- Email: [email protected]
Cancer biology and necrotic changes in metastatic lymph nodes and survival of colon cancer patients
The American Journal of Surgery 189 (2005) 364 –368
Scientific paper
Cancer biology and necrotic changes in metastatic lymph nodes and survival of colon cancer patients Michael Fulmes, M.D., Ph.D.a, Sebouh Setrakian, M.D.b, Prasanta K. Raj, M.D.a, Brent M. Bogard, M.D.a b
a Department of Surgery, Fairview Hospital, Cleveland Clinic Health System, Cleveland, OH, USA Department of Pathology, Fairview Hospital, Cleveland Clinic Health System, Cleveland, OH, USA
Manuscript received September 14, 2004; revised manuscript November 23, 2004 Presented at the 47th Annual Meeting of the Midwest Surgical Association, Mackinac Island, Michigan, August 15–18, 2004
Abstract Background: Identifying factors that can contribute to a better understanding of tumor progression in stage III colon cancer patients continues to be an important task. Necrotic changes in metastatic lymph nodes have not been previously analyzed in English literature. Methods: The study included 48 consecutive colon and rectosigmoid cancer patients with stage III disease who underwent radical surgery. After reviewing the diagnostic slides, a pathologist developed a scale describing the extent of necrotic changes. Results were evaluated using Kaplan-Meier method and log-rank test. Results: Thirty-four (70%) patients had necrotic changes in metastatic lymph nodes. Patients with necrotic changes in metastatic lymph nodes had more risk factors than patients without necrosis. The 5-year survival rate for patients with necrotic changes in metastatic lymph nodes was 85% and for patients without necrosis was 50% (P ⫽ 0.02). Conclusions: The survival of patients with necrotic changes in metastatic lymph nodes was higher (P ⫽ 0.02). These necrotic changes can help us to understand body–tumor relations. © 2005 Excerpta Medica Inc. All rights reserved. Keywords: Colorectal cancer; Metastatic lymph nodes; Necrosis; Survival
Colorectal cancer is highly prevalent in Westernized countries. In 2000, approximately 130,000 cases of colorectal cancer occurred in the United States [1], and colorectal cancer is the second most common cause of cancer death in the United States [1]. In stage III (node-positive) patients, the risk of death from cancer is as high as 70% during the 5-year period after surgical resection [2]. TNM staging is used for prognosis and treatment plan despite the shortcomings of this system [3– 6]. The investigators tried to identify other important evaluation tools, other than TNM staging, that can correlate with the prognosis of colorectal cancer patients. This leads to the hypothesis of substaging. Ratto et al [7] performed analysis of the significance of different factors, and they found that none of these factors Corresponding author. Mario Scarcipino, Department of Surgery, Fairview Hospital, Cleveland Clinic Health System, 18101 Loraine Avenue, Cleveland, OH 44111, USA. Tel.: ⫹1-216-476-7805; fax: ⫹1-216476-7883. E-mail address: [email protected]
were able to predict prognosis, especially in stage II and III patients. When looked at individually, such factors as tumor configuration, mucinous component, venous or perineural invasion, inflammatory reaction, and differentiation grade did not predict survival in most cases. These investigators found that only lymph node involvement, distant metastases, bowel obstruction, vessel invasion, and tumor DNA ploidy are factors independently related to the outcome. Signet-Ring cell cancer, which was not included in the analysis, had an adverse effect on survival in Nissan et al’s study [8]. After the introduction of TNM staging and insufficient prognostic values of the previously mentioned factors, investigators searched for new microscopic factors and also reevaluated known factors. These new factors include the detection of micrometastasis in lymph nodes [9,10], bone marrow [5], and blood [5,11,12]. Only a few studies found [13–15] and demonstrated [14,15] the importance of tumor deposits into paracolic or pararectal fat tissue. Significance
0002-9610/05/$ – see front matter © 2005 Excerpta Medica Inc. All rights reserved. doi:10.1016/j.amjsurg.2004.11.028
M. Fulmes et al. / The American Journal of Surgery 189 (2005) 364 –368
365
Table 1 Demographics of patients with and without necrotic changes in metastatic lymph nodes who underwent survival analysis Patient demographics
Age (mean y) Sex (%) Male Female Right colon (%) Transverse colon (%) Left and descending colon (%) Sigmoid and rectosigmoid colon (%)
With necrotic changes (n ⫽ 20)
Without necrotic changes (n ⫽ 10)
67.4
73.1
9 11 8 2 1 9
5 5 7 0 0 3
(45) (55) (40) (10) (5) (45)
(50) (50) (70)
(30)
of nucleus shape [16], tumor budding [17], and peritoneal free cancer cells [18] were analyzed, but the findings were inconsistent. Bobrow et al [19] and other investigators analyzed necroses in ductal carcinoma in situ. The investigators noticed that regardless of the histologic architecture of the lesion, the presence of extensive necrosis within the affected ducts is associated with a greater tendency for local recurrence after breast-conservation treatment. Recently, Greenson et al [20] analyzed the correlation of necrotic changes in colorectal tumors with microsatellite instability, and Rubio [21] described necrotic changes in the growing edge of the tumor. The role of these studies is important in understanding tumor progression, and the practical application of them must be evaluated. Currently, no data exist in English literature about the phenomenon of necrotic changes in metastatic lymph nodes.
