6.4% [3.6 – 11.0] of the total number of cases. The pT4 tumours were responsible for 63.6% Table 7. Manifestations of invasive growth in pT3 [35.4 – 84.8] of all tumour perforation cases. Perforation and pT4 colorectal carcinoma was seen in 10.1% [4.9 – 19.2] of pT4 cases (Table 5). Frequency, % [95% confidence interval] Para- Lymphatic Venous Perineural Intraneural meter Table 5. Frequency of colorectal carcinoma invasion invasion invasion invasion perforation by the pT characteristics pT3 35.1 [25.3 – 9.1 [4.5 – 29.9 [20.8 – 14.3 [8.2 – Frequency of 46.2] 17.6] 40.9] 23.8] Number of Total case Para- perforation, % perforated count pT4 75.4 [64.0 – 29.0 [19.6 69.6 [57.9 – 47.8 [36.5 – meter [95% confidence cases by pT 84.0] – 40.6] 79.2] 59.4] interval] pT1 0 7 0.0 [0.0 – 40.4] DISCUSSION pT2 2 20 10.0 [2.8 – 30.1] Colorectal cancer as the one of the leading cause of death in the world spears neither women nor men. pT3 2 77 2.6 [0.7 – 8.9] In the present stydy, occurrence in both genders was pT4 7 69 10.1 [5.0 – 19.5] observed as well. In our study, only 4.6% of patients were younger than 50 years. Hypothetically, younger Synchronous second colorectal carcinoma was identified patients can more frequently present with unresectable in 17 cases or 9.8% [6.2 – 15.2]. The other cancer tumour [Berut et al., 2013], and such cases undergoing was mostly associated with pT4 cases, namely, it was palliative treatment only would be excluded from the revealed in 9 patients constituting 13.0% [7.0 – 22.9] present study focusing on major surgical resections. By of all pT4 cases. Among the patients with synchronous literature data, younger patients have higher frequency other carcinoma, lymph node metastases (pN1 and of American Joint Committee on Cancer stage III pN2) were detected in 9 cases, accounting for 52.9% carcinomas exhibiting vascular and perineural invasion [31.0 – 73.8] of the patients affected by synchronous [Ghazi et al., 2012]. In Latvia, many patients are second carcinoma and 10.5% [5.6 – 18.7] of the total diagnosed after the age of 50 years, therefore screening number of cases displaying lymph node metastases. for colorectal cancer, beginning from the age of 50 years, Residual adenomas in our study were detected in 19.1% would have high diagnostic yield. [13.9 – 25.6] of cases, mostly in patients with pT3 and In our study, significant fraction of mucinous colorectal pT4 characteristics of local spread (Table 6). carcinoma was localised in left side of large bowel, while in other studies mucinous carcinoma has been localised Table 6. Frequency of residual adenoma by pT in mostly in right side of colon [Nawa et al., 2008]. colorectal cancer Considering the known association between mucinous Number of cases differentiation and molecular types in colorectal cancer Para- Frequency, % [95% exhibiting residual meter confidence interval] [Umar et al., 2004], different distribution of these types can adenoma be suspected in Latvia. Such differences hypothetically pT1 3 42.9 [15.8 – 75.0] can be attributable both to risk factor distribution and pT2 6 30.0 [14.5 – 51.9] genetic predisposition. Obviously, larger studies are necessary to solve this issue. This study did not focus pT3 15 19.5 [12.2 – 29.7] to study the genetic predisposition. Only 40 cases in pT4 9 13.0 [7.0 – 23.0] our study were right-sided tumours, which in literature are associated with positive family history [Ponz de In the whole study group, tumour invasion in lymphatic Leon et al., 1990]. The low rate of young patients also vessels was found in 82 cases or 47.4% [40.1 – 54.8] 7 ACTA CHIRURGICA LATVIENSIS • 2014 (14/1) is not suggestive of frequent hereditary predisposition. Treatment can significantly influence the lymph node However, this finding is by no means exclusive as yield, especially in rectal tumours [Morcos et al., 2010; hereditary cancers can also develop in aged patients Marks et al., 2010]. However, this confounder was rarely [Vanags et al., 2010].The pT4 tumours have a tendency observed in the present study. In contrast, the lymph to more frequent perforation. It could be associated with node yield is significantly influenced by the location tumour spread through all layers of the bowel wall. of tumour. The highest lymph