International Journal of Colorectal Disease

, Volume 25, Issue 7, pp 823–828

Clinicopathological features of colorectal cancer in patients under 40 years of age

Authors

    • Department of SurgeryOulu University Hospital
    • Department of Surgery, Division of GastroenterologyUniversity of Oulu
  • Heikki Kiviniemi
    • Department of SurgeryOulu University Hospital
Original Article

DOI: 10.1007/s00384-010-0914-9

Cite this article as:
Mäkelä, J.T. & Kiviniemi, H. Int J Colorectal Dis (2010) 25: 823. doi:10.1007/s00384-010-0914-9

Abstract

Objective

The aim was to identify the clinical factors and tumour characteristics that predict survival in patients younger than 40 years with colorectal adenocarcinoma.

Material and methods

Fifty-nine patients with colorectal cancer aged under 40 years were identified from a computer database, and their clinical variables were analysed. The factors predicting long-term survival were compared by both univariate and multivariate analysis.

Results

The prevalence of positive family history of cancer was 27%, and predisposing factors were present in 31% of the patients. All patients underwent resective surgery, 76% radical and 24% palliative resection, and their 5-year survival was 59% and mean survival ±75 months. The recurrence rate after radical resection was 38% being 14%, 30%, 78% and 100% in Dukes classes A, B, C and D. The cumulative 5-year survival of men, 45%, was significantly worse than that of women, 73%, and this phenomenon was closely related to more distended lymphatic and venous invasion of cancer in men. Kaplan–Meier estimates showed that gender, Dukes staging, grade of tumour, lymphatic invasion, the number of lymph nodes with metastases, venous invasion and size of tumour were significant predictors of survival, but in Cox regression model, only venous invasion was the independent prognostic factor of survival.

Conclusions

Young men with colorectal cancer in Northern Finland have poorer prognosis than women. Venous invasion is an independent predictor of survival.

Keywords

Colorectal cancerYoung agePredisposing conditionsPathologySurvival

Introduction

Colorectal cancer is currently the third frequent cancer in Finland, and its incidence has been increasing during last decades, which has been attributed to Westernised lifestyle.

It has been estimated that 3% of colorectal cancer cases in our country develop before age of 40 years [1]. Many have reported that the prognosis of colorectal cancer is worse in these young patients [25], and this has been connected to the more advanced stage at presentation, largely caused by delayed diagnosis [6]. However, in a case control study by Paraf and Jothy, the prognosis of colorectal carcinoma was identical in Canada, when patients younger than 40 years were compared with older patients for identical stages [7], and in that by Chung et al., no difference in survivals between respective age groups was found in Singapore [8].

Nowadays, young people can be operated on with considerably low morbidity and mortality, but their distress and anxiety concerning the prospects of survival needs precise data of prognosis. The evaluation of prognostic variables is complex matter that interplays between patient and tumour-related factors. We, therefore, investigated the 20-year material of patients with colorectal cancer aged under 40 years by collecting the patient information from a computer database of Oulu University Hospital and performed a computer analysis of the predictors of survival. In addition, a special attention was paid to family history of the patients, the follow-up of patients and recurrence of cancer.

Material and methods

During the 20-year period between January 1984 and December 2003, 1,272 patients with colorectal cancer have been evaluated for surgery at the Oulu University Hospital. The 59 patients aged under 40 years were identified using a computer-generated search from a database that prospectively records data concerning both diagnoses and operative procedures. The register includes all the cancer patients treated and operated on from 1980 onwards. The diagnoses have been coded according to the International Classification of the Diseases and the operations performed according to the Finnish classification of surgical procedures.

Clinicopathological features were reviewed both from medical records and computerised data. The clinical data included age, gender, underlying diseases, predisposing hereditary factors, presenting symptoms, delay of diagnosis, specific operative procedures, tumour-related factors, postoperative morbidity, 5-year follow-up, recurrences of the disease and survival.

