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Prognostic evaluation of perineural invasion in rectal cancer
Prognostic Evaluation of Perineural Invasion in Rectal Cancer Kazuo Shirouzu, MD, Hiroharu Isomoto, MD, Teruo Kakegawa, MD, Kurume,Japan
To evaluate whether perineural invasion (PNI) is an important prognostic factor in patients with rectal cancer, we reviewed the records of 373 patients who underwent curative surgery. Thirty-seven patients (9.9%) were identified as having tumors with PNI. The incidence of PNI was significantly increased in lesions categorized as stage III by the International Union Against Cancer (UICC) system ( 2 0 % ) . There was a significant difference in local recurrence between patients with stage III lesions with PNI and those with stage III lesions without PNI (p < 0 . 0 0 5 ) . Also, patients with PNI of stage III lesions had a significantly lower 8-ycar survival rate (26.7%, p < 0 . 0 0 1 ) . We conclude that PNI is an important factor influencing the prognosis of patients with stage IIl disease. PNI should be classified as a subgroup of the clinical stage.
From the First Department of Surgery, Kurume UniversitySchool of Medicine, Kurume,Japan. Requests for reprintsshould be addressedto KazuoShirouzu, MD, First Departmentof Surgery, Kurume UniversitySchool of Medicine, 67 AsahimaehiKurumeshi, 830 Japan. Manuscript submitted September 3, 1991, and acceptedin revised form March 13, 1992.
n the growth pattern of rectal cancer, hematogenous metastasis, lymphogenous metastasis, peritoneal dissemination, local invasion, and perineural invasion (PNI) are important factors. Recently, in Japan, particular attention has been directed to P N I as a prognostic factor. P N I has been recognized since the middle of the 1800s [1], and detailed studies have been made on P N I in pancreatic cancer, gallbladder cancer, prostate cancer, esophageal cancer, and cancers of the head and neck [2-7]. In 1943, Seefeld and Bargen [8] reported on P N I in rectal cancer and identified the relationship among lymph node metastasis, venous invasion, and local recurrence. In 1967, Spratt et al [9] reported on the prevalence and prognosis of individual clinical and pathologic variables, including PNI, associated with colorectal cancer. Recently, Knudsen et al [10], Wied et al [11], Krasna et al [12], and Bentzen et al [13] have reported on the relationship between P N I and prognosis. Since 1982, we also have observed this relationship and have been continuing prospective studies. In this report, the significance of P N I in rectal cancer, particularly its evaluation as a prognostic factor, is assessed from a clinicopathologic viewpoint.
I
PATIENTS AND M E T H O D S Patients: The subjects were 373 patients with rectal cancer who underwent curative surgery at the First Department of Surgery, Kurume University School of Medicine, from January 1982 to December 1990. There were 237 men, with a mean age of 61.1 4- 12.0 years, and 136 women, with a mean age of 62.9 4- 11.0 years. Method of preparing specimens: As we previously reported [14], large sur$ical specimens have been used to study colorectal tumors since 1982. The surgical specimen was initially f'Lxedin 10% formalin. After 1 week of fixation in formalin, the whole tumor mass was cut into longitudinal sections about 5 m m in thickness. Thick, large sections were prepared from the entire tumor, so as to include the oral and anal sides of the tumor. If a tumor was extremely large, then further divisions were performed. Each tumor was divided into 10 sections on average. These sections were dehydrated with alcohol for 1 week and then embedded in paraffin. Next, thin sections about 5 ~m in thickness were cut from the large sections with a microtome. These were mounted on large glass slides and stained with hematoxylin and eosin and elastica van Gieson. One author (KS) prepared the specimens. Histopathologic diagnosis: One of the authors (KS) examined all of the colorectal cancer specimens from 1982 to the present. Histologic findings were detailed in
THE AMERICAN JOURNAL OF SURGERY VOLUME 165 FEBRUARY1993 233
SHIROUZU ET AL
TABLE l
Incidence of Perineural Invasion (PNI) According to UICC Stage (Curative Cases) 0
I
I1
Ill
Total
pNI Negative Positive
33 0
68 0
120* 8 (6)t
115* 29 (20)
336 37 (9.9)
Total
33
68
128
144
373
*p <0.001. +Numbers in parentheses indicate percentages.
