A Clinicopathologic Study on Neural Invasion in Cancer of the Pancreatic Head

Transcription

1 930 A Clinicopathologic Study on Neural Invasion in Cancer of the Pancreatic Head Takukazu Nagakawa, MD, Masafo Kayahara, MD, Keiichi Ueno, MD, Tefsuo Ohta, MD, Ichiro Konishi, MD, Nobuhiko Ueda, MD, and Ifsuo Miyazaki, MD Thirty-four patients who had resection of cancer of the pancreatic head were examined clinicopathologically to elucidate neural invasion of cancer of the pancreatic head to the extrapancreatic nerve plexus. Invasion of cancer to the retropancreatic tissue (rp+) was observed in 29 (85%) of the 34 patients, and neural invasion to the extrapancreatic nerve plexus was observed in 21 (72%) of the 29 patients with rp+. The incidence of invasion to the second region of the nerve plexus of the pancreatic head was high (14 patients; 67%). The degree of the neural invasion tended to increase as the intrapancreatic neural invasion became more severe and lymph vessel invasion more marked. Based on these findings, en bloc resection of the retropancreatic tissue involving the nerve plexus and fat tissue is necessary in the surgical treatment of cancer of the pancreatic head. Cancer 1992; Pancreatic cancer is known to invade nerves. In our department, we have emphasized the importance of retroperitoneal dissection of pancreatic cancer and have focused on recognition of neural invasions up to the nerve plexus of the pancreatic head in pancreatic cancer. '-* Since neural invasion and invasion into the extrapancreatic nerve plexus were added to items in The General Rules of Clinical and Pathological Management for Carcinoma of the Pancreas5 in 1986, neural invasion has been a concern in the treatment of pancreatic cancer. However, the mechanisms by which cancer cells invade nerve and by which the cancer cells in the nerves develop have not been determined clinicopathologicall y. In the current study, resected cases of cancer of the pancreatic head were investigated clinicopathologically to elucidate the significance of invasion into the extrapancreatic nerve plexus, particularly neural invasion. From the Department of Surgery 11, School of Medicine, Kanazawa University, Kanazawa, Japan. Address for reprints: Takukazu Nagakawa, MD, Kanazawa University, School of Medicine, Department of Surgery 11, Takaramachi 13-1, Kanazawa, Ishikawa 920, Japan. Accepted for publication May 20, Patients and Methods Thirty-four patients who could undergo an extensive histopathologic examination were selected from 43 patients who had resection of cancer of the pancreatic head at the Second Department of Surgery, School of Medicine, Kanazawa University, Kanazawa, Japan, between November 1976 and December Excised specimens with cancer involvement were prepared for step sections (at 5-mm intervals) after being fixed in formalin and stained with hematoxylin and eosin and elastica van Gieson. Histologic findings were evaluated according to The General Rules of Clinical and Pathological Management for Carcinoma of the Pancreas by the Japan Pancreas Society.' Tumor size was based on the maximum diameter "t": 2.0 cm or less was classified as t,,2.1 to4.0cmast2,4.1 to6.0cmast3,and6.1cmor more as t,. Lesions included in t, were subdivided into t,, (3 cm or less) and t,, (3.1 cm or more). The local extent of disease also was evaluated as anterior capsule of the pancreas not invaded or invasion of the anterior capsule, and retropancreatic tissue not invaded (rp-) or invasion of the retropancreatic tissue (rp+) depending on whether the retroperitoneum was invaded. The amount of interstitial (connective) tissue in the tumor tissue was classified into three types: medullary, intermediate, and scirrhous. The growth pattern of the tumor was categorized into three types: expansive growth with clear margins as alpha-infiltration, intermediate between alpha-infiltration and gamma-infiltration as beta-interferon, and infiltrative growth without clear margns as gamma-infiltration. The degree of cancer cell invasion into lymph vessels of the pancreas was divided into ly, to ly,. The statistical differences were evaluated with the use of the chi-square test. The neural invasion was evaluated according to the following criteria: Definition of Neural Invasion Because the lateral border of the parineurium often is obscure at the site of cancer and its surrounding area,