A detailed family history was obtained including a patient interview, review of hospital and pathology records and death records.

The mean age of the patients was 36 ± 4 years (range 23–50). There were 29 men, 35 ± 5 years (23–40) and 30 women, 37 ± 4 years (24–40). The age distribution was as follows: six patients under 30 years, 16 patients 30–35 years and 37 patients 35–40 years. The diagnosis and extent of the disease was in every case confirmed at operation and histology of the adenocarcinoma and cancer growth in the surgical specimen by an experienced pathologist. Pathological factors included presence or absence of lymphatic and venous invasion and mucinous sub-typing of cancers (Fig. 1).
https://static-content.springer.com/image/art%3A10.1007%2Fs00384-010-0914-9/MediaObjects/384_2010_914_Fig1_HTML.gif
Fig. 1

Survival curves by venous invasion. The cumulative 5-year survivals in patients with and without venous invasion: No venous invasion 83%, venous invasion 0%, P = 0.0001

The tumours were staged according to the Turnbull modification of the Dukes classification [9], and grading was carried out according to the World Health Organisation’s histological classification system [10]. Right-sided cancers were classified as tumours proximal to the splenic flexure and the remaining were defined as distal cancers. Synchronous tumour was defined as the presence of adenoma or carcinoma at the same time in the colon or rectum. Surgical Metachronous tumour was considered presence of another tumour found away from the primary tumour, when detected at least 1 year after primary operation in colonoscopy. Resection was considered radical when there was macroscopic resection of all malignant tissue and no microscopic evidence of surgical margin spread. The operative procedures performed are presented in Table 1.
Table 1

Predisposing conditions and familial clustering of cancer

Predisposing factor

Patients

N

%

HNPCC

11

19

IBD

4

7

 Ulcerative colitis

3

5

 Crohn’s disease

1

2

FAP

3

5

Total

18

31

Familial clustering of tumours

FDR 3 tumours

2

4

FDR 2 tumours

4

7

FDR 1 tumour

5

9

SDR 1 tumour

1

2

FDR 1 and SDR 1 tumour

4

12

Total

16

27

HNNCC hereditary nonpolyposis colorectal cancer, FDR first-degree relative, SDR second-degree relative

The follow-up of all these patients have been carried out in our outpatient clinic according to the follow-up programme of the Department of Surgery of Oulu University Hospital [11]: The patients have been followed up every 3 months for the first 2 years and, thereafter, every 6 months for 2–5 years or until their death. During each visit, medical history for the interval was obtained, a clinical examination was performed, complete blood cell counts and CEA levels were determined. Colonoscopy was a performed 3 months after surgery to ensure a clean colon, if it had not been performed preoperatively, and at 2 and 5 years. Ultrasonography of the liver was performed once a year after surgery and computed tomography or magnetic resonance imaging of the abdomen only to certain obscure findings. The survival data and the date and cause of death were confirmed in every case in January 2009, when the last patient was followed up at least 5 years.

During the follow-up period, five patients have received adjuvant chemotherapy using 5-fluorouracil–leucovorin combination for Dukes C (N = 3) or D (N = 2) colon cancer and five patients radiotherapy of 40 Gy for Dukes D and one for Dukes C rectosigmoid cancers. Local recurrences were defined as recurrent lesions in the anastomotic area or tumour bed, and others were divided into peritoneal seeding and distant metastases. Ten patients underwent later exploratory laparotomy, seven after radical and three after palliative primary operation, five patients received palliative chemotherapy and one received palliative radiotherapy of 40 Gy.

Statistical analysis was performed using the SPSS for Windows 2009. The associations between categorical data were performed using two-tailed χ2 or Fisher’s exact test, and continuous data were compared by Student’s t test. Survival rates were calculated from the time of primary operation using Kaplan–Meier method and survivals were compared using log-rank test. A multivariate analysis of the factors which influenced survival was carried out using the Cox proportional hazards regression model.