T A B L E II
Perineural Invasion (PNI) and the First Site of Recurrence in Patients With UlCC Stage II Disease (Curative Cases) Local Hepatic Lung Recurrence Metastasis Metastasis Total PNI Negative (n = 120) Positive (n = 8)
3* (2.5) t 1 (12.5)
6* (5) 0
2*
(1.7) 1 (12.5)
11" (9.2) 2 (25)
*Not significant, tNumbers in parentheses indicate percentages.
TABLE Ill
Perineural Invasion (PNI) and the First Site of Recurrence in Patients With UICC Stage III Disease (Curative Cases) Local Hepatic Lung Recurrence Metastasis Metastasis Total PNI Negative (n = 115) Positive (n = 29)
8*
15t
(7)~
(13)
8 (27.6)
8 (27.6)
81.
315
(7)
(27)
3 (10)
19 (65.5)
*p < 0.005. t Not significant. tp <0.001. w in parentheses indicate percentages,
each case, and a pathologic diagnosis was made. The histologic findings and clinical data were entered in a computer database. A positive judgment was made when cancer cells were observed inside the perineurium (Figure 1). In addition, extramural PNI only was examined because Auerbach's plexus invasion alone was extremely rare. Surgical procedure and pathologic stage: Anterior resection was performed in 232 patients, abdominoperineal resection in 96 patients, and total pelvic exenteration 234
THE AMERICAN JOURNAL OF SURGERY
in 20 patients. Wedge resection for early cancers was performed in 25 patients. Pathologic stage was defined according to the T N M classification system of the International Union Against Cancer (UICC) [15,16]. Follow-up investigation: Follow-up investigation was performed during outpatient visits, by letter, or by telephone, and the date of contact was considered to be the final date of confirmation. The final follow-up date was the last day of April 1991. Presence or absence of recurrence was determined by the measurement of serum tumor marker levels and by the results of chest radiography, ultrasound, computed tomography, and magnetic resonance imaging. Statistical analysis: The X 2 test was used to determine the statistical significance of differences, and the Kaplan-Meier method [17] was used to calculate survival rates. Significant differences in the survival rate were assessed using the log-rank test of Pete [18]. RESULTS UICC stage and PNI: We studied 373 patients who underwent curative resection. As shown in Table I, PNI was not found in patients with stage 0 or I disease. In patients with stage II disease, it was observed at a low rate of 6% (8 of 128). However, in patients with stage III disease, PNI was observed at a high rate of 20% (29 of 144). A significant correlation was noted among the groups (p <0.001). Recurrence and PNI: We studied the pattern of recurrence in patients treated by curative surgery who were classified according to stage. We recorded the first site of recurrence as the region of recurrence. As shown in Table II, recurrence occurred in 25% (two of eight) of patients with stage II disease and PNI. However, no significant correlation was noted between patients with PNI and patients without PNI. As shown in Table HI, recurrence occurred at a significantly higher rate of 65.5% (19 of 29) in patients with stage III disease and PNI. A significant correlation was noted with regard to local recurrence between patients with PNI and patients without PNI (p <0.005). Survival rate and PNI: We studied the relationship between survival rate and PNI in patients with stage II disease and in those with stage III disease. As shown in Figure 2, in patients with stage II disease, the 8-year survival rates in those without PNI and in those with PNI were 88.1% and 75%, respectively. No significant difference was observed between the two groups. However, as shown in Figure 3, in patients with stage III disease, the 8year survival rate in those without PNI was 76.8% but the 8-year survival rate in those with PNI was an extremely low rate of 26.7%. The difference between the two groups was significant (p <0.001 using the log-rank test). COMMENTS Many clinical and pathologic factors have been studied as they relate to recurrence and prognosis in patients with colorectal cancer. For example, it is known that factors affecting survival include lymph node metastasis [19], location, surgical resection margin [20], tumor size
VOLUME 165
FEBRUARY 1993
PERINEURAL INVASION IN RECTAL CANCER
Figure 1. Histologic diagnostic criteria for perineural invasion: A positive judgment was made when cancer cells were observed inside the perineurium (PN). This photomicrograph shows the perineural invasion skipped to the extramural autonomic nerve distant from a primary tumor. PN -- perineurium; F = fasciculus; C = cancer cells (hematoxylin and eosin; original magnification X200, reduced by 27 %).