2 Neural Invasion in Cancer of the Pancreatic Head/Nagakawa et al. 931 the cases in which cancer cells were present in the medial perineurium were regarded as having neural invasion. Definition of Invasion to the Extrapancreatic Invasion to the extrapancreatic nerve plexus was defined as neural invasion to the extrapancreatic nerve plexus and was designated by plx-ne. Degree of Neural Invasion Neural invasion in the pancreas was expressed by ne, and invasion to the extrapancreatic nerve plexus was expressed by plx-ne as described above. The degree of invasion was divided into four stages (ne,, ne,, ne2, and ne3 and plx-ne,, plx-ne,, plx-ne,, and plx-ne,) in terms of neural invasion to the intrapancreatic and extrapancreatic nerve plexuses, respectively, according to The General Rules of Clinical and Pathological Management for Carcinoma of the Pancreas. As shown in Table 1, this division was based on the number of nerve fascicles with neural invasion found in one histologic section. Results Invasion to the Tissue Adjacent to the Retropancreatic Surface Of 34 patients with cancer of the pancreatic head, 5 had rp- and 29 had rp+. Of 29 patients with rp+, 8 (28%) had plx-ne- and 21 (72%) had plx-ne+. Thus, the incidence of invasion to the extrapancreatic nerve plexus was high. There was no significant difference between tumor size and invasion to the retropancreatic surface. The incidence of invasion to the retropancreatic region was high regardless of tumor size, particularly in the case of rp+ in two patients with t, tumors (Table 2). Investigation of the relationship between tumor size and inva- Table 1. Degree of Neural Invasion neo, plx-ne, ne,, plx-ne, nez, plx-nez ne3, plx-ne3 No. of nerve fascicles* ne: intrapancreatic neural invasion; plx-ne: invasion to the extrapancreatic nerve pluxus. Ne,-3 and plx-ne,-, express the degree of respective neural invasions. * The average number per slice of nerve fascicles with neural invasion found in one histolosic section. lot Table 2. Correlation of Tumor Size With Retropancreatic Invasion P - P + tl 0 2 tza 3 7 t2b 1 12 t3 1 7 t4 0 1 tl: < 2.0 cm; t2a: cm; t2b: cm; t,: cm; t4: cm; rp-: tumor remains within the pancreas; rp+: evidence of invasion of retroperitoneal connective tissue or retroperitoneal viscera. No significant difference between tumor size and rp. sion to the extrapancreatic nerve plexus in 29 patients with rp+ showed that the incidence of the invasion was high regardless of tumor size and that two patients with t, tumors had invasion to the nerve plexus of the pancreatic head (Table 3). Sites With Invasion to the Extrapancreatic Two patients each had invasion to the nerve plexus of the hepatoduodenal ligament (plx hdl) alone and invasion to the first region of the nerve plexus of the pancreatic head (plx pcl); one of these patients also had invasion to the plx hdl. Eleven patients had invasion to the second region of the nerve plexus of the pancreatic head (plx pcll); 3 of these patients had invasion to the plx hdl. The other three patients had invasion to the plx pcl and plx pcll, and two of these also had invasion to the plx hdl. Overall, 14 patients (67%) had invasion to the plx pcll (Fig. 1 and Table 4). Growth Pattern of the Tumor and Intrapancreatic Neural Invasion One patient with alpha-infiltration had ne, and another had net, but there was a significant difference between the growth pattern of the tumor and the degree of in- Table 3. Correlation of Tumor Size With Invasion to the Extrapancreatic plx-ne- plx-nes plx-ne-: no evidence of invasion of extrapancreatic plexi; plx-ne: evidence of invasion of extrapancreatic plexi; t,: I 2.0 cm; t2a: cm; t2b: cm; ts: cm; t,: cm.