Results

Familial predisposing conditions were recorded in 18 (31%) patients and a positive family history of cancer in 16 (27%) patients (Table 1). In first-degree relatives, 18 colorectal tumours (11 cancers and seven adenomas), three ovarian cancers, two endometrial cancers and one neurogenic sarcoma were detected, whereas in second-degree relatives, two colorectal cancers, two endometrial and one gastric cancer were diagnosed.

The duration of preoperative symptoms did not differ between genders: in men, the duration was under 3 months in 16 (27%) patients, 3–6 months in 11 (19%) patients and over 6 months in two (3%) patients, whereas in women, the respective numbers were 22 (37%), seven (12%) and one (2%). The most common symptoms were rectal bleeding [12], change in bowel habits [11], abdominal pain [9] and intestinal obstruction [9]. Nine patients experienced weight loss preoperatively.

Twenty-three (39%) tumours were located in the proximal colon and 36 (61%) in the distal colon. Rectum [13], sigmoid colon [14] coecum [15] and transverse colon were the most frequent anatomic sites. All tumours were colorectal adenocarcinomas; three of them were developed from serrated adenomas. Twenty-three of 59 (39%) patients aged under 40 years had mucinous cancers, whereas there were 135/1,272 (11%) mucinous cancers in the total material. In addition to three patients with familial polyposis, one synchronous cancer and three synchronous adenomas (two tubular, one tubulovillous) were operated on at the same time as primary tumour.

At laparotomy, 46 (78%) patients had local tumours and 13 presented with metastases (six peritoneal metastases, three hepatic metastases, two omental metastases and one pancreatic and lung metastase). In all cases, a resection of the tumour was performed, and in 76% (45/59) of the cases, radical resections were performed. In three of the radical cases, additional resections were necessary: one total hysterectomy and two hepatic resections.

Resective procedures performed, without any significant differences between family history, age groups, duration of preoperative symptoms, preoperative weight loss or location of tumour, are listed in Table 2. In relation to the two genders, there were no significant differences between age groups, weight loss, number of underlying diseases or location of tumour, but men presented with locally more advanced tumours (Table 3). Women underwent more radical resections, 27/30 (90%), than men, 18/29 (62%), P= 0.012.
Table 2

Resective procedures performed in the 59 patients

Procedure

Radical

Palliative

Total

N

%

N

%

N

%

Anterior resection

17

29

4

7

21

36

Abdominoperineal resection

1

2

2

3

3

5

Hartmann’s procedure

1

2

1

2

2

3

Left hemicolectomy

2

3

1

2

3

5

Right hemicolectomy

11

17

4

7

15

25

Total colectomy

13

22

2

2

15

25

Total

45

76

14

24

59

100

Table 3

The most significant clinical variables in relation to gender

Variable

Gender

P value

M

%

N

%

Size of tumour

<20 mm

2

3

3

5

0.229

20 to 50 mm

13

22

19

32

>50 mm

14

24

8

14

 

Grade of tumour

I

7

12

10

17

0.052

II

10

17

16

27

III

12

20

4

7

Dukes classification

A

5

8

9

15

0.026

B

7

12

13

22

C

4

7

5

9

D

13

22

3

5

Lymphatic invasion

Yes

17

29

6

10

0.002

No

12

20

24

41

Number of lymph nodes with metastases

0

11

19

21

36

0.021

1–4

9

15

7

12

>4

9

15

2

3

Venous invasion

Yes

15

25

2

3

0.001

No

14

24

28

48

Metastasized disease

Yes

15

25

2

3

0.288

No

14

24

28

48

Operative and 30-day mortality was 0%. Postoperative morbidity was 31% (14/59), wound infection [4], intra-abdominal abscess [3], pulmonary infection [3] and anastomotic leakage [2], being the most common complications. Two Hartmann’s operations were performed for anastomotic leaks, one intra-abdominal abscess was drained openly and one intestinal resection was done for postoperative occlusion.