(%) 100
.••'
I" ..... ! . . . . . . . . . . I
PNI (--) (N=120) I =UI--I I II
I
l[lllllll
I[
Illlll
IIII
88.1% II
t
II
I
75% I
I
I
I
I
PNI (+) (N=8)
.?
50 Logrank test N.S.
Figure 2, Perineural invasion (PNI) and survival rate in patients with stage II disease. Analysis by log-rank test showed no significant difference between patients with PNI and those without PNI.
I
o
i
I
4
5
6 P o s t o p e r a t i v e Years
I
I
I
I
7
8
9
10
(%) 100
lit
# ~ .?
I
III
II
I1[
I
I
Iii
ii
I
50 PNI (+) (N=29) I I Logrank
Figure 3. Perineural invasion (PNI) and survival rate in patients with stage III disease. Analysis by log-rank test revealed a significant difference between patients with PNI and those without PNI (p <0.001).
26.-/% I
I
test
p
(X2= 32.5606) 0
I
I
I
1
2
3
I
I
I
4 5 6 P o s t o p e r a t i v e Years
THE A M E R I C A N J O U R N A L O F S U R G E R Y
VOLUME 165
I
I
I
I
7
8
9
10
FEBRUARY 1993
235
SHIROUZU El" AL
[21], histologic grade [22], obstruction [23], perforation [24], venous invasion [25], and lymphatic permeation [26]. However, when surgical specimens are histopathologically examined in detail, cancerous invasion of the extramural perineural space is frequently observed, and there is reason to believe that this factor affects the prognosis [8]. M a n y reports on P N I in cancers other than colorectal have been published [1-7], but, in regard to colorectal cancer, no detailed studies have appeared in Japan, although some reports [8-13] have been published outside of Japan. With regard to the frequency of P N I in rectal cancer, Seefeld and Bargen [8] reported a frequency of 30% and Knudsen [10] reported a rate of 34.9%. Among our patients who had curative surgery, the rate was 9.9%. When the patients were staged by the U I C C system, P N I was not found in patients with stage 0 or I disease. In patients with stage II disease, it was only observed at a low rate of 6%. However, in patients with stage I I I disease, P N I was seen at a high rate of 20%. Therefore, it is thought that there is a close relationship between P N I and lymph node metastasis. In Europe and the United States, Seefeld and Bargen [8], Knudsen et al [10], and Wied et al [11 ] studied the relationship between P N I and lymph node metastasis and reported results similar to ours. In regard to the relationship between PNI, recurrence, and prognosis, Seefeld and Bargen [8], Spratt and Spjat [9], Knudsen et al [10], Wied et al [11], Krasna et al [12], and Bentzen et al [13] reported that, if P N I is present, the recurrence rate is high and the prognosis is poor. In particular, Seefeld and Bargen [8] reported that local recurrence occurred at a high rate of 81.2%. Bentzen et al [13] reported that P N I had the most impact on survival in patients with either Dukes' stage B or C disease. On the other hand, in our patients with stage II disease, P N I seemed to have no important significance in relation to the recurrence and survival rates. However, in patients with stage I I I disease, P N I seems to have an important significance in relation to recurrence, especially local recurrence (p <0.005). In terms of the survival rate, P N I seems to have an extremely important significance in patients with stage I I I disease. Recently, Horn et al [27] reported that P N I had an impact on 5-year survival probability in patients without lymph node metastasis. The results of our study differed slightly from those of some investigators because we only examined extramural P N I . It may be necessary to establish the diagnostic criteria for PNI. Our prospective studies showed that P N I was an important factor influencing the prognosis in patients with stage I I I disease. P N I should be classified as a clinical subgroup.