node yield is reported However, tumour necrosis and inflammation should be in right-sided cases, exceeding the mean number of analyzed in association of perforation in further studies, identified lymph nodes in left-sided and rectal cancers because, as our study showed, perforation was not [Ahmadi et al., 2014]. Our group is characterised by the limited by pT4, where tumour has spread further than predominance of left-sided cancers. In addition, most lamina muscularis propria and has reached bowel surface. of patients were elderly. Aging can result in diminished Surgically induced perforation at the tumour site can activity of immune system [Stocchi et al., 2011], also develop. To discriminate such event from the true morphologically paralleling lymph node involution tumour perforation, clarification from surgeons can be [Shia et al., 2012]. It has been suggested that the mean helpful [Fleming et al., 2012]. lymph node yield decreases by 1 for every 7 years Patients affected by pT4 cancer in our study in 13% of advancement of age [Ahmadi et al., 2014] or by 9% for all cases had synchronous second carcinoma. There are every 10 years of age [Chou et al., 2010]. To improve published data that patients with synchronous colorectal the assessment of tumour dissemination via lymphatic carcinomas have also higher incidence of benign polyps route, is has been suggested to evaluate the lymph node [Abe et al., 2006]. ratio, i.e. the ratio between the number of metastatic By recent estimates, perineural invasion can have similar and examined lymph nodes [Costi et al., 2014] or the log prognostic role as lymphovascular invasion [Compton et odds of positive lymph nodes [Arslan et al., 2014]. Stage al., 2012; Gagliardi et al., 2013]. Our study showed that migration phenomenon has been recognized in colon 69.6% pT4 tumours had perineural and 75.4% lymphatic carcinoma implying that lower tumour stages have invasion, while invasion in vessels were found only in been identified, e.g., in patients undergoing treatment 29.0% of pT4 cases. Notably, the perineural, lymphatic in non-teaching hospitals or in hospitals where lymph and vascular invasion was statistically significantly more nodes were retrieved by less experienced clinicians. frequent in pT4 carcinomas suggesting inherent higher However, even under these circumstances there were invasive capacity in these advanced tumours. no interinstitutional differences in recurrence according The mostly accepted guidelines for colorectal carcinoma to tumour stage [Ueno et al., 2014]. Thus, our data investigation suggest that at least 12 lymph nodes must display the actual problems and challenges in colorectal be retrieved. However, variations exist between different cancer surgery. countries [Compton et al., 2000; Kuijpers et al., 2013]. In our study, at least 12 lymph nodes were identified in CONCLUSIONS 46.2% of patients, while in 26.0% cases the number of 1. Colorectal cancer occurs with equal frequency in retrieved lymph nodes was 8 to 11 and in 27.8% - less both sexes, often after the age of 60. Colorectal than 8 lymph nodes were identified. This is in accordance cancer screening would have high efficiency if with Zhang et al., recently reporting that only 27.9% started at the age of 50 years. of colorectal patients had at least 12 examined lymph 2. Among radically operated colorectal cancers, nodes [Zhang et al., 2013]. In addition, many authors adenocarcinoma is the predominant histological have noted that the target number of 12 retrieved lymph type. Rectum is the most frequently affected nodes is not always possible to reach even in USA and anatomic localisation. Frequent localisation of European clinics [Li Destri et al., 2014]. In northwest of mucinous colorectal carcinoma in left side of the England, at least 12 lymph nodes have been identified intestine was found. However, wider studies are in less than 50% of resected colorectal cancer materials desirable. [Mitchell et al., 2009]. Similarly, Johnson et al. reported 3. The pT4 tumours have a tendency to increased that 12 lymph nodes have been retrieved only in 55.3% frequency of perforation. It could be associated of colorectal surgery materials including any removed with but not limited by transmural tumour