One metachronical colon cancer; seven adenomas, three tubular adenomas with moderate dysplasia, four tubulovillous adenomas, one with mild and three with moderate dysplasia and four hyperplastic polyps were detected during endoscopic surveillance in 5-year follow-up.

The cancer of coecum was resected radically, three patients underwent colon resection for large adenomas and the other polyps were removed in endoscopically. One patient with HNPCC developed peri-ampullar pancreatic cancer, and a radical pancreatoduodenectomy was performed.

The recurrence rate in 5 years after radical resection was 38% (17/45). The median asymptomatic period after radical resection until recurrence was 9 months, 61% of the recurrences developed in a year and 89% in 2 years. The recurrence rates in Dukes stages were as follows: Dukes A 14% (2/14), Dukes B 30% (6/20), Dukes C 78% (7/9), Dukes D 100% (2/2). Of the recurrences, four were local, seven patients had peritoneal seeding and six distant metastases, five in the liver and one in the lung.

Three radical re-resections, two abdominoperineal resections and one anterior resection, one palliative colonic resection and four diverting colostomies have been performed for recurrent cancer after radical primary surgery. Five patients have received systemic chemotherapy, and one patient has received pelvic radiotherapy as treatment of recurrence.

The overall cumulative 5-year survival of the whole series was 59%, and the mean survival was 75 ± 6 months. The cumulative 5-year survival according to the Dukes stages was as follows: Dukes A 93%, Dukes B 75%, Dukes C 33% and Dukes D 25%. The cumulative 5-year survival was 45% for men and 73% for women (p > 0.003); after radical resection, it was 66% and after palliative resection 7%.

On univariate analysis, Dukes staging, grade of tumour, lymph node involvement, lymphatic and venous invasion and metastasized disease were significantly predictive for longer survival (Table 4), whereas age, diagnostic delay, loss of weight, number of underlying diseases, tumour site, location of tumour and mucinous tumour were insignificant variables.
Table 4

Univariate analysis of the prognostic factors for 5-year survival (Kaplan–Meier Analysis)

Variable

5-year survival

Mean survival

95% Confidence interval

P value log-rank test

N

%

Months

Gender

Men

13

45

35

26.186–44.021

0.003

Women

22

73

53

58.252–58.789

Dukes staging

A

13

93

109

96.703–121.868

0.001

B

15

75

96

78.249–112.751

C

3

33

44

12.845–74.711

D

4

25

37

16.949–57.156

Grade of tumour

I

14

82

99

81.993–116.007

0.001

II

17

65

82

65.209–99.868

III

4

25

37

14.905–59.845

Lymphatic invasion

Invasion

3

13

28

14.114–42.495

0.001

No invasion

32

91

104

95.662–114.116

Number of lymph nodes with metastases

0

27

84

103

91.912–114.151

0.001

1–4

6

38

50

26.648–72.852

>4

2

18

30

8.074–52.654

Venous invasion

Invasion

0

0

13

8.486–18.808

0.0001

No invasion

35

83

100

89.875–109.887

Metastasized disease

Metastasis

4

31

41

17.400–65.677

0.002

No metastasis

31

67

85

71.265–97.735

Size of tumour

<20 mm

3

60

68

27.004–108.596

0.001

20–50 mm

27

84

100

87.921–112.829

>50 mm

6

27

40

21.592–58.044

In Cox proportional hazard model, only venous invasion (p < 0.001) was independent prognostic factor. Following radical re-resection for recurrent cancer, two patients have survived over 2 years, but the median survival after recurrence remained in 11 months.

Discussion

For the majority of people with a family history of colorectal cancer, particularly those who are 60 years or older, the excess risk of colorectal cancer is not large. The relative risk in all patients with one affected first-degree relative is 1.72, in patients with two or more affected first-degree relatives 2.75 and in those aged under the age 45 with one or more affected first-degree relatives 5.37 [15]. An average of 22.7% of young colorectal cancer patients have reported to have a positive colorectal cancer family history [14], and consequently, 26.6% of those under 40 years have it [16], which is very well in line with our finding, 27%, in Northern Finland.