Although this detailed study reaffirms generally accepted observations made by others, it provides updated documentation of the importance of extramural perineural invasion independent of anatomic stage. The study does focus on tumors that have penetrated the 236
muscularis, which are the subset of rectal cancers that are most actively considered for adjunctive therapy. REFERENCES 1. Ballantyne A J, McCarten AB. The extension of cancer of the head and neck through peripheral nerves. Am J Surg 1963; 106: 651-67. 2. Ernst PP. Ueber das Wachstum und die Verbreitung bosartiger Geschwulste, insbesondere des Krebses in den Lymphbahnen der Nerven; ein Beitrag zur Biologic des Krebses. Beitr z path Anat u z allg Path (Suppl) 1905; 7: 29-51. 3. Fahim RB, McDonald JR, Richard JC. Carcinoma of the gallbladder. Ann Surg 1962; 156:114-24. 4,. Drapiewski JF. Carcinoma of the pancreas: a study of neoplastic invasion of nerves and its possible clinical significance. Am J Clin Pathol 1944; 14: 549-56. 5. Rodin AE, Larson DL, Roberts DK. Nature of the perineural space invaded by prostatic carcinoma. Cancer 1967; 20: 1772-9. 6. Warren S, Harris PN, Graves RC. Osseus metastasis of carcinoma of prostate, with special reference to perineural lymphatics. Arch Pathol 1936; 22: 139-60. 7. Takubo K, Takai A, Yamashita K, et al. Light and electron microscopic studies on peripheral invasion by esophageal carcinoma. J Natl Cancer Inst 1985; 74: 987-93. 8. Seefeld PH, Bargen JA. The spread of carcinoma of the rectum: invasion of lymphatics, vein and nerves. Ann Surg 1943; 118: 76-90. 9. Spratt JS, Spjut HJ. Prevalence and prognosis of individual clinical and pathologic variables associated with colorectal carcinoma. Cancer 1977; 20: 1976-85. 10. Knudsen JB, Nilsson T, Sprechler M, Johansen A, Christensen N. Venous and nerve invasion as prognostic factors in postoperative survival of patients with resectable cancer of the rectum. Dis Colon Rectum 1983; 26: 613-7. 11. Wied U, Nilsson T, Krudsen JB, Sprechler M, Johansen A. Postoperative survival of patients with potentially curable cancer of the colon. Dis Colon Rectum 1985; 28: 333-5. 12. Krasna M J, Flancbaum L, Cody RP, Shneibaum S, Ari GB. Vascular and neural invasion in colorectal carcinoma--incidence and prognostic significance. Cancer 1988; 61: 1018-23. 13. Bentzen SM, Balslev I, Pederson M, et al. A regression analysis of prognostic factors after resection of Dukes' B and C carcinoma of the rectum and rectosigmoid. Does postoperative radiotherapy change the prognosis? Br J Cancer 1988; 58: 195-201. 14. Shirouzu K, Isomoto H, Kakegawa T. A prospective clinicopathologic study of venous invasion in colorectal cancer. Am J Surg 1991; 162: 216-22. 15. AJCC. Manual for staging of cancer. 3rd ed. Beahrs OH, Henson DE, Hutter RV, Meyers MH. Philadelphia: J.B. Lippincott, 1988. 16. UICC. TNM classification of malignant tumours. 4th ed. Hermanek P, Sobin LH, Berlin: Springer, 1987. 17. Kaplan EL, Meier P. Non parametric estimation from incomplete observation. J Am Stat Assoc 1958; 53: 457-81. 18. Peto R, Pike MC, Armitage NE, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples. Br J Cancer 1977; 35: 1-39. 19. Gunderson LL, Sosin H. Areas of failure found at reoperation (second or symptomatic look) following "curative surgery" for adenocarcinoma of the rectum. Clinicopathologic correlation and implications for adjuvant therapy. Cancer 1974; 34: 1278-92. 20. Enker WE, Laffer UT, Block GE. Enhanced survival of patients with colon and rectal cancer is based upon wide anatomic resection. Ann Surg 1979; 190: 350-60. 21. Davies GC, Ellis H. Radical surgery in locally advanced cancer
THE AMERICAN JOURNAL OF SURGERY VOLUME 165 FEBRUARY 1993
PERINEURAL INVASIONIN RECTALCANCER
of the large bowel. Clin Oncol 1975; 1: 21-6. 22. Dukes CE, Bussey H JR. The spread of rectal cancer and its effect on prognosis. Br J Cancer 1958; 12: 309-20. 23. Welch JP, Donaldson GA. Management of severe obstruction of the large bowel due to malignant disease. Am J Surg 1977; 27: 492-9. 24. Welch JP, Donaldson GA. Perforative carcinoma of the colon and rectum. Ann Surg 1974; 180: 734-40.