spread. lymph nodes [Johnson et al., 2010]. The Dutch Surgical 4. The pT4 colorectal cancer is characterized by invasion Colorectal Audit recognised that at least 10 lymph nodes of lymphatic vessels, perineural and intraneural have been examined in 73% of colon cancers and 58% invasion. Perineural and lymphatic invasion in of rectal cancers [Kuijpers et al., 2013]. The median pT4 tumours was statistically significantly more value of identified lymph nodes in our study was 11. In frequent than in less advanced cancers and can be United States, the median number of retrieved lymph pathogenetically associated with wide local tumour nodes has increased from 12 in the year 2004 to 17 in spread. 2010 [Budde et al., 2014]. Thus, our study has identified a clear potential for improvement. However, it must Conflict of interest: None be also emphasised that in USA the growing number of retrieved lymph nodes has not been accompanied by higher frequency of stage III disease [Budde et al., 2014]. 8 ACTA CHIRURGICA LATVIENSIS • 2014 (14/1) REFERENCES 14. Gagliardi G, Newton TR, Bailey HR. Local excision 1. Abe S, Terai T, Sakamoto N, Beppu K, Nagahara A, of rectal cancer followed by radical surgery because Kobayashi O, Ohkusa T, Ogihara T, Hirai S, Kamano of poor prognostic features does not compromise T, Miwa H, Sato N. 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Revised Bethesda E-mail: Ilze.Strumfa@rsu.lv guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability // J Natl Cancer Inst, 2004; 96:261 – 268 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Acta Chirurgica Latviensis de Gruyter

Frequency of Morphologic Prognostic Factors in Surgically Treated Colorectal Cancer

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10.2478/chilat-2014-0101
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10.2478/chilat-2014-0101 ACTA CHIRURGICA LATVIENSIS • 2014 (14/1) ORIGINAL ARTICLE Frequency of Morphologic Prognostic Factors in Surgically Treated Colorectal Cancer Inese Drike*, Ilze Strumfa*, Andrejs Vanags**, Janis Gardovskis** *Department of Pathology, Riga Stradins University, Latvia **Department of Surgery, Riga Stradins University, Latvia SUMMARY Introduction. Colorectal cancer is one of the most frequent malignant tumours worldwide. In Latvia, the incidence and mortality from colorectal cancer has increased over the past five years. Surgery is the mainstay of colorectal cancer treatment. However, the prognosis of an individual patient after the operation depends on many factors. Here, we report the prognostically important morphologic factors in potentially radically operated colorectal cancer patients in order to create the "morphologic prognostic portrait" - the basic morphologic characteristics of colorectal cancer in Latvian patients. Such data could be helpful in prognostic estimates. Aim of the study was to describe the local tumour spread by pT, to evaluate the occurrence of certain morphologic prognostic factors and to assess lymph node involvement in potentially radically operated colorectal cancer patients. Material and methods. In a retrospective study, 173 consecutive patients who underwent a potentially radical operation in a single university hospital within the year 2012 were identified by archive search. The pathology reports that have been created by protocol approach and diagnostic microscopy slides were reanalysed. Tumour morphology and pTN parameters were assessed according to the World Health Organization and the American Joint Committee on Cancer classifications. Results. The study included 98 women (56.6%) and 75 men (43.4%). The mean age of patients was 68.5 years [95% confidence interval: 66.9 – 70.1]. Only 4.6% [2.4 – 8.9] of patients were younger than 50 years. The most frequent histological tumour types were colorectal adenocarcinoma in 86.7% [80.8 – 90.9] patients and mucinous carcinoma in 9.2% [5.7 – 14.5] of patients. Evaluating the pT parameter, pT3 was found in 43.2% [36.1 – 50.6] and pT4 in 39.8% [32.8 – 47.2] of cases. Lymphatic invasion was found in 35.1% [25.3 – 46.2] of pT3 and 75.4% [64.0 – 84.0] of pT4 cases; p < 0.001. Perineural cancer invasion in pT3 and pT4 tumours was found in 29.9% [20.8 – 40.9] and 69.6% [57.9 – 79.2], respectively; p < 0.001. Conclusions. Colorectal cancer affects both genders with equal frequency. The tumour is mostly diagnosed after the age of 60 years. Adenocarcinoma is the predominant colorectal cancer type in radically operated patients. Perineural and lymphatic invasion in pT4 tumours is statistically significantly more frequent than in less advanced tumours and thus may be pathogenetically linked to wide local tumour spread. Key words: colorectal cancer, morphology, prognostic factors, synchronous colorectal cancer INTRODUCTION Colorectal cancer is one of the most frequent malignant tumours worldwide. In Latvia the incidence and mortality from colorectal cancer has increased (Figure 1) over the past five years. According to the Centre for Disease Prevention and Control of Latvia, there were 1233 new colorectal cancer cases in Latvia in 2012. Among these cases, the largest proportion of patients was diagnosed in the third and fourth stage, characterised by cancer spread beyond the primary tumour (data by the Centre for Disease Prevention and Control of Latvia). For colorectal cancer, the known 2008 2009 2010 2011 2012 unfavorable prognostic factors comprise marked local Year spread of the tumour, metastatic involvement of the New colorectal carcinoma cases, 2008 - 2012 lymph nodes, the development of perforation, presence of residual adenoma, and invasion in the perineural space and blood or lymphatic vessels [Marzouk and Fig. 1. The number of newly diagnosed colorectal Schofield, 2011; Walsh and Carey, 2013]. Presence of carcinoma cases in Latvia per year. synchronous second colorectal carcinoma has been Data: the Centre for Disease Prevention and analysed as a prognostic factor as well [Cunliffe et al., Control of Latvia 1984; Takeuchi et al., 1997]. Count ACTA CHIRURGICA LATVIENSIS • 2014 (14/1) AIM OF THE STUDY SD 10.4 years [67.7 – 71.8] and men estimated as 67.0 ± The aim of this study was to describe the local tumour SD 10.6 [64.5 – 69.4]. The lack of statistical difference spread by pT, the frequency of certain morphologic was confirmed by p = 0.811. prognostic factors and to assess lymph node involvement in radically operated colorectal cancer patients from Latvia. Women MATERIAL AND METHODS Men In a retrospective study, 173 consecutive patients who underwent potentially radical surgical treatment of colorectal cancer in a single university hospital within st st 2012 (January 1 – December 31 , 2012) were identified by archive search. The corresponding pathology reports 10 and diagnostic microscopy slides were retrieved. Within the present study, potentially radical operations were defined as major colonic and rectal resections, namely, 40-49 50-59 60-69 70-79 80-89 90-99 partial, subtotal or total colectomy, anterior rectal resection, Hartmann operation, rectosigmoidectomy Patie nt age groups in colorectal cancer and rectal extirpation [Bhangu et al., 2013]. The data on neoadjuvant chemotherapy were assessed by medical Fig. 2. The age and gender distribution of the records. The tumour morphology and pTN parameters studied surgically treated colorectal carcinoma were evaluated according to the classifications and cases criteria as defined by World Health Organization and the American Joint Committee on Cancer [Hamilton Colorectal adenocarcinoma was found in 86.7% [80.8 – and Aaltonen, 2010; Edge et al., 2010]. The presence 90.9] of patients with colon cancer. Mucinous carcinoma of perforation and synchronous second colorectal was found in 9.2% [5.7 – 14.5] cases. There were single carcinoma was analysed by pathology reports. Tumour cases of medullary and undifferentiated carcinoma as perforation was defined as a defect in the bowel wall well as few cases of primary signet ring cell carcinoma through the tumour [Swamy, 2010]. The presence of of the large bowel and moderately differentiated (G2) residual adenoma, perineural and intraneural invasion neuroendocrine tumour (Table 1, Figure 3). and involvement of lymphatic vessels and veins in the process were analysed in the retrieved diagnostic Table 1. Histological type of colorectal tumour by pathology slides [Fleming et al., 2012]. As the current gender recomendations highlight the importance of a sufficient Frequency, Tumour type Number Women Men