Factors Influencing the Late Results of Operation for Carcinoma

of the Pancreas

Toshio Sato, MD, Sendai, Japan

Yoichi Saitoh, MD, Sendai, Japan

Noboru Noto, MD, Sendai, Japan

Seiki Matsuno, MD, Sendai, Japan

With marked improvement in the direct results of radical resection for pancreatoduodenal cancer, the follow-up results of this operation have become in- creasingly favorable as well. However, as far as car- cinoma of the pancreas is concerned, the results of operation continue to be discouraging. The present study reports our results of surgical treatment for carcinoma of the pancreas, with special reference to factors influencing the late results of operation.

Material

Our experience included 151 patients with carcinoma of the pancreas who presented at the surgical clinic of Tohoku University Hospital from January 1960 to December 1976. Ninety-five patients (66 males, 29 females) had carcinoma of the head of the pancreas and fifty-six patients (37 males, 19 females) had carcinoma of the body and tail of the pancreas. Mean age of the patients was 56.6 years: 56.5 years for those with carcinoma of the head of the pancreas and 56.8 years for those with carcinoma of the body and tail of the pancreas. Pancreatectomy was carried out in twenty-two patients with carcinoma of the head of the pancreas (23.2 per cent) and in five patients with carcinoma of the body and tail of the pancreas (8.9 per cent).

Of the ninety-five patients with carcinoma of the head of the pancreas, twenty-two underwent pancreatoduode- nectomy, including three who underwent total pancrea- tectomy, whereas fifty-nine patients underwent a palliative operation and the remaining fourteen only exploratory laparotomy. Eighteen of the ninety-five patients (18.9 per cent) died within one month postoperatively as a direct result of surgery: three (13.6 per cent) after radical resec- tion; 11 (18.6 per cent) after a palliative operation; and four (28.5 per cent) after exploratory laparotomy. Of the fifty- six patients with carcinoma of the body and tail, four un- derwent caudal pancreatectomy and one total pancrea- tectomy, whereas seven underwent a palliative procedure

From the Department of Surgery, Tohoku University School of Medicine, Sendai, Japan.

Reprint requests should be addressed to T. Sato. MD, Department of Surgery, Tohoku University School of Medicine, Sendai 980, Japan.

and forty-four exploratory laparotomy. Nine of the fifty-six patients (16.1 per cent) suffered direct operative deaths: one after a palliative operation and eight after exploratory laparotomy.

Results

Follow-Up

Of the nineteen patients who underwent radical resection for carcinoma of the head of the pancreas, fifteen died within one year ten months. Three of the remaining four patients are now living six years ten months, five years, and one year two months. One other patient died three years two months after op- eration. Of the three patients subjected to total pancreatectomy, one died of intraabdominal bleeding seventeen days after operation and the other two died of cancer recurrence and fulminant hepatitis one year ten months and three months after operation. Three year and five year survival rates of those who un- derwent resection were 18.8 per cent and 13.3 per cent, respectively. (Table I.) The mean survival pe- riods of operated patients were 16.4 months for those who had radical resection, 4.5 months for those who had a palliative operation, and 2.2 months for those who had exploratory laparotomy. Of five patients who underwent resection for carcinoma of the body and tail of the pancreas, the single patient with total pancreatectomy showed the longest survival (1 year

TABLE I Survival Rates After Pancreatoduodenectomy for Patients with Pancreaticoduodenal Cancer

Tumor Site 3 Years No. of Survivors

5 Years 10 Years

Pancreas 3/16 (18.8%) 2115 (13.3%) Of7 Common 9127 (33.3%) 4/19 (21.1%) o/11

bile duct Ampulla 5/13 (38.5%) .5/13 (38.5%) 3/11 (27.3%)

of Vater Total 17756 (30.4%) 11/47 (23.2%) 3729 (10.3%)

582 The American Journal of Surgery

Surgical Results of Pancreatic Carcinoma

TABLE II Grouping and Name of Lymph Node Affected by Carcinoma of the Pancreas

Location of Lymph Nodes in Each Group -.--____ Group I (N,) Group Ii (N2) Group III (Ns)

Carcinoma of the Head Along common hepatic artery Along superior and inferior pancreatico-

duodenal artery In hepatoduodenal ligament At root of mesenterium Suprapyloric and infrapyloric

Carcinoma of the Body and Tail Along splenic artery

Along inferior pancreatic artery At root of mesenterium

Along splenic artery Along greater and lesser curvature Along inferior pancreatic artery Around middle colic artery

At splenic hilus Around celiac artery

Around abdominal aorta

Along superior and inferior pancreatico- duodenal artery

Around celiac artery In hepatoduodenal ligament

Along greater and lesser curvature

Around middle colic artery Around abdominal aorta

Along common hepatic artery Suprapyloric and infrapyloric _

6 months), whereas the other four with caudal pan- createctomy all died within one year of operation. The mean survival periods of patients operated on

were 11.0 months for those who underwent resection, 3 3 months for those who underwent a palliative operation, and 3.5 months for those who underwent

exploratory laparotomy.