3 932 CANCER February 15,1992, Volume 69, No. 4 Table 5. Correlation of Tumor Growth Pattern With Intrapancreatic Neural Invasion INFn (2 cases) 1 (50%) 1 (500/,) 0 0 INFO (14 cases) 0 9 (64%) 4 (29%) 1 (7%) INFy (18 cases) 0 12 (67%) 5 (28%) 1 (5%) INFa: expansive growth with clear margins; INFO: intermediate between a and y; INFy: infiltrative growth without clear margins; neo: no neural invasion; ne,: minimal neural invasion; nez: moderate neural invasion; ne3: severe neural invasion. Significant difference between growth pattern and intrapancreatic neural invasion (P < 0.05) the tumor and the degree of the intrapancreatic neural invasion (P < 0.01) (Table 6). Relationship Between Intrapancreatic Neural Invasion and Invasion to the Extrapancreatic Figure 1. Nerve plexi around the head of the pancreas. Plx hdl: nerve plexus of the hepatoduodenal ligament; plx pcl: first region of the pancreatic head; plx pcll second region of the nerve plexus of the pancreatic head; plx sma: nerve plexus around the superior mesenteric artery; rcg: right celiac ganglion; Icg: left celiac ganglion; ca: celiac artery; sma: superior mesecteric artery. trapancreatic neural invasion in patients with beta-infiltration and those with gamma-infiltration (P < 0.05) (Table 5). Relationship Between the Amount of Interstitial Connective Tissue in the Tumor Tissue and Intrapancreatic Neural Invasion The incidence of intrapancreatic neural invasion was higher in the intermediate and scirrhous types than in the medullary type. There was a significant difference between the amount of interstitial connective tissue in Table 4. Site of Invasion to the Extrapancreatic Site No. of cases Plx hdl 2 Plx pci 2 PIX pcil 11 Plx pci Others 3 ~ PIX hdi: nerve plexus of the hepatopencreatic ligament; PIX pci: first portion of the pancreatic nerve plexus; Plx pci1 second portion of the pancreatic nerve plexus. None of the patients with ne, had invasion to the plxne,. However, of 29 patients with rp+, 1 with ne, and 1 with ne3 had invasion to the plx-ne,. The cases with intrapancreatic neural invasion were divided into ne, and ne2 to ne3 to determine the presence or absence of invasion to the extrapancreatic nerve plexus. Of 18 cases with ne,, 6 (33%) were negative and 12 (66%) were positive for invasion to the plex-ne. However, of 11 cases with ne2 to ne,, 2 (18%) were negative and 9 (82%) were positive for invasion to the plx-ne. This shows that the incidence of invasion to the extrapancreatic nerve plexus increased with an increase in the incidence of intrapancreatic neural invasion (Table 7). Relationship Between Lymph Vessel Invasion and Intrapancreatic Neural Invasion As shown in Table 8, no correlation was found between lymph vessel invasion and intrapancreatic neural invasion. However, when the cases with lymph vessel invasion were divided into ly, to ly, and ly, to ly, and those with intrapancreatic neural invasion were divided into ne, to ne, and ne, to ne3, of ten cases with ly, to ly,, Table 6. Relationship Between Amount of Intestinal Connective Tissue and Intrapancreatic Neural Invasion nea riel ne2 ne3 Med (2 cases) 1 (50%) 1 (50%) 0 0 Int (15 cases) 0 9 (60%) 5 (33%) 1 (7%) Sci (17 cases) 0 12 (71%) 4 (23%) 1 (6%) Med: medullary type; Int: intermediate type; Sci: scirrhous type; ne,: no neural invasion; ne,: minimal neural invasion; ne2: moderate neural invasion; ne3: severe neural invasion. Significant difference between amount of the tumor and intrauancreatic neural invasion (P < 0.01L