25. Talbot IC, Ritchie S. The clinical significance of invasion of veins by rectal cancer. Br J Surg 1980; 67: 439-42. 26. Minsky B, Mies C, Rich T, Recht A. Lymphatic vessel invasion is an independent prognostic factor for survival in oolorectal cancer. Int J Radiat Oncel Biol Phys 1989; 17: 311-8. 27. Horn A, Dahl O, Morild I. The role of venous and neural invasion on survival in rectal adenocarcinoma. Dis Colon Rectum 1990; 33: 598-601.
THE AMERICAN JOURNAL OF SURGERY VOLUME 165 FEBRUARY 1993 237
To evaluate whether perineural invasion (PNI) is an important prognostic factor in patients with rectal cancer, we reviewed the records of 373 patients who underwent curative surgery. Thirty-seven patients (9.9%) were identified as having tumors with PNI. The incidence of PNI was significantly increased in lesions categorized as stage III by the International Union Against Cancer (UICC) system ( 2 0 % ) . There was a significant difference in local recurrence between patients with stage III lesions with PNI and those with stage III lesions without PNI (p < 0 . 0 0 5 ) . Also, patients with PNI of stage III lesions had a significantly lower 8-ycar survival rate (26.7%, p < 0 . 0 0 1 ) . We conclude that PNI is an important factor influencing the prognosis of patients with stage IIl disease. PNI should be classified as a subgroup of the clinical stage.
From the First Department of Surgery, Kurume UniversitySchool of Medicine, Kurume,Japan. Requests for reprintsshould be addressedto KazuoShirouzu, MD, First Departmentof Surgery, Kurume UniversitySchool of Medicine, 67 AsahimaehiKurumeshi, 830 Japan. Manuscript submitted September 3, 1991, and acceptedin revised form March 13, 1992.
n the growth pattern of rectal cancer, hematogenous metastasis, lymphogenous metastasis, peritoneal dissemination, local invasion, and perineural invasion (PNI) are important factors. Recently, in Japan, particular attention has been directed to P N I as a prognostic factor. P N I has been recognized since the middle of the 1800s [1], and detailed studies have been made on P N I in pancreatic cancer, gallbladder cancer, prostate cancer, esophageal cancer, and cancers of the head and neck [2-7]. In 1943, Seefeld and Bargen [8] reported on P N I in rectal cancer and identified the relationship among lymph node metastasis, venous invasion, and local recurrence. In 1967, Spratt et al [9] reported on the prevalence and prognosis of individual clinical and pathologic variables, including PNI, associated with colorectal cancer. Recently, Knudsen et al [10], Wied et al [11], Krasna et al [12], and Bentzen et al [13] have reported on the relationship between P N I and prognosis. Since 1982, we also have observed this relationship and have been continuing prospective studies. In this report, the significance of P N I in rectal cancer, particularly its evaluation as a prognostic factor, is assessed from a clinicopathologic viewpoint.
I
PATIENTS AND M E T H O D S Patients: The subjects were 373 patients with rectal cancer who underwent curative surgery at the First Department of Surgery, Kurume University School of Medicine, from January 1982 to December 1990. There were 237 men, with a mean age of 61.1 4- 12.0 years, and 136 women, with a mean age of 62.9 4- 11.0 years. Method of preparing specimens: As we previously reported [14], large sur$ical specimens have been used to study colorectal tumors since 1982. The surgical specimen was initially f'Lxedin 10% formalin. After 1 week of fixation in formalin, the whole tumor mass was cut into longitudinal sections about 5 m m in thickness. Thick, large sections were prepared from the entire tumor, so as to include the oral and anal sides of the tumor. If a tumor was extremely large, then further divisions were performed. Each tumor was divided into 10 sections on average. These sections were dehydrated with alcohol for 1 week and then embedded in paraffin. Next, thin sections about 5 ~m in thickness were cut from the large sections with a microtome. These were mounted on large glass slides and stained with hematoxylin and eosin and elastica van Gieson. One author (KS) prepared the specimens. Histopathologic diagnosis: One of the authors (KS) examined all of the colorectal cancer specimens from 1982 to the present. Histologic findings were detailed in
THE AMERICAN JOURNAL OF SURGERY VOLUME 165 FEBRUARY1993 233
SHIROUZU ET AL
TABLE l
Incidence of Perineural Invasion (PNI) According to UICC Stage (Curative Cases) 0
I
I1
Ill
Total
pNI Negative Positive
33 0
68 0
120* 8 (6)t
115* 29 (20)
336 37 (9.9)
Total
33
68
128
144
373
*p <0.001. +Numbers in parentheses indicate percentages.