Fig. 1. Grade ⫹1 necrosis with neutrophil infiltration limited to few glandular lumens.
necrosis with neutrophil infiltration limited to few glandular lumens; grade ⫹2 necrosis with neutrophil infiltration limited to few glandular lumens and penetrates the basal membrane; grade ⫹3 necrosis with neutrophil infiltration involving up to 50% of the lymph node; and grade ⫹4 severe necrosis with neutrophil infiltration involving most of the lymph node (Figs. 1– 4). Survival data were obtained from our cancer registry, from surgeons’ office records, and by contacting patients. Patients who underwent palliative surgery without adjuvant chemotherapy and who died from non– cancerrelated causes, or who had tumor deposits in paracolic fat tissue, were not included in this survival analysis. Statistical analysis
Patients and Methods After receiving Institutional Review Board approval for the study, we analyzed 48 consecutive patients with colon and rectosigmoid cancer who underwent radical surgery between 1996 and 1998 at a large community teaching hospital. Patients were 52 to 90 years old (mean 72.3) (Table 1). Staging revealed 1 patient (2%) as T2, 38 (79%) patients as T3, and 8 (16.7%) patients as T4. Moderately well-differentiated adenocarcinoma was detected in 24 (50%), poorly differentiated adenocarcinoma in 17 (35.4%), and mucinous adenocarcinoma in 7 (14.6%) patients. Fifteen patients (31%) had ⬎3 metastatic lymph nodes (N2). Seven patients underwent palliative surgery for locally advanced disease or disease with simultaneous gastric cancer or bladder cancer with multiple myeloma. One patient had metastasis to the greater omentum. One experienced pathologist, who was unaware of clinical details and treatment outcome, reviewed all original hematoxylin and eosin–stained slides. The pathologist developed a system for evaluation of necrotic changes. The extent of necrosis was graded into 4 categories: grade ⫹1
Statistical analysis of 5-year survival was performed for patients who met the inclusion criteria. Kaplan-Meier method
Fig. 2. Grade ⫹2 necrosis with neutrophil infiltration limited to few glandular lumens with penetrating basal membrane.
366
M. Fulmes et al. / The American Journal of Surgery 189 (2005) 364 –368 Table 2 Risk factors for patients with and without necrotic changes in metastatic lymph nodes who underwent survival analysis
Fig. 3. Grade ⫹3 necrosis with neutrophil infiltration involving up to 50% of the lymph node.
was used to calculate survival, and log-rank test was used to estimate the difference in survival for the 2 groups. P ⬍0.05 was considered significant.
Results Necrotic changes in metastatic lymph nodes were found in 34 (70%) patients: ⫹1 in 7 (20.6%), ⫹2 in 7 (20.6%), ⫹3 in 13 (38%), and ⫹4 in 7 (20.6%). During the follow-up period, 26 deaths were reported in the patient population; 23 of these were cancer related. The group of patients with necrotic changes had more risk factors compared with patients without necrotic changes (Table 2). All five patients with ⫹4 necrotic change survived 5 years. The 5-year survival rate in the group with necrotic changes in metastatic lymph nodes was 85% compared with a 50% survival rate in the group without necrotic changes (P ⫽ 0.02) (Fig. 5).
Fig. 4. Grade ⫹4 severe necrosis with neutrophil infiltration involving most of the lymph node.