4 Neural Invasion in Cancer of the Pancreatic Head/Nagakawa et al. 933 Table 7. Relationship Between Intrapancreatic Neural Invasion and Invasion to the Extrapancreatic plx-ne, plx-ne, plx-ne2 plx-ne, ne, (18 cases) 6 (33%) 7 (39%) 5 (28%) 0 ne2 (9 cases) 1 (llo/o) 5 (56%) 2 (22%) 1 (llo/o) ne3 (2 cases) 1(50%) (50%) ~ pix-ne,: no evidence of invasion of extrapancleatic piexi; pix-nel: minimal invasion of extrapancreatic nerve plexi; plx-ne,: moderate invasion of extrapancreatic nerve plexi; pix-ne,: severe invasion of extrapancreatic nerve plexl eight (80%) had ne, to ne, and two (20%) had ne2 to ne,. Among 24 cases with ly, to ly,, 15 (62%) had ne, to ne, and 9 (38%) had ne, to ne,, showing a slight increase in intrapancreatic neural invasion in the ly, to ly, cases. Relationship Between Lymph Vessel Invasion and Invasion to the Extrapancreatic The 29 cases with rp+ were examined for the relationship between lymph vessel invasion and invasion to the extrapancreatic nerve plexus. None of the cases with ly, had plx-ne invasion, whereas those with ly, or greater had plx-ne. Cases with lymph vessel invasion were divided into two groups, ly, to ly, and ly, to ly,, which were compared for the presence or absence of invasion to the extrapancreatic nerve plexus. Four (57%) of 7 cases with ly, to ly, were positive for plx-ne, whereas 17 (77%) of 22 cases with ly, to ly, were positive for plxne. Thus, the invasion to the extrapancreatic nerve plexus was marked in cases with increased lymph vessel invasion (Table 9). Relationship Between Intrapancreatic Neural Invasion and Lymph Node Metastasis As shown in Table 10, there was no correlation between intrapancreatic neural invasion and lymph node metastasis in the 34 patients with resection. Table 9. Relationship Between Lymph Vessel Invasion and Invasion to the Extrapancreatic ~ plx-ne, plx-ne, plx-ne, plx-ne, lyo (1 case) lyi (6 cases) 2 (33%) 2 (33%) 1(17%) 1(17%) ly2 (13 cases) 4 (31%) 6 (46%) 2 (15%) 1 (So/,) ly, (9 cases) 1 (19%) 4 (44%) 4 (44%) 0 ly,: no invasion of lymphatic vessels; ly,: minimal invasion of lymphatic vessels; ly,: moderate invasion of lymphatic vessels; ly,: severe invasion of lymphatic vessels; pix-ne,: no evidence of invasion of extrapancleatic nerve plexi; plx-ne,: minimal invasion of extrapancleatic nerve plexi; plx-ne2: moderate invasion of extrapancleatic nerve plexi; plx-ne,: severe invasion of extrapancleatic nerve plexi. Relationship Between Invasion to the Extrapancreatic and Lymph Node Metastasis The 29 cases with rp+ were examined for the relationship between invasion to the extrapancreatic nerve plexus and lymph node metastasis. As shown in Table 11, none of the cases with no showed plx-ne,, but there was no correlation as a whole between these parameters. Relationship Between Invasion to the Extrapancreatic and the Site of Lymph Node Metastasis Of the 29 patients with rp+, 6 (75%) of 8 without invasion to the plx-ne had positive results for lymph node metastasis; 13 metastases occurred in 6 of these patients (75%), whereas 14 metastases occurred in 2 (25%). Seventeen (81%) of 21 patients with invasion to the plx-ne had metastases; 13 metastases occurred in 15 patients (71%) (as in the plx-ne- group), and 14 metastases occurred in 9 patients (43%) (slightly higher than that in the plx-ne- group). Furthermore, the incidence of metastasis was investigated in the 21 patients with invasion to the plx-ne according to the site of invasion to the extrapancreatic nerve plexus. There was no difference in the incidence of 14 lymph node metastases among Table 8. Relationship Between Lymph Vessel Invasion and Intrapancreatic Neural Invasion ne, ne, ne2 ne3 lyo (2 cases) 0 1(50%) 1(50%) 0 lyl (8 cases) 1 (13%) 6 (74%) 0 1(13%) ly2 (14 cases) 0 9 (64%) 4 (29%) 1 (7%) ly, (10 cases) 0 6(60%) 4(40%) 0 ly,: no invasion of lymphatic vessels; ly,: minimal invasion of lymphatic vessels; ly2: moderate invasion of lymphatic vessels; ly,: severe invasion of lymphatic vessels; ne,: no neural invasion; ne,: minimal neural invasion; ne2: moderate neural invasion; ne3: severe neural invasion. Table 10. Relationship Between Intrapancreatic Neural Invasion and Lymph Node Metastasis no (8 cases) 0 6 (75%) 2 (25%) 0 n, (18 cases) 1 (6%) 11 (60%) 5 (28%) 1 (6%) n2 (8 cases) 0 5 (63%) 2 (25%) 1 (12%) n,: no evidence of regional lymph node involvement; n,: evidence of lymph node involvement in the primary group; n,: evidence of lymph node involvement in the secondary group; ne,: no neural invasion; riel: minimal neural invasion; ne,: moderate neural invasion: ne,: severe neural invasion.

