췌장암 환자의 치료적 절제후 생존과 재발 양상

Abstract

[한글]

췌장암은 장기의 해부학적 특수성으로 임상 증상이나 이학적 소견이 특징적이지 않아 조기 진단이 매우 어려우며, 진단 당시에 이미 주변 장기로 전이되어 치료적 절제가 불가능한 경우가 많아 예후가 매우 불량한 악성 종양이다. 췌장암의 경우에도 다른 악성 종양과 마찬가지로 치료적 절제술이 가장 좋은 방법이나 치료적 절제술을 시행하더라도 반 수 이상에서 재발하며, 5년 생존율은 10%내외이다. 그러나 일부 보고에 의하면 치료적 절제후 실제 생존율이 20%가 넘는다는 보고도 있다. 췌장암의 예후에 관여하는 인자로는 종양의 크기, 림프절 침범 여부, 조직학적 분화도, 병기 등과 같은 임상병리학적 특징과 아울러 암세포의 생물학적 특징으로 DNA ploidy와 암유전자 및 종양 억제 유전자의 돌연변이 유무 등이 거론되고 있다. 그 중 p53 종양 억제 유전자는 가장 활발하게 연구되고 있는 유전자의 하나로, 췌장암에서의 돌연변이율은 40%내외로 보고되고있으나, 생존율과의 관계는 확실하지 않다. 본 연구에서는 1991년부터 1996년까지 연세대학교 의과대학 세브란스병원에 내원하여 췌장암으로 진단 및 치료를 받은 환자중 생존 여부가 확인된 250예를 대상으로 치료적 절제군과 비치료적 절제군, 보존적 치료군으로 나누어 생존율을 비교하였으며, 치료적 절제를 시행받은 군의 생존에 미치는 각종 임상 병리학적 인자와 재발율 및 재발 양상을 알아보았다. 또한 치료적 절제를 받은 군에서 p53 단백발현율과 P53 단백발현과 각종 임상적 인자와의 관계, 생존율 및 재발율의 차이를 분석하여 다음과 같은 결과를 얻었다.

1. 전체 환자 250예를 병기별로 분류해보면 제 1기가 10예(4%), 제 2기가 41예(16,4%), 제 3기가 71예(28.4%), 제 4기가 128예(51.2%)로 대부분의 경우에서 진단 당시 진행된 병기에서 발견되었다. 전체 환자의 1년 생존율은 16%이었으며, 5년 생존율은 4%로 예후가 불량하였다

2. 치료방법에 따른 분류를 보면 치료적 절제를 시행받은 경우가 31예(12,4%)이었으며, 비치료적 절제를 시행받은 경우가 33예(13.2%), 보존적 치료를 시행받은 경우가 186예(74.4%)이었다. 각 군간의 생존율을 비교해보면 치료적 절제군의 1년 생존율은 58%, 비치료

적 절제군의 생존율은 27%, 보존절 치료군은 7%이었으며(p<0.01), 치료적 절제군의 5년 생존율은 12%이었다. 중앙 생존기간은 치료적 절제군이 14개월, 비치료적 절제군이 9개월, 보존적 치료군이 3개월로 각 군간에 의미있는 차이가 있었다(p<0.01).

3. 췌장암의 치료적 절제후 생존에 영향을 미치는 인자를 분석해보면 60세미만인 군의 중앙 생존 기간은 22개월, 60세 이상군은 10개월로 의미있는 차이를 나타내었으며(p=0.026), 림프절 전이군의 중앙 생존 기간은 10개월, 림프절 비전이군은 24개월로 의미있는 차

이를 나타내었다(p=0,014). 또한 병기별로 보면 제 1기인 경우 중앙 생존 기간이 44개월, 제 2기가 13개월, 제 3기가 10개월로 의미있는 차이를 나타내었다(p=0.019). 그러나 성별, 진단시 총 빌리루빈 수치, CEA, CA 19-9, 췌장암의 위치, 췌장암의 크기, 수술후 보조 치료(항암제 및 방사선치료)유무는 생존에 별다른 영향을 나타내지 못하였다.

4. 치료적 절제를 시행받은 31예중 25예(80.6%)에서 재발을 하였으며, 중앙 재발기간은 10개월이었다. 재발 장소를 정확히 알 수 있었던 경우는 13예이었는데, 재발 양상을 보면 췌장부위의 재발이 9예(69%)로 가장 많았고, 간재발이 8예(62%), 림프절에 재발한 경우가 7예(54%)순이었다.

5. 치료적 절제를 시행받은 31예중 15예(48.4%)에서 면역화학조직염색법에 의한 p53 단백발현이 암세포의 핵에서 관찰되었으며, 16예(51.6%)에서는 단백발현을 관찰할 수 없었다.