Patient risk factors
With necrotic changes (n ⫽ 20)
Without necrotic changes (n ⫽ 10)
T3 (%) T4 (%) N1 (%) N2 (%) NX (%) Unknown (%) Poorly differentiated (%) Moderately well-differentiated (%) Mucinous (%) Metastatic to omentum (%) Vascular invasion (%) Lymph vessel invasion (%) Perineural invasion (%)
18 2 13 6 1 1 9 7 3 1 3 3 1
9 1 9 1 0 0 2 4 4 0 0 0 1
(90) (10) (65) (30) (5) (5) (45) (35) (15) (5) (15) (15) (5)
(90) (10) (90) (10)
(20) (40) (40)
(10)
Comments Cancer is a dynamic process involving an interaction of body systems and a pool of heterogeneous cancer cells. As mentioned, data correlating tumor features and survival can be controversial because some findings appear to influence survival, whereas other investigators studying the same factors have found no role for prognosis. Patients with noninherited genetic disturbances, micrometastases to lymph nodes and other tissues, free cancer cells in the peritoneal cavity, blood stream, and bone marrow, and other evidence of tumor spreading even after palliative surgery can still have a favorable outcome because of the body’s varying response to different tumor biology. So far in the literature, we have found chronic inflammatory reaction to the primary site of the tumor to be a morphologic and easy, low-cost detectable feature [22] that has not found well-excepted practical value and has yielded results that are still controversial. First, the data are not sufficiently objective. Otherwise, the histologic criteria for qualitative and quantitative evaluation differ from study to study. Second, cytokines, which are produced during
Fig 5. Five-year survival of colorectal cancer patients: those with versus without necrotic changes.
M. Fulmes et al. / The American Journal of Surgery 189 (2005) 364 –368
inflammatory reaction, can actually stimulate growing and metastatic ability of tumor cells [23,24]. Necrotic changes of tumor as a first line of defense in regional lymph nodes can be evidence of the body’s reaction to tumor. Necrosis itself can be different in nature. Inflammatory necrosis of an infectious nature was not found in our study patients. Most likely, necrosis was not attributed to hypoxia because we found necrotic changes in cases of extensive metastasis and also in small areas of metastatic lesions and vice versa. Moreover, investigators have shown that hypoxia stimulates the production of angiogenic growth factors [25]. Necrosis caused by blocking of the cell cycle in the G2-M phase can be the result of apoptosis or chemotherapy [26], but apoptosis is not a characteristic feature of tumors and chemotherapy was not performed before surgery in our study patients. Our last explanation for the reason of necrosis is an immune response to tumor, which leads to a cascade of changes in lymph nodes involving tumor necrosis factor (TNF) production and other cytokines. Other investigators have identified biochemical pathways for TNF production in cancer cells [27,28], which most likely facilitates tumor advancement into adjacent tissues and vessels [28]. In contrast, TNF also attracts neutrophils and other cells to the region of tumor growth [29]. Therapeutic exogenous stimulation of production of TNF showed tumor regression in ⬎20% of metastatic or recurrent colorectal cancer cases [30]. Ito et al [31] studied concentration of TNF and survival. They found that patients in the TNFproducing group had a higher 5-year survival rate than those in the non–TNF-producing group. Five-year survival for the TNF-producing group was 78% and for the non–TNF-producing group was 50% (the difference was not statistically significant). The data support our findings and suggestion of the immunocytokine etiology of these changes. Tumor-stimulated macrophages produce TNF-alpha and interferons, which stimulate natural killer lymphocytes [32]. We believe this cascade of events contributes to tumor necrosis in regional lymph nodes, in blood, and in distant organs, which subsequently improves patient survival. Our study patients received chemotherapy, and we cannot be certain if patients who had necrotic changes were already fighting the cancer and if chemotherapy enhanced this immune response. Because we can expect opposite events, patients with necrotic changes had an overwhelming lymphocyte and cytokine response (such as the syndrome of systemic inflammatory response in patients with sepsis), and chemotherapy just liquidates this response, thus helping the body react to the tumor more efficiently. This hypothesis is supported by the data of Kimball et al. [33]. They concluded that the finding regarding the effect of chemotherapy might reflect the ability of levamisol to normalize either a depressed or an excessively exuberant immune response. The data regarding 5-FU are also controversial in terms of stimulating or depressing the immune system [34]. According to our data, necrosis in metastatic lymph nodes correlates with increased survival in patients who
367
underwent adjuvant chemotherapy and can be a microscopic equivalent of TNF and other antitumor cytokine production. In contrast, we can hypothesize that adjuvant chemotherapy modulates the immune system in improving response to tumor cell invasion in the group of patients who have necrotic changes in metastatic lymph nodes. Today, we do not have reliable factors that would help us to predict the development of metastases or recurrence. It is important to analyze as many factors as possible and to consider the individual contribution of these factors for predicting treatment failure. Most importantly, clinicopathologic judgment should be used for the implication of this information in the treatment of each individual patient. In conclusion, the survival of patients with necrotic changes in metastatic lymph nodes was higher than in patients without necrotic changes (P ⫽ 0.02). These necrotic changes can help us to understand body–tumor relations and help us evaluate treatments that might lead us to improved survival in the Duke’s C category of patients with worse prognosis after radical surgery. Further studies on a larger patient population and on different modalities of therapy would be beneficial in confirming our findings and discovering some mechanisms of tumor metastasis.