Classification of the Macroscopic Stage of Carcinoma

We classified the macroscopic stage of carcinoma to study its relationship to prognosis. The classifi-

cation was made in a total of 110 available patients, consisting of seventy-five with carcinoma of the head

of the pancreas and thirty-five with carcinoma of the body and tail of the pancreas.

Lymph Node Metastasis. Lymph node metastasis in patients with carcinoma of the head of the pan-

creas observed at the time of laparotomy occurred frequently at the root of mesenterium (55.5 per cent),

at the posterior aspect of the head of the pancreas (53.S per cent), along the common hepatic artery

(33.Z per cent), and within the hepatoduodenal ligament (31.1 per cent), whereas it occurred infre- quently along the splenic artery (6.7 per cent), at the splenic hilus (2.2 per cent), and around the celiac

artery (8.9 per cent). On the other hand, lymph node metastasis in patients with carcinoma of the body and tail was high in incidence along the splenic artery (64.3 per cent), along the common hepatic artery (64.3 per cent), and at the root of the mesenterium (57.1 per cent), whereas the incidence was relatively low at the posterior aspect of the head of the pancreas and within the hepatoduodenal ligament. In addi- tion, in twenty patients with carcinoma of the head o-F the pancreas undergoing resection, including three undergoing total pancreatectomy, metastases were histologically identified in twenty-seven of forty- eight lymph nodes along the posterior arcade of the p,ancreaticoduodenal artery, in eight of sixteen lymph nodes along the common hepatic artery, and in some

Volume 136, November 1976

each within the hepatoduodenal ligament and the suprapyloric and infrapyloric lymph nodes. However, in the body and tail of the pancreas, lymph node metastasis was found in only one of four nodes along

the inferior pancreatic artery and another one of seven along the splenic artery, but in no nodes at the

splenic hilus. This result has led us to believe it reasonable to

assort the lymph nodes according to their association

with either the head or the body and tail of the pan- creas. Accordingly, we classified the regional lymph nodes of the pancreas as shown in Table II: lymph nodes of groups I, II, and III are referred to as Nr, Nz,

and N:l, respectively. Distant lymph nodes located further than group III are referred to as N,+. N1 (+), NZ (+), and N:3 (+) indicate positive metastasis in lymph nodes of groups I, II, and III, respectively. N (-) indicates no lymph node metastasis. Of patients with carcinoma of the head of the pancreas, 32 per cent had lymph nodes classified as N (--) and 40 per cent had nodes classified as N1 (+). Of patients with carcinoma of the body and tail, 11.4 per cent had

lymph nodes classified as N (-) and 37.1 per cent had nodes classified as N2 (+). (Table III.)

Capsular Invasion. Macroscopic cancer invasion to the pancreatic capsule was classified as follows: Co, no invasion to the capsule; C,, suspected invasion to the capsule; Cz, definite invasion to the capsule; and Cz, invasion into surrounding tissues. Since the in- filtration of cancer into the duodenum is considered different from that into the stomach or the major blood vessels, cases of infiltration limited to the wall of the duodenum not extending to the capsule or the surrounding tissues were not classified C:3, but rather Cl-C2, according to the extent of infiltration. In pa- tients with carcinoma of the head, 20.0 per cent had disease graded Co and 73.3 per cent had C1 and C2 invasion. Of patients with carcinoma of the body and tail, only 8.6 per cent had no capsular invasion (Cc). (Table IV.)