6. p53 단백발현 유무를 살펴보면 연령, 성별, 종양의 위치, 종양의 크기, 림프절전이 여부, 병기 등에 따른 차이가 없었다. p53 단백발현이 있었던 15예의 중앙 생존 기간은 14개월로 발현이 없었던 16예의 15개월과 의미있는 차이가 없었다(p=0.389). 또한 p53 단

백발현에 따른 재발율을 보면, 재발 없이 생존하고 있는 6예중 2예(33%)에서, 재발하였거나 흑은 재발로 추정되는 25예중 13예(52%)에서 발현되어 의미있는 차이는 없었다(p=0,411).

이상의 결과로 보아 췌장암은 치료적 절제군에서 비치료적 절제군 및 보존적치료군에 비해 생존기간이 길었다. 그러나 치료적 절제후에도 대부분의 경우에서 재발을 하였으며, p53 단백발현 유무와 췌장암의 임상병리적 특징 및 생존율과의 상관관계는 없었다. 따라

서 췌장암의 장기 생존율을 기대하기 위해서는 조기발견과 조기치료가 필요하리라 생각된다.

Survival and recurrence pattern after curative resection of pancreatic cancer

Young Woong Whang

Department of Medicine The Graduate School, Yonsei University

(Directed by Professor Jin Kyung Kang)

Ductal adenocarcinoma of the pancreas is a lethal disease because early diagnosis

is difficult due to non-specific clinical manifestation and most cases were

diagnosed at advanced stage. Curative resection is only hope for the cure of

pancreatic adenocarcinoma. But after curative resection, most cases of pancreatic

adenocarcinoma were recurred. So 5-year survival rate is about 5-10%. Hut according

to some reports, 5-year survival rate of pancreatic adenocarcinoma after curative

resection is more than 20%. Factors influencing survival after curative resection

of pancreatic adenocarcinoma are clinicopathologic factors such as tumor size,

lymph node involvement, tumor size and stage and biologic factors such as DNA

ploidy, oncogene and tumor suppressor gene. Among them, the mutation rate of p53

turner suppressor gene in pancreatic cancer is about 40%. But the correlation

between mutation of p53 tumor suppressor gene and survival is obscure. The records

of 250patients who diagnosed and treated as pancreatic cancer from January 1991 to

December 1996 were reviewed retrospectively, We classify the patients as 3

groups(curative resection, non-curative resection, and conservative treatment). And

we analyzed factors influencing survival, recurrence rate and recurrence pattern

after curative resection. In addition, we evaluated the expression rate of p53

protein and attempted to clarify the associaton between expression of p53 and

clinicopathologic features including survival in curative resection group.

1. In total 250 cases, the number of patients with stage 1 was 10(4%), stage 2;

41(16.4%), stage 3; 71(28.4%) and stage 4; 128(51.2%). The 1-year survival rate of

total patients was 16% and the 5-year survival rate 4%.

2. According to treatment modality, curative resections were performed in 31

cases(12.4%), non-curative resection; 33 cases(13.2%), and conservative treaeent;

186 cases(74,4%), The 1-year survival rate after curative resection was 58%,

non-curative resection; 27%, conservative treatment; 7%. The 5-year survival rate

of curative resection group was 12%. The median survival time was prolonged in the

patients with curative resection compared t? non-curative resection or conservative

treatment(curative resection; 14 months, non-curative resection; 9 wonts, and

conservative treatment; 3 months)(p<0.01).

3. The factors influencing survival rate after curative resection were age, lympn

node involvement, and stage. The median survival time of the patients less than 60

years was 22 months, but the patients more than 60years; 10 months(p=0.026). The

median survival time of the patients with lymph node involvement was 24 months, but

the patients without lymph node involvement; 10 months(p=0.014). There were

significant differences in median survival time according to stage (stageⅠ; 44

months vs stageⅡ; 13 months and stageⅢ; 10 months)(p=0.019). Sex, total

bilirubin, CEA, CA 19-9, turner location, tumor size and adjuvant therapy did not

influence the survival rate.

4. Among 31 cases of curative resection, 25 cases(80.6%) were recurred, The

median recurrence time was 10 months after curative resection. Local

retroperitoneal recurrence was 69%, liver metastasis; 61%, and lymph node

metastasis; 54%.

5. Positive nuclear p53 immunoactivity was detected in 15 cases(48.4%) of 31

patients with curative resection.