number of lymph nodes found for adequate staging % [95% CI] of colorectal cancer [Compton et al., 2000; Kuijpers Adeno- 150 86.7 84 66 et al., 2013], the total number of retrieved lymph carcinoma [80.8 – 90.9] nodes was also assessed. The slides were routinely Mucinous 16 9.2 97 stained with hematoxylin and eosin. Additional carcinoma [5.7 – 14.5] immunohistochemical investigation was performed upon necessity if the tumour histogenesis was otherwise Signet ring 3 1.7 21 unclear. Descriptive statistical analysis was perfomed. cell carcinoma [0.5 – 4.9] The descriptive data were expressed as mean ± standard Neuro- 2 1.2 20 deviation (SD), median with interquartile range or endocrine [0.3 – 4.1] frequency. To detect statistically significant differences, tumour the 95% confidence interval (CI) was calculated by CIA Medullary 1 0.6 01 software (Altman et al., 2000) and the findings were carcinoma [0.1 – 3.2] further confirmed by the χ2 test regarding frequency Undifferen- 1 0.6 10 and two sample t-test regarding the mean values. tiated [0.1 – 3.2] Differences were considered statistically significant, if p carcinoma value was less than 0.05. Abbreviation in the Table: CI, confidence interval RESULTS The study included 173 patients: 98 women (56.6%) and 75 men (43.4%). The mean age of patients was 68.5 ± SD 10.6 years [95% CI: 66.9 – 70.1], ranging from 41 to 97 years. Only 8 patients were younger than 50 years, comprising 4.6% [2.4 – 8.9] of the study group (Figure 2). No statistically significant difference was found regarding the mean age of women estimated as 69.7 ± Patient count ACTA CHIRURGICA LATVIENSIS • 2014 (14/1) Fig. 3. The histological types of colorectal carcinoma. 3A-B, adenocarcinoma. Note low-grade architecture in 3A and high-grade in 3B; 3C-D, mucinous carcinoma. Note mucus lakes in both 3C and 3D as well as slight fibrosis in 3C; 3E, signet ring cell carcinoma; 3F, undifferentiated carcinoma; 3G-H, neuroendocrine tumour. Note the characteristic architecture in 3G and cytoplasmic expression of synaptophysin in 3H. 3A, B, E, F, G: haematoxylin-eosin; 3C, Masson’s trichrome; 3D, PAS; 3H, immunoperoxidase. Original magnification: 3A, B, C, D, F, G: 100x; 3E and H: 400x. 5 ACTA CHIRURGICA LATVIENSIS • 2014 (14/1) Descen- Evaluating the anatomic localization of the tumour ding 7 00 0 0 0 and the related type of the operations, it was found colon that radical surgery in relation to colorectal cancer Sigmoid was performed mostly on the left part of the bowel, 39 6 0 0 0 0 colon representing 76.9% [70.1 – 82.5] of cases. The most Rectum 62 4 1 0 1 0 frequent single localization of colorectal cancer was the rectum, where the tumour was detected in 39.3% [32.3 – Evaluating the T parameter, pT3 carcinoma represented 46.7] of cases (Table 2). Few patients affected by rectal 43.2% [36.1 – 50.6], and pT4 – 39.8% [32.8 – 47.2] of cancer underwent neoadjuvant treatment: 7.4% [2.8 – all cases (Figure 4). Among the pT3 cases, 77.9% [67.5 – 16.5]. 85.7] were localised in left side, but among pT4 – 75.4% [64.0 – 84.0] cases were left-sided paralleling the general Table 2. The anatomic localisation of surgically distribution of colorectal carcinoma (Table 4). treated colorectal carcinoma Number Frequency, 95% CI of the Table 4. pT parameter distribution of colorectal Site of cases % frequency carcinoma by the affected side of large bowel Caecum 11 6.3 3.6 – 11.0 Number of cases Ascending 22 12.7 8.5 – 18.5 Right side Left side colon pT Transverse 20 11.6 7.6 – 17.2 Frequ- 95% Frequ- 95% Count Count colon ency, % CI ency, % CI Descending 7 4.1 1.9 – 8.1 colon 1. 9 – 0.9 – pT1 3 7.5 4 3.0 Sigmoid 45 26.0 20.1 – 33.0 20.6 7.7 colon 1. 