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Sat0 et al

TABLE III Lymph Node Metastasis

Degree of No. of Patients

Ca of Body Metastasis Ca of Head and Tail Total

N (-) 24 (32.0%) 4 (11.4%) 28 (25.5%) NI (+) 30 (40.0%) 8 (22.9%) 38 (34.5%) Nz (+) 15 (20.0%) 13 (37.1%) 28 (25.5%) N3(+) 5 (6.7%) 9 (25.7%) 14 (12.7%) N4(+) 1(1.3%) 1 (2.9%) 2 (1.8%) Total 75 35 110

Carcinoma of the Pancreas. As to individual staging of carcinoma of the pancreas, stages corre- sponding to items of Table V were obtained, and the highest stage among them was adopted as that for each individual. Pancreas cancer with peritoneal dissemination and liver metastasis was designated stage IV. According to this classification, of patients with carcinoma of the head of the pancreas, 9.3 per cent had stage I disease, 29.3 per cent had stage II disease, 22.7 per cent had stage III disease, and 38.7 per cent had stage IV disease. Of patients with car- cinoma of the body and tail of the pancreas, none had stage I disease, 17.1 per cent had stage II disease, 20.0 per cent had stage III disease, and 62.9 per cent had stage IV disease. In all, 46.4 per cent of patients had stage IV disease. (Tables VI and VII.)

Prognosis according to the Macroscopic Stage of Carcinoma

The relationship between the stages of carcinoma of the pancreas and postoperative survival was studied in reference to the type of operation per- formed in seventy-five patients with carcinoma of the head of the pancreas and in thirty-five with carci- noma of the body and tail of the pancreas. In the patients with carcinoma of the head, the mean sur- vival periods were 2.2 months for those who under- went exploratory laparotomy and 4.5 months for those who underwent a palliative operation. No pa- tient with stage IV disease underwent resection. Those with stage III disease who underwent resection had survival periods markedly shorter than those with stage I or stage II disease. The mean survival of 16.4 months for those who underwent resection

TABLE V Staaina of Carcinoma of the Pancreas

Lymph Node Capsular Stage Metastasis Invasion

I N (-) co II Ni (+) NP(+) Cl

Ill N3(+) c2

IV N4(+) c3

Note: When peritoneal dissemination and liver metastasis were involved, the disease was considered stage IV.

TABLE IV Capsular Invasion

No. of Patients Degree of Ca of Body Invasion Ca of Head and Tail Total

Co 15 (20.0%) 3 (8.6%) 18 (16.4 %) Cl 22 (29.3%) 7(20%) 29 (26.4 %) CP 33 (44.0%) 15 (42.9%) 48 (43.6 %) c3 5 (6.7%) 10 (28.8%) 15 (13.6 %) Total 75 35 110

compared favorably with the survival of patients who underwent a palliative operation. (Table VI.) Of the patients with carcinoma of the body and tail, none with stage II or IV disease underwent resection. The mean survival period was 11.0 months for patients w.ith resection, contrasted with the shorter periods of 3.5 months and 3.3 months for those who uader- went exploratory laparotomy and a palliative oper- ation, respectively. (Table VII.)

The relationship in nineteen patients who under- went pancreatoduodenectomy between postoperative survival periods and various factors including the size of tumor, lymph node metastasis, and cancer inva- sion to the pancreatic capsule was determined. With relation to the size of tumor, the mean survival pe- riods were 19.5 months in four patients with a tumor less than 2 cm in diameter (T,), 11.3 months in twelve patients with a tumor 2 to 5 cm in diameter (Tz), and 29.3 months in three patients with a tumor with 5 to 10 cm in diameter (Ts). Six patients without lymph node metastasis survived a mean of 22.0 months, compared with thirteen patients with lymph node metastasis who survived 13.1 months. In relation to cancer invasion to the pancreatic capsule, nine pa- tients with no iniasion survived a mean of 24.8 months, compared with ten patients with positive invasion who survived a mean of 8.9 months. The results suggest that in resected patients prognosis is not affected by the size of tumor, but it is influenced by lymph node metastasis and cancer invasion to the pancreatic capsule, particularly by the latter.

Residual Cancer at Cut Edge of the Pancreas

Among the present patients with carcinoma of the head of the pancreas subjected to pancreatoduode- nectomy, five could be autopsied. Of these five pa- tients, two died six months and eleven months after operation. One of these two had evidence of cancer recurrence in the remaining pancreas at the site of the pancreaticojejunostomy and one in the tail of the pancreas. Three patients, including these two, with cancer recurrence in the pancreas showed metastasis in both lobes of the liver. In one of these three with hepatic metastasis autopsied one year after opera- tion, no carcinoma was found in the remaining pan-

584 The American Journal of Surgery

Surgical Results of Pancreatic Carcinoma

TABLE VI Survival and Stage of Carcinoma of the Head of the Pancreas (75 patients)

Survival (mo) of Patients according to Stage Average Surgical Stage I Stage II Stage III Stage IV Survival Total

Treatment Survival Patients Survival Patients Survival Patients Survival Patients (mo) Patients ____

Exploratory laparotomy 3.0 1 2.0 5 2.2 6 Palliative operation 1.5 1 5.8 13 4.8 9 3.9 24 4.5 47

Resection 21.3 6 19.1 9 6.6 7 16.4 22 Average 18.5 11.7 5.6 3.7 8.6

Total 7 22 17 29 75

cress, but there were extensive metastases around the

bile duct and at, the hepatic hilus as well as in the liver.