Acknowledgment The authors thank Mario Scarcipino for his assistance with this article.
References [1] Greenlee RT, Murray T, Bolden S, et al. Cancer statistics, 2000. CA Cancer J Clin 2000;50:7–33. [2] MacDonald J, Astrow A. Adjuvant therapy of colon cancer. Semin Oncol 2001;28:30 – 40. [3] Miyake Y, Yamamoto H, Fujivara Y, et al. Extensive micrometastases to lymph nodes as a marker for rapid recurrence of colorectal cancer: a study of lymphatic mapping. Clin Cancer Res 2001;7:1350 – 1357. [4] Liefers G-J, Cleton-Jansen A-M, van de Velde CJH, et al. Micrometastases and survival in stage II colorectal cancer. N Engl J Med 1998;339:223–228. [5] Leinung ST, Wurl P, Shonfelder A, et al. Detection of cytokeratinpositive cells in bone marrow in breast cancer and colorectal carcinoma in comparison with other factors of prognosis. J Hematother Stem Cell Res 2000;9:905–911. [6] Gunderson LL, Sargent DJ, Tepper JE, et al. Impact of T and N substage on survival and disease relapse in adjuvant rectal cancer: a pooled analysis. Int J Radiat Oncol Biol Phys 2002;54:386 –396. [7] Ratto C, Sofo L, Ippoliti M, et al. Prognostic factors in colorectal cancer: literature review for clinical application. Dis Colon Rectum 1998;41:1033–1049. [8] Nissan A, Guillem JG, Paty PB, et al. Signet-ring cell carcinoma of the colon and rectum: a matched control study. Dis Colon Rectum 1999;42:1176 –1180. [9] Oberg A, Stenling R, Tavelin B, et al. Are lymph node micrometastases of any clinical significance in Dukes stages A and B colorectal cancer? Dis Colon Rectum 1998:41:1244 –1249.
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[10] Ratto C, Ricci R, Rossi C, et al. Mesorectal microfoci adversely affect the prognosis of patients with rectal cancer. Dis Colon Rectum 2002; 45:733–743. [11] Bessa X, Elizalde JI, Boix L, et al. Lack of prognostic influence of circulating tumor cells in peripheral blood of patients with colorectal cancer. Gastroenterology 2001;120:1084 –1092. [12] Koch M, Weitz J, Kienle P, et al. Comparative analysis of tumor cell dissemination in mesenteric, central, and peripheral venous blood in patients with colorectal cancer. Arch Surg. 2001;136:85– 89. [13] Quirke P, Durdey P, Dixon M, et al. Local recurrence of rectal adenocarcinoma due to inadequate surgical resection: hystopathological study of lateral tumor spread and surgical excision. Lancet 1986; 1:996 –998. [14] Ueno H, Mochizuki H, Tamakuma S. Prognostic significance of extranodal microscopic foci discontinuous with primary lesion in rectal cancer. Dis Colon Rectum 1998;41:55– 61. [15] Masliak V, Savran V, Fulmes M. The efficacy of the surgical treatment of colorectal cancer with metastases into perienteric fatty tissue. Lik Sprava 1999;6:55– 60. [16] Mitmaker B, Begin LR, Gordon PH. Nuclear shape as a prognostic discriminant in colorectal carcinoma. Dis Colon Rectum 1991;34: 249 –259. [17] Goldstein N, Hart J. Histologic features associated with lymph node metastasis in stage T1 and superficial T2 rectal adenocarcinomas in abdominoperineal resection specimens. Am J Clin Pathol 1999;111: 51–58. [18] Lennon A, Mulcahy H, Hyland J, et al. Peritoneal involvement in stage II colon cancer. Am J Clin Pathol 2003;119:108 –113. [19] Bobrow L, Happerfield L, Gregory W, et al. Ductal carcinoma in situ: assessment of necrosis and nuclear morphology and their association with biological markers. J Pathol 1995;176:333–341. [20] Greenson J, Bonner J, Ben-Yzhak O, et al.Phenotype of microsatellite unstable colorectal carcinomas: well differentiated and focally mucinous tumors and the absence of dirty necrosis correlate with microsatellite instability. Am J Pathol 2003;27:563–570. [21] Rubio C. Colorectal carcinomas. Possible mechanisms of local tumor progression. Anticancer Res 2003;23:347–350. [22] Jass JR. Lymphocytic infiltration and survival in rectal cancer. J Clin Pathol 1986;39:585–589.