T A B L E II
Perineural Invasion (PNI) and the First Site of Recurrence in Patients With UlCC Stage II Disease (Curative Cases) Local Hepatic Lung Recurrence Metastasis Metastasis Total PNI Negative (n = 120) Positive (n = 8)
3* (2.5) t 1 (12.5)
6* (5) 0
2*
(1.7) 1 (12.5)
11" (9.2) 2 (25)
*Not significant, tNumbers in parentheses indicate percentages.
TABLE Ill
Perineural Invasion (PNI) and the First Site of Recurrence in Patients With UICC Stage III Disease (Curative Cases) Local Hepatic Lung Recurrence Metastasis Metastasis Total PNI Negative (n = 115) Positive (n = 29)
8*
15t
(7)~
(13)
8 (27.6)
8 (27.6)
81.
315
(7)
(27)
3 (10)
19 (65.5)
*p < 0.005. t Not significant. tp <0.001. w in parentheses indicate percentages,
each case, and a pathologic diagnosis was made. The histologic findings and clinical data were entered in a computer database. A positive judgment was made when cancer cells were observed inside the perineurium (Figure 1). In addition, extramural PNI only was examined because Auerbach's plexus invasion alone was extremely rare. Surgical procedure and pathologic stage: Anterior resection was performed in 232 patients, abdominoperineal resection in 96 patients, and total pelvic exenteration 234
THE AMERICAN JOURNAL OF SURGERY
in 20 patients. Wedge resection for early cancers was performed in 25 patients. Pathologic stage was defined according to the T N M classification system of the International Union Against Cancer (UICC) [15,16]. Follow-up investigation: Follow-up investigation was performed during outpatient visits, by letter, or by telephone, and the date of contact was considered to be the final date of confirmation. The final follow-up date was the last day of April 1991. Presence or absence of recurrence was determined by the measurement of serum tumor marker levels and by the results of chest radiography, ultrasound, computed tomography, and magnetic resonance imaging. Statistical analysis: The X 2 test was used to determine the statistical significance of differences, and the Kaplan-Meier method [17] was used to calculate survival rates. Significant differences in the survival rate were assessed using the log-rank test of Pete [18]. RESULTS UICC stage and PNI: We studied 373 patients who underwent curative resection. As shown in Table I, PNI was not found in patients with stage 0 or I disease. In patients with stage II disease, it was observed at a low rate of 6% (8 of 128). However, in patients with stage III disease, PNI was observed at a high rate of 20% (29 of 144). A significant correlation was noted among the groups (p <0.001). Recurrence and PNI: We studied the pattern of recurrence in patients treated by curative surgery who were classified according to stage. We recorded the first site of recurrence as the region of recurrence. As shown in Table II, recurrence occurred in 25% (two of eight) of patients with stage II disease and PNI. However, no significant correlation was noted between patients with PNI and patients without PNI. As shown in Table HI, recurrence occurred at a significantly higher rate of 65.5% (19 of 29) in patients with stage III disease and PNI. A significant correlation was noted with regard to local recurrence between patients with PNI and patients without PNI (p <0.005). Survival rate and PNI: We studied the relationship between survival rate and PNI in patients with stage II disease and in those with stage III disease. As shown in Figure 2, in patients with stage II disease, the 8-year survival rates in those without PNI and in those with PNI were 88.1% and 75%, respectively. No significant difference was observed between the two groups. However, as shown in Figure 3, in patients with stage III disease, the 8year survival rate in those without PNI was 76.8% but the 8-year survival rate in those with PNI was an extremely low rate of 26.7%. The difference between the two groups was significant (p <0.001 using the log-rank test). COMMENTS Many clinical and pathologic factors have been studied as they relate to recurrence and prognosis in patients with colorectal cancer. For example, it is known that factors affecting survival include lymph node metastasis [19], location, surgical resection margin [20], tumor size
VOLUME 165
FEBRUARY 1993
PERINEURAL INVASION IN RECTAL CANCER
Figure 1. Histologic diagnostic criteria for perineural invasion: A positive judgment was made when cancer cells were observed inside the perineurium (PN). This photomicrograph shows the perineural invasion skipped to the extramural autonomic nerve distant from a primary tumor. PN -- perineurium; F = fasciculus; C = cancer cells (hematoxylin and eosin; original magnification X200, reduced by 27 %).