5 934 CANCER February 15, 1992, Volume 69, No. 4 Table 11. Relationship Between Invasion to the Extrapancreatic and Lymph Node Metastasis plx-ne, plx-ne, plx-ne, plx-ne, no (6 cases) 2 (33%) 3 (50%) 1 (17%) 0 n, (15 cases) 5 (33%) 6 (40%) 3 (20%) 1 (7%) n2 (8 cases) 1(13%) 3 (37%) 3 (37%) 1 (13%) no: no evidence of regional lymph node involvement; n,: evidence of lymph node involvement in the primary group; n2: evidence of lymph node involvement in the secondary group: plx-neo: no evidence of invasion of extrapancleatic nerve plexi; plx-ne,: minimal invasion of extrapancleatic nerve plexi; plx-n,: moderate invasion of extrapancleatic nerve plexi; plx-ne,: severe invasion of extrapancleatic nerve plexi. the sites of invasion: 6 (43%) of 14 patients with plx pcll and 3 (43%) of 7 patients with invasion to sites other than the plx pcll (Fig. 1). Discussion With the goal of improving the treatment of pancreatic cancer, extended surgery was introduced in Japan in 1973 when Fortner6 developed regional pancreatectomy. In our department, the range of dissection has gradually increased since the end of 1973, and pancreatectomy with wide-range retroperitoneal dissection by a translateral retroperitoneal approach was developed in 1977.' Owing to the increase in clinicopathologic studies on development toward the pancreatic tail and lymph node metastasis, resection of the pancreatic head is increasingly thought of as a basic surgical proced~re.~-" However, only a few reports have been published on the pattern of development to the retropancreatic tissue,2*",12 particularly on the significance of neural invasion that is frequently seen in malignant tumors of the pancreatobiliary ~ystem.~,'~,'* Because we noticed neural invasion up to the nerve plexus of the pancreatic head in pancreatic cancer, we emphasized the importance of wide dissection of the retroperitone~m.~ The incidence of local recurrence in the retroperitoneum was high.15 Based on these findings, retropancreatic tissue, and particularly neural invasion, should be studied clinicopathologically when considering which specific procedure should be performed. However, many points are unclear regarding intraneural invasion by cancer cells, invasion of nerves by cancer cells, and the clinicopathologc significance of neural invasion. In this article, we have reported on a clinicopa thologic study on neural invasion, particularly invasion to the extrapancreatic nerve plexus. Macroscopic classification of nerves in the pancreas was reported by Yoshioka and Wakabayasi,I6 Ageenko and Gva~ava,'~ and Debeyre," but the definition of the extrapancreatic nerve plexus was established with reference to the classification by the Japan Pancreas Society in The General Rules of Clinical and Pathological Management for Carcinoma of the Pan~reas.~ In normal autopsy cases, invasion to the nerve plexus around the superior mesenteric artery (plx sma) is found to have a relatively distinct boundary in the retroperitoneal tissue, whereas its surrounding area shows accompanying fibrosis in invasion by cancer or inflammation." Therefore, the borderline between the plx pcll and the plx sma becomes obscure, making it difficult to determine a precise borderline by examining excised specimens alone. Although no classification was established for the plx sma among the plx in the current study, some cases classified as plx pcll included the plx sma. The incidence of neural invasion in pancreatic cancer ranges from 53.5% to 100%.2~7~1'~13~'4~'9 Th' 1s wide range seems to result from a difference in opinion about the criteria for perineural invasion. In this study, neural invasion was defined as invasion in which cancer cells are observed in the medial side of the penneurium. When considering surgical treatment of pancreatic cancer, it should be determined whether