[23] Choi P, Zelig M. Similarity of colorectal cancer in Crohn’s disease and ulcerative colitis: implications for carcinogenesis and prevention. Gut 1994;35:950 –954. [24] Ueda T, Shimada E, Urakawa T. Serum levels of cytokines in patients with colorectal cancer: possible involvement of interleukin-6 and interleukin-8 in hematogenous metastasis. J Gastroenterol 1994;29: 423– 429. [25] Leith J, Michelson S. Levels of selected growth factors in viable and necrotic regions of xenografted HCT-8 human colon tumours. Cell Prolif 1995;28:279 –286. [26] Subbegowda R, Frommel T. Aspirin toxicity for human colonic tumor cells results from necrosis and is accompanied by cell cycle arrest. Cancer Res 1998;58:2772–2776. [27] Takagi K, Tomita K, Fukushima Y, et al. Endogenous TNF inducibility and prognosis of colorectal cancer. Anticancer Res 1998;18: 4141– 4146. [28] Naylor S, Stamp G, Balkwill F. Investigation of cytokine gene expression in human colorectal cancer. Cancer Res 1990;50:4436 – 4440. [29] Ackermann MF, Lamm KR, Wiegand GW, et al. Antitumor activity of murine neutrophils demonstrated by cytometric analysis. Cancer Res 1989;49:528 –532. [30] Fukushima Y, Tanizaki E, Takagi K, et al. Inducibility of endogenous tumor necrosis factor by tumor cells from colorectal tumor patients at Dukes stage C as a novel prognostic factor following curative operation. Dis Colon Rectum 1995;38:1059 –1066. [31] Ito H, Yagita A, Fujitsuka M, et al. Tumor necrosis factor production and colon cancer. Jpn J Cancer Res 1996;87:1160 –1164. [32] Ching L-M, Joseph W, Zhuang L, et al. Interaction between endotoxin and the antitumor agent 5,6-dimethylxanthenone-4-acetic acid in the induction of tumor necrosis factor and hemorrhagic necrosis of colon 38 tumours. Cancer Chemother Pharmacol 1994;35:153–160. [33] Kimball E, Schneider C, Fisher M, et al. Levamisole causes differential cytokine expression by elicited mouse peritoneal macrophages. J Leukocyte Biol 1992;52:349 –356. [34] Lukaci J, Kusici Z, Kovacevic D, et al. Neutrophil and monocyte phagocytic functions in patients in patients with colorectal adenocarcinoma during fluorotherapy. Anticancer Res 1995;15:2805–2810.