9 – 8.0 – pT2 3 7.5 17 12.8 20.6 19.6 Rectum 68 39.3 32.3 – 46.7 28.5 – 36.9 – pT3 17 42.5 60 45.1 Abbreviation in the Table: CI, confidence interval 57.8 53.6 28.5 – 31.2 – pT4 17 42.5 52 39.1 Left-sided colorectal adenocarcinoma accounted for 57.8 47.6 117 cases or 87.9% [81.3 – 92.5] of left side operations. Total 40 133 Mucinous colorectal carcinoma was found in 9.0% [5.2 – 15.1] of all left side operations. There were 62 Abbreviation in the Table: CI, confidence interval of the cases of rectal adenocarcinoma, corresponding to 41.3% frequency [33.8 – 49.3] of the total number of adenocarcinomas. In sigmoid colon, adenocarcinomas were found in 26.0% [19.6 – 33.6] of cases. Mucinous carcinoma of the sigmoid colon represented 37.5% [18.5 – 61.4] of all mucinous cancer cases (Table 3). Table 3. Histological type of tumour by anatomic localisation site Number of cases Signet Undif- Muci- Medul- Neuro- Localisa- Adeno- ring feren- nous lary endo- tion carci- cell tiated carci- carci- crine T1 T2 T3 T4 noma carci- carci- noma noma tumour pT distribution in colorectal cancer noma noma Caecum 8 2 0 0 1 0 Fig. 4. pT distribution in surgically treated colorec- Ascen- tal carcinoma ding 19 2 0 0 0 1 colon The number of identified lymph nodes ranged from 1 Trans- to 33. The median value was 11, interquartile range verse 15 2 2 1 0 0 8. The mean number of investigated lymph nodes per colon patient was 11.8 ± SD 6.4 [10.8 – 12.8]. In 80 cases (46.2%), the number of identified lymph nodes reached or exceeded 12 while in 45 (26.0%) cases the number of Count ACTA CHIRURGICA LATVIENSIS • 2014 (14/1) retrieved lymph nodes found was 8 to 11. No metastasis of patients. There was no lymphatic invasion in pT1 in regional lymph nodes (pN0) was detected in 49.1% tumours: 0% [0 –35.4]. Regarding pT2 carcinomas, such [41.8 – 56.5] of cases. The pN1 spread (1 – 3 metastases invasion was found in 3 cases, corresponding to 15.0% in regional lymph nodes) was identified in 27.8% [21.6 – [5.2 – 36.0] of pT2 cases. Evaluating the lymphatic 34.8] patients. If more than 12 lymph nodes were invasion in pT3 and pT4 tumors, it was present in retrieved, pN1 was detected in 28.7% [19.9 – 39.5] 35.1% [25.3 – 46.2] of pT3 and 75.4% [64.0 – 84.0] of cases and pN2 in 22.5% [14.7 – 32.8] of cases. In of pT4 cases. The statistical significance of the observed patients with 8 to 11 identified lymph nodes, pN1 was difference was confirmed by p < 0.001. Invasion into found in 24.4% [14.2 – 38.7] and pN2 in 20.0% [10.9 – veins was observed in 29.0% [19.6 – 40.6] of pT4 cases, 33.8] of cases. Comparing the pN distribution (pN0 versus but intraneural growth – in 47.8% [36.5 – 59.4] of pN1 versus pN2) between the patients with less than 8 pT4 carcinomas. Both findings were significantly more retrieved lymph nodes, 8 – 11 or at least 12 identified frequent than in pT3, p = 0.002. Perineural cancer lymph nodes, there were no statistically significant invasion in pT3 and pT4 tumours were found in 29.9% difference as shown by χ2 test, resulting in p = 0.917. [20.8 – 40.9] and 69.6% [57.9 – 79.2], respectively Perforation, defined as a complete defect in bowel (Table 7). The statistical significance of the observed wall through the tumour, was observed in 11 cases, difference was again confirmed by p < 0.001. corresponding to 6.4% [3.6 – 11.0] of the total number of cases. The pT4 tumours were responsible for 63.6% Table 7. Manifestations of invasive growth in pT3 [35.4 – 84.8] of all tumour perforation cases. Perforation and pT4 colorectal carcinoma was seen in 10.1% [4.9 – 19.2] of pT4 cases (Table 5). Frequency, % [95% confidence interval] Para- Lymphatic Venous Perineural Intraneural meter Table 5. Frequency of colorectal carcinoma invasion invasion invasion invasion perforation by the pT characteristics pT3 35.1 [25.3 – 9.1 [4.5 – 29.9 [20.8 – 14.3 [8.2 – Frequency of 46.2] 17.6] 40.9] 23.8] Number of Total case Para- perforation, % perforated count pT4 75.4 [64.0 – 29.0 [19.6 69.6 [57.9 – 47.8 [36.5 – meter [95% confidence cases by pT 84.0] – 40.6] 79.2] 59.4] interval] pT1 0 7 0.0 [0.0 – 40.4] DISCUSSION pT2 2 20 10.0 [2.8 – 30.1] Colorectal cancer as the one of the leading cause of death in the world spears neither women nor men. pT3 2 77 2.6 [0.7 – 8.9] In the present stydy, occurrence in both genders was pT4 7 69 10.1 [5.0 – 19.5] observed as well. In our study, only 4.6% of patients were younger than 50 years. Hypothetically, younger Synchronous second colorectal carcinoma was identified patients can more frequently present with unresectable in 17 cases or 9.8% [6.2 – 15.2]. The other cancer tumour [Berut et al., 2013], and such cases undergoing was mostly associated with pT4 cases, namely, it was palliative treatment only would be excluded from the revealed in 9 patients constituting 13.0% [7.0 – 22.9] present study