neural invasion will be retained in the pancreas or will develop up to the extrapancreatic nerve plexus. In addition, no distinct definition has been included in the general rules as to whether invasion to the extrapancreatic nerve plexus indicates only neural invasion to the nerve plexus or invasion to the nerve plexus in a wide sense, which includes invasion to the lymph vessels in the vicinity of the extrapancreatic nerves. Therefore, invasion to the extrapancreatic nerve plexus was defined as neural invasion in the extrapancreatic nerve plexus in the current study. In addition to neural invasion in the extrapancreatic nerve plexus, lymph vessel invasion and invasion in the connective tissue in fat tissues also were observed in almost all cases of evidence of invasion of retroperitoneal connective tissue in the current study. Nagai et al." and Wada et all9 reported approximately the same results and defined invasion to the nerve plexus in a wide sense. In small pancreatic cancers of 2 cm or less, the incidence of invasion to the retropancreatic tissue is high.2,13 In our cases, the incidences of retropancreatic invasion and invasion to the extrapancreatic nerve plexus were high regardless of tumor diameter. These results support the concept that en bloc excision of the retropancreatic tissue is necessary for treatment in the current situation, where it is difficult to determine preoperatively the presence or absence of retropancreatic invasion. There were no consistent tendencies in the relationships among tissue type, growth pattern, or amount of interstitial connective tissue and degree of neural invasion. Nagayo et al'* who observed neural invasion in 53.5% of their cases of pancreatic cancer, reported a

6 Neural Invasion in Cancer of the Pancreatic Head/Nagakawa et al. 935 strong tendency toward neural invasion in highly differentiated adenocarcinoma. However, Miller et dz0 and Drapiewski l reported no correlation between malignancy and the incidence of neural invasion. The plx pcll was invaded by cancer in the extrapancreatic nerve plexus in 67% of our cases. Matsuda and Nimura14 also observed invasion to the plx pcll in seven of eight patients, and two of the seven patients had invasion up to the plx sma. However, as previously stated, it is difficult to differentiate the plx pcll from the plx sma by examining only excised specimens. In the current study, the cases of plx sma invasion were included in plx pcll. Color clips recently have been used during surgery for precise identification of the extrapancreatic nerve plexus. Matsuda and Nimura14 reported no correlation between lymph vessel invasion and perineural invasion. And, although no distinct correlation was observed between intrapancreatic and extrapancreatic neural invasion and lymph vessel invasion in the current study, the incidence of invasion to the extrapancreatic nerve plexus was high among the cases with severe lymph vessel invasion. Furthermore, invasion to the extrapancreatic nerve plexus tended to increase when the intrapancreatic neural invasion was increasingly marked. Matsuda and Nimura14 reported high metastasis rates for lymph nodes around the prepancreas and retropancreas, which were similar to ours. There was no difference in the metastasis rate for lymph nodes around the root of the superior mesenteric artery between the cases with and without invasion to the plx pcll. Ohyama, who encountered a patient who had neural invasion in the nerve plexus of the pancreatic head and around the bile duct despite the absence of lymph node metastasis, reported that the prognosis was poor when the neural invasion was severe. Drapiewski l found lymph node metastasis in 17 of 70 patients with pancreatic cancer associated with neural invasion among 83 autopsy cases of pancreatic cancer. Standard surgery for cancer