In three patients subjected to total pancreatec- tomy, two with carcinoma of the head of the pancreas had cancer cells on the usual line of resection, and the other with carcinoma of the body and tail showed cancer infiltration on the line of resection of caudal pancreatectomy, this patient undergoing later ad-

ditional resection of the remaining head of the pan- creas. The patient died from fulminant hepatitis three months after operation with no hepatic me- tast asis grossly, although several metastatic tumors in the right lobe of the liver were revealed at autop-

sy.

Comments

According to previous reports, in patients with carcinoma of the head of the pancreas undergoing

radical resection, the most important factor in- fluencing the follow-up results is the presence of re-

gional lymph node metastasis. Richards and Sosin [I], in their patients undergoing pancreatoduode- nectomy, noted a mean survival of 22.3 months for eleven patients without lymph node metastasis ver- sus 12.7 months for eleven other patients with lymph node metastasis. Warren et al [2], observing lymph node metastasis in 28 per cent of their patients

uncergoing pancreatoduodenectomy, also noted five year survival in 16.8 per cent of seventy-seven pa- tients without lymph node metastasis and in 7.4 per cent of twenty-seven patients with lymph node me- t.astasis. In the present series, six patients without lyrrph node metastasis survived a mean of 22.0

months versus 13.1 months for thirteen patients with lymph node metastasis. The results indicate that in cancer of the pancreas, like in cancer of other organs, the presence of lymph node metastasis significantly

affects the prognosis of the patients. The regional lymph nodes of the pancreas to be

dissected have not yet been clearly defined, with their naming varying with different authors. We think it valid to classify the regional lymph nodes of the

pancreas as shown in Table II. In carrying out pan- creatoduodenectomy or caudal pancreatectomy, it is essential to excise all the lymph nodes not only in

group I, but also in group II, as thoroughly as possi- ble.

Direct invasion of carcinoma of the pancreas is seen in two ways: into the surrounding tissues or or- gans and into the parenchyma of the pancreas. In the present series, the tumor remained within the pan-

creatic parenchyma in 20.0 per cent of the patients with carcinoma of the head, compared with only 8.6

per cent of the paGents with carcinoma of the body and tail. Of patients with carcinoma of the head of

the pancreas who underwent resection, those with- out capsular invasion survived a mean of 24.8 months contrasted with 8.9 months for those with capsular

invasion. This result suggests that the presence of cancer invasion to the pancreatic capsule strongly influences the prognosis of the patients.

In patients with carcinoma of the head of the pancreas, the boundary of the tumor is often obscure because secondary pancreatitis on t.he caudal side is likely to cause the parenchyma to feel solid upon palpation. Thus, not infrequently cancer cells remain on the line of resection. Hicks and Brooks [s] found cancer cells on the line of resection aft.er pancreato-

TABLE VII Survival and Stage of Carcinoma of the Body and Tail (35 patients)

Surgical Treatment

Survival (mo) of Patients according to Stage Stage I Stage II Stage III

Survival Patients Survival Patients Survival Patients

Average survival Total

(mo) Patients ---

Exploratory laparotomy 2.9 4 3.7 17 3.7 21 Palliative operation 3.0 1 3.5 3 3.0 5 3.3 9 Resection 11.0 5 11.0 5 Average 9.7 3.1 3.6 4.9 Total 6 7 22 35

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Sat0 et al

duodenectomy in six of their eleven patients. Brooks and Culebras [4] also observed cancer cells on the usual line of resection in seven of sixteen patients subjected to total pancreatectomy. Residual cancer was also identified by Warren et al [2] in eighteen of 150 resected patients (13 per cent) with carcinoma of the head of the pancreas. In four of our patients subjected to total pancreatectomy, two with carci- noma of the head had cancer cells on the usual line of resection and one with carcinoma of the body and tail showed residual cancer cells at the cut edge of caudal pancreatectomy. From the point of view of the possibility of thorough dissection of the regional lymph nodes and lymphatic network as well as the eradication of cancer foci, total pancreatectomy is preferable to pancreatoduodenectomy. However, up to now, total pancreatectomy does not seem to have improved significantly the survival rate of the pa- tients.