Scientific paper
Cancer biology and necrotic changes in metastatic lymph nodes and survival of colon cancer patients Michael Fulmes, M.D., Ph.D.a, Sebouh Setrakian, M.D.b, Prasanta K. Raj, M.D.a, Brent M. Bogard, M.D.a b
a Department of Surgery, Fairview Hospital, Cleveland Clinic Health System, Cleveland, OH, USA Department of Pathology, Fairview Hospital, Cleveland Clinic Health System, Cleveland, OH, USA
Manuscript received September 14, 2004; revised manuscript November 23, 2004 Presented at the 47th Annual Meeting of the Midwest Surgical Association, Mackinac Island, Michigan, August 15–18, 2004
Abstract Background: Identifying factors that can contribute to a better understanding of tumor progression in stage III colon cancer patients continues to be an important task. Necrotic changes in metastatic lymph nodes have not been previously analyzed in English literature. Methods: The study included 48 consecutive colon and rectosigmoid cancer patients with stage III disease who underwent radical surgery. After reviewing the diagnostic slides, a pathologist developed a scale describing the extent of necrotic changes. Results were evaluated using Kaplan-Meier method and log-rank test. Results: Thirty-four (70%) patients had necrotic changes in metastatic lymph nodes. Patients with necrotic changes in metastatic lymph nodes had more risk factors than patients without necrosis. The 5-year survival rate for patients with necrotic changes in metastatic lymph nodes was 85% and for patients without necrosis was 50% (P ⫽ 0.02). Conclusions: The survival of patients with necrotic changes in metastatic lymph nodes was higher (P ⫽ 0.02). These necrotic changes can help us to understand body–tumor relations. © 2005 Excerpta Medica Inc. All rights reserved. Keywords: Colorectal cancer; Metastatic lymph nodes; Necrosis; Survival
Colorectal cancer is highly prevalent in Westernized countries. In 2000, approximately 130,000 cases of colorectal cancer occurred in the United States [1], and colorectal cancer is the second most common cause of cancer death in the United States [1]. In stage III (node-positive) patients, the risk of death from cancer is as high as 70% during the 5-year period after surgical resection [2]. TNM staging is used for prognosis and treatment plan despite the shortcomings of this system [3– 6]. The investigators tried to identify other important evaluation tools, other than TNM staging, that can correlate with the prognosis of colorectal cancer patients. This leads to the hypothesis of substaging. Ratto et al [7] performed analysis of the significance of different factors, and they found that none of these factors Corresponding author. Mario Scarcipino, Department of Surgery, Fairview Hospital, Cleveland Clinic Health System, 18101 Loraine Avenue, Cleveland, OH 44111, USA. Tel.: ⫹1-216-476-7805; fax: ⫹1-216476-7883. E-mail address: [email protected]
were able to predict prognosis, especially in stage II and III patients. When looked at individually, such factors as tumor configuration, mucinous component, venous or perineural invasion, inflammatory reaction, and differentiation grade did not predict survival in most cases. These investigators found that only lymph node involvement, distant metastases, bowel obstruction, vessel invasion, and tumor DNA ploidy are factors independently related to the outcome. Signet-Ring cell cancer, which was not included in the analysis, had an adverse effect on survival in Nissan et al’s study [8]. After the introduction of TNM staging and insufficient prognostic values of the previously mentioned factors, investigators searched for new microscopic factors and also reevaluated known factors. These new factors include the detection of micrometastasis in lymph nodes [9,10], bone marrow [5], and blood [5,11,12]. Only a few studies found [13–15] and demonstrated [14,15] the importance of tumor deposits into paracolic or pararectal fat tissue. Significance
0002-9610/05/$ – see front matter © 2005 Excerpta Medica Inc. All rights reserved. doi:10.1016/j.amjsurg.2004.11.028
M. Fulmes et al. / The American Journal of Surgery 189 (2005) 364 –368
365
Table 1 Demographics of patients with and without necrotic changes in metastatic lymph nodes who underwent survival analysis Patient demographics
Age (mean y) Sex (%) Male Female Right colon (%) Transverse colon (%) Left and descending colon (%) Sigmoid and rectosigmoid colon (%)
With necrotic changes (n ⫽ 20)
Without necrotic changes (n ⫽ 10)
67.4
73.1
9 11 8 2 1 9
5 5 7 0 0 3
(45) (55) (40) (10) (5) (45)
(50) (50) (70)
(30)
of nucleus shape [16], tumor budding [17], and peritoneal free cancer cells [18] were analyzed, but the findings were inconsistent. Bobrow et al [19] and other investigators analyzed necroses in ductal carcinoma in situ. The investigators noticed that regardless of the histologic architecture of the lesion, the presence of extensive necrosis within the affected ducts is associated with a greater tendency for local recurrence after breast-conservation treatment. Recently, Greenson et al [20] analyzed the correlation of necrotic changes in colorectal tumors with microsatellite instability, and Rubio [21] described necrotic changes in the growing edge of the tumor. The role of these studies is important in understanding tumor progression, and the practical application of them must be evaluated. Currently, no data exist in English literature about the phenomenon of necrotic changes in metastatic lymph nodes.