(%) 100
.••'
I" ..... ! . . . . . . . . . . I
PNI (--) (N=120) I =UI--I I II
I
l[lllllll
I[
Illlll
IIII
88.1% II
t
II
I
75% I
I
I
I
I
PNI (+) (N=8)
.?
50 Logrank test N.S.
Figure 2, Perineural invasion (PNI) and survival rate in patients with stage II disease. Analysis by log-rank test showed no significant difference between patients with PNI and those without PNI.
I
o
i
I
4
5
6 P o s t o p e r a t i v e Years
I
I
I
I
7
8
9
10
(%) 100
lit
# ~ .?
I
III
II
I1[
I
I
Iii
ii
I
50 PNI (+) (N=29) I I Logrank
Figure 3. Perineural invasion (PNI) and survival rate in patients with stage III disease. Analysis by log-rank test revealed a significant difference between patients with PNI and those without PNI (p <0.001).
26.-/% I
I
test
p
(X2= 32.5606) 0
I
I
I
1
2
3
I
I
I
4 5 6 P o s t o p e r a t i v e Years
THE A M E R I C A N J O U R N A L O F S U R G E R Y
VOLUME 165
I
I
I
I
7
8
9
10
FEBRUARY 1993
235
SHIROUZU El" AL
[21], histologic grade [22], obstruction [23], perforation [24], venous invasion [25], and lymphatic permeation [26]. However, when surgical specimens are histopathologically examined in detail, cancerous invasion of the extramural perineural space is frequently observed, and there is reason to believe that this factor affects the prognosis [8]. M a n y reports on P N I in cancers other than colorectal have been published [1-7], but, in regard to colorectal cancer, no detailed studies have appeared in Japan, although some reports [8-13] have been published outside of Japan. With regard to the frequency of P N I in rectal cancer, Seefeld and Bargen [8] reported a frequency of 30% and Knudsen [10] reported a rate of 34.9%. Among our patients who had curative surgery, the rate was 9.9%. When the patients were staged by the U I C C system, P N I was not found in patients with stage 0 or I disease. In patients with stage II disease, it was only observed at a low rate of 6%. However, in patients with stage I I I disease, P N I was seen at a high rate of 20%. Therefore, it is thought that there is a close relationship between P N I and lymph node metastasis. In Europe and the United States, Seefeld and Bargen [8], Knudsen et al [10], and Wied et al [11 ] studied the relationship between P N I and lymph node metastasis and reported results similar to ours. In regard to the relationship between PNI, recurrence, and prognosis, Seefeld and Bargen [8], Spratt and Spjat [9], Knudsen et al [10], Wied et al [11], Krasna et al [12], and Bentzen et al [13] reported that, if P N I is present, the recurrence rate is high and the prognosis is poor. In particular, Seefeld and Bargen [8] reported that local recurrence occurred at a high rate of 81.2%. Bentzen et al [13] reported that P N I had the most impact on survival in patients with either Dukes' stage B or C disease. On the other hand, in our patients with stage II disease, P N I seemed to have no important significance in relation to the recurrence and survival rates. However, in patients with stage I I I disease, P N I seems to have an important significance in relation to recurrence, especially local recurrence (p <0.005). In terms of the survival rate, P N I seems to have an extremely important significance in patients with stage I I I disease. Recently, Horn et al [27] reported that P N I had an impact on 5-year survival probability in patients without lymph node metastasis. The results of our study differed slightly from those of some investigators because we only examined extramural P N I . It may be necessary to establish the diagnostic criteria for PNI. Our prospective studies showed that P N I was an important factor influencing the prognosis in patients with stage I I I disease. P N I should be classified as a clinical subgroup.
Although this detailed study reaffirms generally accepted observations made by others, it provides updated documentation of the importance of extramural perineural invasion independent of anatomic stage. The study does focus on tumors that have penetrated the 236
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