- Email: [email protected]
The Prognostic Relevance of Histological Subtype in Patients With Peritoneal Metastases From Colorectal Cancer: A Nationwide Population-Based Study
Original Study
The Prognostic Relevance of Histological Subtype in Patients With Peritoneal Metastases From Colorectal Cancer: A Nationwide Population-Based Study Lieke G.E.M. Razenberg,1,2 Yvette R.B.M. van Gestel,2 Valery E.P.P. Lemmens,2 Johannes H.W. de Wilt,3 Geert-Jan Creemers,1 Ignace H.J.T. de Hingh4 Abstract The prognostic relevance of commonly identified histological subtypes in patients with peritoneal metastases from colorectal cancer (adenocarcinoma, mucinous adenocarcinoma, and signet-ring cell carcinoma) is currently unclear. This study involved 4277 patients diagnosed with synchronous peritoneal metastases from colorectal cancer between 2005 and 2012 in The Netherlands. Histological subtype was identified as an important prognostic factor in patients with synchronous peritoneal metastases from colorectal cancer. Background: With evolving treatment possibilities for peritoneal metastases (PM) from colorectal cancer (CRC), adequate prognostication and patient selection for treatment becomes increasingly important. We investigated the prognostic relevance of commonly identified histological subtypes in PM of CRC (adenocarcinoma [AC], mucinous AC [MC], and signet-ring cell carcinoma [SC]), which is currently unclear. Patients and Methods: This study involved 4277 patients diagnosed with synchronous PM from CRC between 2005 and 2012 in The Netherlands. KaplaneMeier analysis and log-rank testing were performed to estimate survival. Subsequently a Cox proportional hazard model was used to calculate hazard ratios for the risk of death. Results: Most of the CRC patients were diagnosed with AC (n ¼ 3008; 70%), whereas MC and SC were found in 958 (22%) and 311 (7%) patients, respectively. SC was associated with the highest risk of death in colon and rectal cancer, with median survival rates of respectively, 6.6 and 6.9 months. For MC, median survival varied from 10.9 months in colon and 9.8 months in rectal cancer (P > .05). In colon cancer, MC was associated with a significantly lower risk of death compared with AC (hazard ratio, 0.9; 95% confidence interval, 0.79-0.95). In rectal cancer, no such effect was observed. AC was associated with a significantly poorer survival rate in the case of primary colonic tumor localization (7.4 months in colon vs. 10.9 months in rectal cancer). Conclusion: Histological subtype is an important prognostic factor in patients with synchronous PM of colorectal origin. This knowledge will aid clinicians in counseling of patients and clinical decision-making regarding possible treatment options. Clinical Colorectal Cancer, Vol. -, No. -, --- ª 2015 Elsevier Inc. All rights reserved. Keywords: Adenocarcinoma, Colorectal cancer, Mucinous adenocarcinoma, Signetering-cell carcinoma, Synchronous peritoneal metastases
1
Department of Oncology, Catharina Hospital, Eindhoven, The Netherlands Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, The Netherlands 3 Department of Surgery, Radboud University Medical Centre, Nijmegen, The Netherlands 4 Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands 2
Submitted: Feb 12, 2015; Revised: May 26, 2015; Accepted: May 29, 2015 Address for correspondence: Ignace H.J.T. de Hingh, MD, PhD, Department of Surgery, Catharina Hospital, Michelangelolaan 2, 5623 EJ, Eindhoven, The Netherlands Fax: þ31-40-2443370; e-mail contact: [email protected]
1533-0028/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clcc.2015.05.011
Introduction Colorectal carcinomas are histologically classified according to the World Health Organization classification system.1 Adenocarcinoma (AC) is the most frequently diagnosed histological subtype, followed by mucinous AC (MC), and signet-ring cell carcinoma (SC). The histological subtype has been suggested to play a role in the development and natural course of patients with colorectal cancer (CRC).2,3 The prognostic significance of histological subtype is not clear in the specific subset of CRC patients who presenting with
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Prognostic Relevance of Histological Subtype peritoneal metastases (PM). The limited data available are derived from few studies with insufficient statistical power because of the low prevalence of MC and SC. Peritoneal dissemination is a well known manifestation of metastatic CRC, which is present in approximately 7% of CRC patients at the time of diagnosis.4 Recently, several risk factors for the development of PM have been identified, including right-sided tumor, advanced T-stage, advanced N-stage, poor differentiation grade, and younger age at diagnosis.5 In the current era of evolving treatment options for patients with PM, identification of prognostic factors is essential to provide adequate counseling on prognosis and accurate patient selection for treatment. Therefore, the current nationwide population-based study on the clinicopathological characteristics and prognosis of patients with synchronous PM from primary colorectal tumors of different histological subtypes was performed.