Fig. 1. Grade ⫹1 necrosis with neutrophil infiltration limited to few glandular lumens.
necrosis with neutrophil infiltration limited to few glandular lumens; grade ⫹2 necrosis with neutrophil infiltration limited to few glandular lumens and penetrates the basal membrane; grade ⫹3 necrosis with neutrophil infiltration involving up to 50% of the lymph node; and grade ⫹4 severe necrosis with neutrophil infiltration involving most of the lymph node (Figs. 1– 4). Survival data were obtained from our cancer registry, from surgeons’ office records, and by contacting patients. Patients who underwent palliative surgery without adjuvant chemotherapy and who died from non– cancerrelated causes, or who had tumor deposits in paracolic fat tissue, were not included in this survival analysis. Statistical analysis
Patients and Methods After receiving Institutional Review Board approval for the study, we analyzed 48 consecutive patients with colon and rectosigmoid cancer who underwent radical surgery between 1996 and 1998 at a large community teaching hospital. Patients were 52 to 90 years old (mean 72.3) (Table 1). Staging revealed 1 patient (2%) as T2, 38 (79%) patients as T3, and 8 (16.7%) patients as T4. Moderately well-differentiated adenocarcinoma was detected in 24 (50%), poorly differentiated adenocarcinoma in 17 (35.4%), and mucinous adenocarcinoma in 7 (14.6%) patients. Fifteen patients (31%) had ⬎3 metastatic lymph nodes (N2). Seven patients underwent palliative surgery for locally advanced disease or disease with simultaneous gastric cancer or bladder cancer with multiple myeloma. One patient had metastasis to the greater omentum. One experienced pathologist, who was unaware of clinical details and treatment outcome, reviewed all original hematoxylin and eosin–stained slides. The pathologist developed a system for evaluation of necrotic changes. The extent of necrosis was graded into 4 categories: grade ⫹1
Statistical analysis of 5-year survival was performed for patients who met the inclusion criteria. Kaplan-Meier method
Fig. 2. Grade ⫹2 necrosis with neutrophil infiltration limited to few glandular lumens with penetrating basal membrane.
366
M. Fulmes et al. / The American Journal of Surgery 189 (2005) 364 –368 Table 2 Risk factors for patients with and without necrotic changes in metastatic lymph nodes who underwent survival analysis
Fig. 3. Grade ⫹3 necrosis with neutrophil infiltration involving up to 50% of the lymph node.
was used to calculate survival, and log-rank test was used to estimate the difference in survival for the 2 groups. P ⬍0.05 was considered significant.
Results Necrotic changes in metastatic lymph nodes were found in 34 (70%) patients: ⫹1 in 7 (20.6%), ⫹2 in 7 (20.6%), ⫹3 in 13 (38%), and ⫹4 in 7 (20.6%). During the follow-up period, 26 deaths were reported in the patient population; 23 of these were cancer related. The group of patients with necrotic changes had more risk factors compared with patients without necrotic changes (Table 2). All five patients with ⫹4 necrotic change survived 5 years. The 5-year survival rate in the group with necrotic changes in metastatic lymph nodes was 85% compared with a 50% survival rate in the group without necrotic changes (P ⫽ 0.02) (Fig. 5).
Fig. 4. Grade ⫹4 severe necrosis with neutrophil infiltration involving most of the lymph node.
Patient risk factors
With necrotic changes (n ⫽ 20)
Without necrotic changes (n ⫽ 10)
T3 (%) T4 (%) N1 (%) N2 (%) NX (%) Unknown (%) Poorly differentiated (%) Moderately well-differentiated (%) Mucinous (%) Metastatic to omentum (%) Vascular invasion (%) Lymph vessel invasion (%) Perineural invasion (%)
18 2 13 6 1 1 9 7 3 1 3 3 1
9 1 9 1 0 0 2 4 4 0 0 0 1
(90) (10) (65) (30) (5) (5) (45) (35) (15) (5) (15) (15) (5)
(90) (10) (90) (10)
(20) (40) (40)
(10)
Comments Cancer is a dynamic process involving an interaction of body systems and a pool of heterogeneous cancer cells. As mentioned, data correlating tumor features and survival can be controversial because some findings appear to influence survival, whereas other investigators studying the same factors have found no role for prognosis. Patients with noninherited genetic disturbances, micrometastases to lymph nodes and other tissues, free cancer cells in the peritoneal cavity, blood stream, and bone marrow, and other evidence of tumor spreading even after palliative surgery can still have a favorable outcome because of the body’s varying response to different tumor biology. So far in the literature, we have found chronic inflammatory reaction to the primary site of the tumor to be a morphologic and easy, low-cost detectable feature [22] that has not found well-excepted practical value and has yielded results that are still controversial. First, the data are not sufficiently objective. Otherwise, the histologic criteria for qualitative and quantitative evaluation differ from study to study. Second, cytokines, which are produced during
Fig 5. Five-year survival of colorectal cancer patients: those with versus without necrotic changes.