Present results show that the size of the tumor had no distinctive influence on the length of survival of the patient. Even large tumors, if limited within the pancreatic parenchyma, often occurred in patients with a long survival.

As factors affecting prognosis, we have considered lymph node metastasis and cancer invasion to the pancreatic capsule to classify the macroscopic stages of carcinoma of the pancreas. There have been sev- eral previous attempts to grade the stages of carci- noma of the pancreas. Hermreck, Thomas, and Friesen [5] placed emphasis on lymph node metas- tasis rather than on capsular invasion. Their grading was as follows: stage I, local disease only; stage II, invasion into surrounding tissues (duodenum, portal vein, and mesenteric vessels); stage III, metastases to regional lymph nodes; and stage IV, generalized carcinoma. An almost similar classification was presented by Dencker [6]. Leadbetter, Foster, and Haines [7], following the definition of the Vermont Tumor Registry, classified the stages as follows: stage I, confinement to the organ of origin; stage II, in- volvement of regional lymph nodes or adjacent tissue; and stage III, distant metastatic involvement. Such differences in stage classification seem to account for dissimilar evaluations of lymph node metastasis and capsular invasion. The classification of Hermreck, Thomas, and Friesen [5] is similar to Duke’s classi- fication, the validity of which has been evaluated in colonic cancer, in which prognosis is more affected by lymph node metastasis than by serosal infiltra- tion. Our results, however, indicated that prognosis was affected more significantly by capsular invasion than by lymph node metastasis, implying that car- cinoma of the pancreas, as opposed to colonic cancer, is more similar to gastric cancer, in which prognosis

is usually unfavorable when there is serosal invasion. Among our patients with carcinoma of the head of the pancreas, those subjected to pancreatectomy had a longer survival than those subjected to a palliative operation, but in those with stage III disease, resec- tion proved less significant. In patients with carci- noma of the body and tail, some with stage II disease were able to undergo resection but showed no long- term survival (mean survival, only 11.0 months). Brooks and Culebras [4] recommended total pan- createctomy for patients with stages I and II disease according to the classification of Hermreck, Thomas, and Friesen [5] and a bypass operation for those with stages III and IV disease. The time now seems ripe for surgeons to determine exactly the stage of pro- gression of carcinoma of the pancreas to select the most promising type of operation adapted to each stage of the disease.

Summary

In 151 patients with carcinoma of the pancreas presenting at the surgical clinic of Tohoku University Hospital, predominant factors affecting postopera- tive prognosis were studied with relation to the stages of the disease. The presence of lymph node metas- tasis and of cancer invasion to the pancreatic capsule, particularly the latter, was apparently a significant factor most cruci,ally affecting the survival of the patients who underwent pancreatoduodenectomy. The mean survival periods of resected patients were 16.4 months for those with carcinoma of the head of the pancreas and 11.0 months for those with carci- noma of the body and tail of the pancreas, distinctly longer than after palliative operations. However, in patients with stage III disease, pancreatoduodenec- tomy tended to lead to a shorter period of survival, suggesting that surgery at that stage is generally unpromising for cure.

References

1. Richards AB. Sosin H: Carcinoma of the pancreas: the value of radical and palliative surgery. Ann Surg 177: 325, 1973.

2. Warren KW, Choe IX, Plaza J, Relihan M: Results of radical resection for periampullary cancer. Ann Surg 181: 534, 1975.

3. Hicks RE, Brooks JR: Total pancreatectomy for ductal carcinoma. Surg Gynecol Obstef 133: 16, 1971.

4. Brooks JR, Culebras JM: Cancer of the pancreas. Palliative op- eration, Whipple procedure, or total pancreatectomy? Am J Surg 131: 516, 1976.

5. Hemueck AS, Thomas CY, Friesen SR: Importance of pathologic staging in the surgical management of adenocarcinoma of the exocrine pancreas. .Am J Surg 127: 653, 1974.

6. Dencker H:. Pancreaticoduodenkctomy for periampullary tu- mours. Acta Chir Stand 138: 293, 1972.

7. Leadbetter A, Foster RS, Haines CR: Carcinoma of the pancreas. Results from the Vermont Tumor Registry. Am J Surg 129: 356, 1975.

586 The American Journal of Surgery