focusing on major surgical resections. By of all pT4 cases. Among the patients with synchronous literature data, younger patients have higher frequency other carcinoma, lymph node metastases (pN1 and of American Joint Committee on Cancer stage III pN2) were detected in 9 cases, accounting for 52.9% carcinomas exhibiting vascular and perineural invasion [31.0 – 73.8] of the patients affected by synchronous [Ghazi et al., 2012]. In Latvia, many patients are second carcinoma and 10.5% [5.6 – 18.7] of the total diagnosed after the age of 50 years, therefore screening number of cases displaying lymph node metastases. for colorectal cancer, beginning from the age of 50 years, Residual adenomas in our study were detected in 19.1% would have high diagnostic yield. [13.9 – 25.6] of cases, mostly in patients with pT3 and In our study, significant fraction of mucinous colorectal pT4 characteristics of local spread (Table 6). carcinoma was localised in left side of large bowel, while in other studies mucinous carcinoma has been localised Table 6. Frequency of residual adenoma by pT in mostly in right side of colon [Nawa et al., 2008]. colorectal cancer Considering the known association between mucinous Number of cases differentiation and molecular types in colorectal cancer Para- Frequency, % [95% exhibiting residual meter confidence interval] [Umar et al., 2004], different distribution of these types can adenoma be suspected in Latvia. Such differences hypothetically pT1 3 42.9 [15.8 – 75.0] can be attributable both to risk factor distribution and pT2 6 30.0 [14.5 – 51.9] genetic predisposition. Obviously, larger studies are necessary to solve this issue. This study did not focus pT3 15 19.5 [12.2 – 29.7] to study the genetic predisposition. Only 40 cases in pT4 9 13.0 [7.0 – 23.0] our study were right-sided tumours, which in literature are associated with positive family history [Ponz de In the whole study group, tumour invasion in lymphatic Leon et al., 1990]. The low rate of young patients also vessels was found in 82 cases or 47.4% [40.1 – 54.8] 7 ACTA CHIRURGICA LATVIENSIS • 2014 (14/1) is not suggestive of frequent hereditary predisposition. Treatment can significantly influence the lymph node However, this finding is by no means exclusive as yield, especially in rectal tumours [Morcos et al., 2010; hereditary cancers can also develop in aged patients Marks et al., 2010]. However, this confounder was rarely [Vanags et al., 2010].The pT4 tumours have a tendency observed in the present study. In contrast, the lymph to more frequent perforation. It could be associated with node yield is significantly influenced by the location tumour spread through all layers of the bowel wall. of tumour. The highest lymph node yield is reported However, tumour necrosis and inflammation should be in right-sided cases, exceeding the mean number of analyzed in association of perforation in further studies, identified lymph nodes in left-sided and rectal cancers because, as our study showed, perforation was not [Ahmadi et al., 2014]. Our group is characterised by the limited by pT4, where tumour has spread further than predominance of left-sided cancers. In addition, most lamina muscularis propria and has reached bowel surface. of patients were elderly. Aging can result in diminished Surgically induced perforation at the tumour site can activity of immune system [Stocchi et al., 2011], also develop. To discriminate such event from the true morphologically paralleling lymph node involution tumour perforation, clarification from surgeons can be [Shia et al., 2012]. It has been suggested that the mean helpful [Fleming et al., 2012]. lymph node yield decreases by 1 for every 7 years Patients affected by pT4 cancer in our study in 13% of advancement of age [Ahmadi et al., 2014] or by 9% for all cases had synchronous second carcinoma. There are every 10 years of age [Chou et al., 2010]. To improve published data that patients with synchronous colorectal the assessment of tumour dissemination via lymphatic carcinomas have also higher incidence of benign polyps route, is has been suggested to evaluate the lymph node [Abe et al., 2006]. ratio, i.e. the ratio between the number of metastatic By recent estimates, perineural invasion