Earlier, the frequency of predisposing conditions has reported to be an average of 16% in young patients [14], 11.7% before the age 45 years [17] and 38.4% in patients under 40 years, when the patients with a suspected HNPCC are included [18]. Thirty-one percent of our patients had predisposing conditions, which is a very reliable finding, because all our patients with predisposing conditions belong either to local (IBD) or to national registries (FAP, HNPCC).

Young men in Northern Finland seem to have more advanced local disease, with more often lymphatic and venous invasion, than women, but at least in our material, this is not caused by longer duration of preoperative symptoms leading to diagnostic delay. The average delay in presentation, when thought to be related to patient factors, is longer according to a medline literature 6.2 months [14] than in our material 3.3 months, being 3.5 months for men and 2.8 months for women.

When operative mortality is zero, it is extremely important to characterise the independent prognostic factors that possibly influence on survival. In proportional hazards regression model, after controlling for age and stage, males, patients with high-grade tumour, a tumour with venous invasion or tumour adherent to another organ or structure had significantly poorer survival [19]. Liang et al. from Taiwan reported that young patients tend to have more poorly differentiated, mucin-producing and advanced tumours with high incidence of synchronous and metachronous tumours [20]. We had an over-representation of mucinous tumours in this series, but the survival of these patients was not significantly worse than that of those with non-mucinous tumours. Earlier survival of the patients with colorectal mucinous adenocarcinomas and colorectal signet-ring cell carcinomas has been reported to be poorer in advanced stages [21], but in this series, venous invasion remained as the only independent prognostic factor of survival.

The 5-year survival for colorectal cancer patients treated before 40 years has risen since 1970s in Finland because it was 41% between 1970 and 1979 [13], and now, it is 59% in Northern Finland. This is actually the same 59% as in our follow-up study concerning all age groups of patients, which ended in 1995 [11], and this confirms the finding of Fante et al. that survivals between different age groups do not differ significantly [12]. In 951 patients aged less than 40 years with colorectal cancer operated in Denmark 1943–1967, the crude 5-year survival was 32% and the 5-year survival after radical operation 65% [22]. The latter is nearly the same as the 5-year survival after radical surgery in Northern Finland (66%).

A high index of suspicion for colorectal cancer and endoscopic screening of high-risk individuals; first of all, the patients with a positive family history of colorectal cancer and predisposing conditions are needed to shorten diagnostic delay in young patients [23]. The cost–benefit analysis has showed that screening colonoscopy in 40-to 50-year-old first-degree relatives of patients with colorectal cancer is beneficial [24]. When all this is done, there is no more evidence to suggest that younger patients have worse prognosis and do not survive as long as older patients [25, 26].

During the last years, the fluoropyramide-based chemotherapy plus the anti-vascular endothelial growth factor antibody bevacizumab is considered standard first-line treatment for metastatic colorectal cancer [25, 26]. In our series, modern forms of chemotherapy was not used, but it has recently been shown that patients with mucinous colorectal cancer have poorer response to 5-fluorouracil-based first-line [27] and oxaliplatin/irinotecan-based combination chemotherapy [28] and an unfavourable prognosis compared with non-mucous colorectal cancer patients. This reflects the difficulties in the treatment of this special patient group.

The recurrence rate in present series, 38%, was lower than in our 5-year follow-up study, 41% [11]. In spite of this, the follow-up of these young patients must be comprehensive with endoscopy because of large number of metachronous colonic tumours.

In conclusion, venous invasion is an independent predictor of survival among patients aged under 40 years with colorectal cancer. Men present with more advanced local disease than women, which leads to a worse prognosis. The follow-up of these patients have to be exact.

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© Springer-Verlag 2010