of the pancreatic head differs among institutions. Excision of the plx sma is limited to one half of the right side because of the possibility of digestive disturbance. In one hospital, dissection of the N2 lymph node is performed with adjunctive therapy without excision of the nerve plexus in another, and the lymph nodes and connective tissue running along the major artery are excised totally and prophylactically for patients with n, or less and definite invasion of retroperitoneal tissues or less in a third. Even with small pancreatic cancers, the incidence of retropancreatic invasion is reported to be high.3 The results of the current study show that circumferential dissection of the plx sma is necessary, and pancreatectomy with wide-range dissection of the retroperiton- eum involving complete dissection of the extrapancreatic nerve plexus currently is the basic procedure. References Nagakawa T, Kurachi M, Konishi K, Miyazaki I. Retroperitoneal dissection in carcinoma of the pancreas: Translateral retroperitoneal approach. Igakunoayumi 1979; 111: (in Japanese). Nagakawa T, Kurachi M, Konishi K, Miyazaki I. Translateral retroperitoneal approach in radical surgery for pancreatic carcinoma. Jpn ] Surg 1982; 12: Nagakawa T, Konishi I, Higashino Y et al. The spread and prognosis of carcinoma in the region of the pancreatic head. Ipn J Surg 1989; 19: Nagakawa T. Significance of the Extended Radical Operation for Pancreatic Cancer: Surgical Results and Postoperative Problems. Tokyo: New Trends in Gastroenterology, 1987; Japan Pancreas Society. The General Rules of Clinical and Pathological Management for Carcinoma of the Pancreas. Tokyo: Kanehara Pub Comp, 1986; (abstract in English). Fortner JG. Regional resection of cancer of the pancreas: A new surgical approach. Surgery 1973; 73: Brooks JR, Culebras jm. Carcinoma of the pancreas, palliative operation, Whipple procedure, or total pancreatectomy? Am I Surg 1976; Ihse J, Lilija P, Arnesjo B et 01. Total pancreatectomy for cancer: An appraisal of 65 cases. Ann Surg 1977; 186: Moosa AR. Pancreatic cancer: Approach to diagnosis, selection for surgery and choice of operation. Cancer 1982; 50: Herter FP, Coorperman AM, Ahloborn TV. Surgical experience with pancreatic and periampullary cancer. Ann Surg 1982; Nagai H, Kuroda A, Morioka Y. Lymphatic and local spread of T1 and T2 pancreatic cancer. Ann Surg 1986; 204: Nagayo T, Murakami N, Matuoka Y. Local neural invasion of carcinoma of the gallbladder, the bile duct and the pancreas. Cfin Cancer 1976; 22: (in Japanese). Nagakawa T, Higasino Y, Miyazaki I. Neural invasion of pancreatobiliary carcinoma: Biliary tract and pancreas. Biliay Tract and Pancreas 1986; 5: (in Japanese). Matsuda M, Nimura Y. Perineural invasion of carcinoma of the head of the pancreas. ]pn ] Surg 1983; 84: (abstract in English). Nagakawa T, Asano E, Konishi K, Miyazaki I. Significance of the retroperitoneal dissection in operation of carcinoma of the pancreas based on investigation of the autopsied cases. Geka 1981; 42: (in Japanese). Yoshioka H, Wakabayasi T. Pancreatic nerve plexus. Operation 1957; (in Japanese). Ageenko IA, Gvazava OE. Surgical anatomy of the pancreatic nerve. Khirurgiia 1933; 16:93-99 (in Russia). Debeyre J. Nerfs du pancreas. C R Assoc Anat 1933; 32: Wada Y, Kurodas H, Morioaka Y. Occur and histological spread of carcinoma of the pancreas. Semin Dig Surg 1986; 25: Miller JR, Baggenstoss AH, Comfort MW. Carcinoma of the pancreas: Effect of histological type and grade of malignancy on its behavior. Cancer 1951; Drapiewski JF. Carcinoma of the pancreas: A study of neoplastic invasion of nerves and its possible clinical significance. A m ] Cfin Pathol 1944; 14: Ohyama K. Clinicopathological study on resected cases of carcinoma of the pancreas: Prognosis and lymphatic metastasis. Jppn J Surg 1984;