can have similar and examined lymph nodes [Costi et al., 2014] or the log prognostic role as lymphovascular invasion [Compton et odds of positive lymph nodes [Arslan et al., 2014]. Stage al., 2012; Gagliardi et al., 2013]. Our study showed that migration phenomenon has been recognized in colon 69.6% pT4 tumours had perineural and 75.4% lymphatic carcinoma implying that lower tumour stages have invasion, while invasion in vessels were found only in been identified, e.g., in patients undergoing treatment 29.0% of pT4 cases. Notably, the perineural, lymphatic in non-teaching hospitals or in hospitals where lymph and vascular invasion was statistically significantly more nodes were retrieved by less experienced clinicians. frequent in pT4 carcinomas suggesting inherent higher However, even under these circumstances there were invasive capacity in these advanced tumours. no interinstitutional differences in recurrence according The mostly accepted guidelines for colorectal carcinoma to tumour stage [Ueno et al., 2014]. Thus, our data investigation suggest that at least 12 lymph nodes must display the actual problems and challenges in colorectal be retrieved. However, variations exist between different cancer surgery. countries [Compton et al., 2000; Kuijpers et al., 2013]. In our study, at least 12 lymph nodes were identified in CONCLUSIONS 46.2% of patients, while in 26.0% cases the number of 1. Colorectal cancer occurs with equal frequency in retrieved lymph nodes was 8 to 11 and in 27.8% - less both sexes, often after the age of 60. Colorectal than 8 lymph nodes were identified. This is in accordance cancer screening would have high efficiency if with Zhang et al., recently reporting that only 27.9% started at the age of 50 years. of colorectal patients had at least 12 examined lymph 2. Among radically operated colorectal cancers, nodes [Zhang et al., 2013]. In addition, many authors adenocarcinoma is the predominant histological have noted that the target number of 12 retrieved lymph type. Rectum is the most frequently affected nodes is not always possible to reach even in USA and anatomic localisation. Frequent localisation of European clinics [Li Destri et al., 2014]. In northwest of mucinous colorectal carcinoma in left side of the England, at least 12 lymph nodes have been identified intestine was found. However, wider studies are in less than 50% of resected colorectal cancer materials desirable. [Mitchell et al., 2009]. Similarly, Johnson et al. reported 3. The pT4 tumours have a tendency to increased that 12 lymph nodes have been retrieved only in 55.3% frequency of perforation. It could be associated of colorectal surgery materials including any removed with but not limited by transmural tumour spread. lymph nodes [Johnson et al., 2010]. The Dutch Surgical 4. The pT4 colorectal cancer is characterized by invasion Colorectal Audit recognised that at least 10 lymph nodes of lymphatic vessels, perineural and intraneural have been examined in 73% of colon cancers and 58% invasion. Perineural and lymphatic invasion in of rectal cancers [Kuijpers et al., 2013]. The median pT4 tumours was statistically significantly more value of identified lymph nodes in our study was 11. In frequent than in less advanced cancers and can be United States, the median number of retrieved lymph pathogenetically associated with wide local tumour nodes has increased from 12 in the year 2004 to 17 in spread. 2010 [Budde et al., 2014]. Thus, our study has identified a clear potential for improvement. However, it must Conflict of interest: None be also emphasised that in USA the growing number of retrieved lymph nodes has not been accompanied by higher frequency of stage III disease [Budde et al., 2014]. 8 ACTA CHIRURGICA LATVIENSIS • 2014 (14/1) REFERENCES 14. Gagliardi G, Newton TR, Bailey HR. Local excision 1. Abe S, Terai T, Sakamoto N, Beppu K, Nagahara A, of rectal cancer followed by radical surgery because Kobayashi O, Ohkusa T, Ogihara T, Hirai S, Kamano of poor prognostic features does not compromise T, Miwa H, Sato N. 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Journal

Acta Chirurgica Latviensisde Gruyter

Published: Nov 24, 2014

Keywords: Medicine; Clinical Medicine; Surgery; Surgery, other

References