6. No clear correlation was found between p53-Positive immunostaing and

clinicopathologic features such as age, sex, tumor location, turner size, lymph

node involvement and stage, etc. The median survival time was 14months in the group

of p53 positive and 15 months in the group of p53 negative. So no significant

difference was noted between two groups(p=0389). In 6 cases who survive without

recurrence, 2 cases(33%)were p53 positive and in 25 cases with recurrence, 13

cases(52%) were p53 positive. So there was no correlation between the presence of

p53 overexpression and recurrence(p=0.411).

These results suggest that the survival time of pancreatic cancer was prolonged

in the patients with curative resection compared to the patients with non-curative

resection or conservative treatment. But, most cases after curative resection were

recurred. And there was no clear correlation between p53-positive immunostaing and

clinicopathologic features including survival. So early diagnosis and early

treatment is requred to prolong the survival time of pancreatic adenocarcinoma.

[영문]

Ductal adenocarcinoma of the pancreas is a lethal disease because early diagnosis is difficult due to non-specific clinical manifestation and most cases were diagnosed at advanced stage. Curative resection is only hope for the cure of pancreatic adenocarcinoma. But after curative resection, most cases of pancreatic adenocarcinoma were recurred. So 5-year survival rate is about 5-10%. Hut according to some reports, 5-year survival rate of pancreatic adenocarcinoma after curative resection is more than 20%. Factors influencing survival after curative resection of pancreatic adenocarcinoma are clinicopathologic factors such as tumor size, lymph node involvement, tumor size and stage and biologic factors such as DNA ploidy, oncogene and tumor suppressor gene. Among them, the mutation rate of p53

turner suppressor gene in pancreatic cancer is about 40%. But the correlation between mutation of p53 tumor suppressor gene and survival is obscure. The records of 250patients who diagnosed and treated as pancreatic cancer from January 1991 to December 1996 were reviewed retrospectively, We classify the patients as 3

groups(curative resection, non-curative resection, and conservative treatment). And we analyzed factors influencing survival, recurrence rate and recurrence pattern after curative resection. In addition, we evaluated the expression rate of p53

protein and attempted to clarify the associaton between expression of p53 and clinicopathologic features including survival in curative resection group.

1. In total 250 cases, the number of patients with stage 1 was 10(4%), stage 2; 41(16.4%), stage 3; 71(28.4%) and stage 4; 128(51.2%). The 1-year survival rate of total patients was 16% and the 5-year survival rate 4%.

2. According to treatment modality, curative resections were performed in 31 cases(12.4%), non-curative resection; 33 cases(13.2%), and conservative treaeent; 186 cases(74,4%), The 1-year survival rate after curative resection was 58%, non-curative resection; 27%, conservative treatment; 7%. The 5-year survival rate of curative resection group was 12%. The median survival time was prolonged in the patients with curative resection compared t? non-curative resection or conservative treatment(curative resection; 14 months, non-curative resection; 9 wonts, and conservative treatment; 3 months)(p<0.01).

3. The factors influencing survival rate after curative resection were age, lympn node involvement, and stage. The median survival time of the patients less than 60 years was 22 months, but the patients more than 60years; 10 months(p=0.026). The median survival time of the patients with lymph node involvement was 24 months, but the patients without lymph node involvement; 10 months(p=0.014). There were significant differences in median survival time according to stage (stageⅠ; 44 months vs stageⅡ; 13 months and stageⅢ; 10 months)(p=0.019). Sex, total bilirubin, CEA, CA 19-9, turner location, tumor size and adjuvant therapy did not influence the survival rate.

4. Among 31 cases of curative resection, 25 cases(80.6%) were recurred, The median recurrence time was 10 months after curative resection. Local retroperitoneal recurrence was 69%, liver metastasis; 61%, and lymph node metastasis; 54%.

5. Positive nuclear p53 immunoactivity was detected in 15 cases(48.4%) of 31 patients with curative resection.

6. No clear correlation was found between p53-Positive immunostaing and clinicopathologic features such as age, sex, tumor location, turner size, lymph node involvement and stage, etc. The median survival time was 14months in the group of p53 positive and 15 months in the group of p53 negative. So no significant difference was noted between two groups(p=0389). In 6 cases who survive without recurrence, 2 cases(33%)were p53 positive and in 25 cases with recurrence, 13 cases(52%) were p53 positive. So there was no correlation between the presence of

p53 overexpression and recurrence(p=0.411).

These results suggest that the survival time of pancreatic cancer was prolonged in the patients with curative resection compared to the patients with non-curative resection or conservative treatment. But, most cases after curative resection were recurred. And there was no clear correlation between p53-positive immunostaing and clinicopathologic features including survival. So early diagnosis and early treatment is requred to prolong the survival time of pancreatic adenocarcinoma.