M. Fulmes et al. / The American Journal of Surgery 189 (2005) 364 –368
inflammatory reaction, can actually stimulate growing and metastatic ability of tumor cells [23,24]. Necrotic changes of tumor as a first line of defense in regional lymph nodes can be evidence of the body’s reaction to tumor. Necrosis itself can be different in nature. Inflammatory necrosis of an infectious nature was not found in our study patients. Most likely, necrosis was not attributed to hypoxia because we found necrotic changes in cases of extensive metastasis and also in small areas of metastatic lesions and vice versa. Moreover, investigators have shown that hypoxia stimulates the production of angiogenic growth factors [25]. Necrosis caused by blocking of the cell cycle in the G2-M phase can be the result of apoptosis or chemotherapy [26], but apoptosis is not a characteristic feature of tumors and chemotherapy was not performed before surgery in our study patients. Our last explanation for the reason of necrosis is an immune response to tumor, which leads to a cascade of changes in lymph nodes involving tumor necrosis factor (TNF) production and other cytokines. Other investigators have identified biochemical pathways for TNF production in cancer cells [27,28], which most likely facilitates tumor advancement into adjacent tissues and vessels [28]. In contrast, TNF also attracts neutrophils and other cells to the region of tumor growth [29]. Therapeutic exogenous stimulation of production of TNF showed tumor regression in ⬎20% of metastatic or recurrent colorectal cancer cases [30]. Ito et al [31] studied concentration of TNF and survival. They found that patients in the TNFproducing group had a higher 5-year survival rate than those in the non–TNF-producing group. Five-year survival for the TNF-producing group was 78% and for the non–TNF-producing group was 50% (the difference was not statistically significant). The data support our findings and suggestion of the immunocytokine etiology of these changes. Tumor-stimulated macrophages produce TNF-alpha and interferons, which stimulate natural killer lymphocytes [32]. We believe this cascade of events contributes to tumor necrosis in regional lymph nodes, in blood, and in distant organs, which subsequently improves patient survival. Our study patients received chemotherapy, and we cannot be certain if patients who had necrotic changes were already fighting the cancer and if chemotherapy enhanced this immune response. Because we can expect opposite events, patients with necrotic changes had an overwhelming lymphocyte and cytokine response (such as the syndrome of systemic inflammatory response in patients with sepsis), and chemotherapy just liquidates this response, thus helping the body react to the tumor more efficiently. This hypothesis is supported by the data of Kimball et al. [33]. They concluded that the finding regarding the effect of chemotherapy might reflect the ability of levamisol to normalize either a depressed or an excessively exuberant immune response. The data regarding 5-FU are also controversial in terms of stimulating or depressing the immune system [34]. According to our data, necrosis in metastatic lymph nodes correlates with increased survival in patients who
367
underwent adjuvant chemotherapy and can be a microscopic equivalent of TNF and other antitumor cytokine production. In contrast, we can hypothesize that adjuvant chemotherapy modulates the immune system in improving response to tumor cell invasion in the group of patients who have necrotic changes in metastatic lymph nodes. Today, we do not have reliable factors that would help us to predict the development of metastases or recurrence. It is important to analyze as many factors as possible and to consider the individual contribution of these factors for predicting treatment failure. Most importantly, clinicopathologic judgment should be used for the implication of this information in the treatment of each individual patient. In conclusion, the survival of patients with necrotic changes in metastatic lymph nodes was higher than in patients without necrotic changes (P ⫽ 0.02). These necrotic changes can help us to understand body–tumor relations and help us evaluate treatments that might lead us to improved survival in the Duke’s C category of patients with worse prognosis after radical surgery. Further studies on a larger patient population and on different modalities of therapy would be beneficial in confirming our findings and discovering some mechanisms of tumor metastasis.
Acknowledgment The authors thank Mario Scarcipino for his assistance with this article.
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