Patients and Methods Data and Patients All patients newly diagnosed with cancer in The Netherlands are registered by the Netherlands Cancer Registry (NCR). The NCR covers the entire Dutch population of approximately 16 million inhabitants. Data on patient and tumor characteristics are collected from medical records by specially trained registry staff, using the registration and coding manual of the NCR. Pathologists enter histopathological and cytopathological reports of the diagnosed cancers in the nationwide Dutch Pathology Network, which subsequently submits the data to the NCR. In the NCR, the tumor, node, metastases (TNM) system is used for stage classification of the
primary tumor.6 In case of missing pathological data, clinical TNM stage is used. Anatomical site of the tumor is registered according to the International Classification of Diseases for Oncology (ICD-O).7 Data on location of distant metastases were available in the NCR in 8 of 9 regions since 2005. Since 2007 data on site of metastases were available in all 9 regions and complete in approximately 95% of all patients with metastasized disease. In total, 4623 patients were diagnosed with synchronous PM from CRC between 2005 and 2012, representing 4.6% of the total CRC group and 21.2% of the synchronous metastasized CRC group. Most (96%) of these patients were diagnosed with either AC (ICD-O: 8140, 8144, 8120, 8255, 8261, 8263, 8560), MC (ICD-O: 8480, 8481, 8470), or SC (ICD-O: 8490). The remaining subgroup (n ¼ 169), mostly consisted of patients with small cell carcinoma, undifferentiated carcinoma, carcinoid, neuroendocrine carcinoma, and other even less frequent histological subtypes and was excluded. In addition, patients with primary appendiceal cancer (ICD-O: C18.1; n ¼ 177) were excluded because they reflect a distinct entity with a different prognosis.8 Tumor localization was further divided into colonic (ICD-O: C18, excluding C18.1) and rectal cancers (ICD-O: C19-20). The final database included 4277 CRC patients with PM (Figure 1).
Statistical Analysis Differences in patient and tumor characteristics between the different histological subtypes were compared and analyzed using a 2-sided c2 test. Survival time was defined as the time between diagnosis of CRC and death or lost to follow-up. Patients still alive at the end of follow-up (January 1, 2014) and those who emigrated were
Figure 1 Number of Patients With Synchronous PM of Colorectal Origin Diagnosed Between 2005 and 2012 in The Netherlands
2
-
Abbreviations: AC ¼ adenocarcinoma; MC ¼ mucinous carcinoma; PM ¼ peritoneal metastases; SC ¼ signet-ring cell carcinoma.
Clinical Colorectal Cancer Month 2015
Lieke G.E.M. Razenberg et al censored. Crude survival estimates were calculated with the KaplaneMeier method and presented up to 36 months. Median survival was presented in months with corresponding 95% confidence intervals (CIs). Differences in survival proportions between the histological subtypes were calculated with a log-rank test. Univariable Cox regression analysis was performed to identify relevant and prognostic patient and tumor characteristics for the risk of death. Subsequently, multivariable Cox regression analyses were carried out to estimate independent hazard ratios on the risk of death for the histological subtypes. All analyses were performed with SAS/STAT statistical software (SAS system 9.3; SAS Institute, Cary, NC).
Results Between January 2005 and December 2012, a total of 4277 patients were diagnosed with synchronous PM from AC, MC, or SC CRC in The Netherlands.
Clinical Features of Histological Subtypes Sex was distributed equally between the histological subsets. In the SC group, the proportion of patients diagnosed at a younger age (< 60 years) was greater and advanced T and N stages were more frequently present in patients with SC tumors. Moreover, differentiation grade was unfavorable for patients with SC compared with
Table 1 General Characteristics of Patients Diagnosed Between 2005 and 2012 in The Netherlands With Synchronous PM of Colorectal Origin (n [ 4277)
Characteristic
Adenocarcinoma (n [ 3008; 70%)
Mucinous (n [ 958; 22%)
n
n
%
Signet-Ring Cell (n [ 311; 7%)
%
n
%
P .18
Sex Male
1521
51
483
50
174
56
Female
1487
49
475
50
137
44
615
20
215
22
92
30
60-70
903
30
269
28
91
29
>70
1490
50
474
50
128
41
2005-2006
574
19
209
22
57
18
2007-2008
722
24
252
26
80
26
2009-2010
810
27
237
25
81
26
2011-2012
902
30
260
27
93
30
2590
86
856
89
265
85
418
14
102
11
46
15
59
2
8
1
5
1
Age, Years <60
<.01
Period .22
Localization Colon Rectum
<.05
T Stage T1,2 T3
764
25
257
27
58
19
T4
1369
46
488
51
182
59
816
27
205
21
66
21
N0
403
13
140
15
27
8
N1
794
26
218
23
58
19
N2
979
33
355
37
134
43
Nx
832
28
245
25
92
30
1112
37
290
30
10
3
728
24
223
23
166
53
1168
39
445
47
135
44
PM only
1109
39
517
54
184
59
PM with systemic metastases
1899
61
441
46
127
41
T0,X
<.0001
N Stage <.0001
Differentiation Grade Well/moderate Poor/undifferentiated Unknown
<.0001
Extent of Metastatic Disease <.0001
Abbreviation: PM ¼ peritoneal metastases.
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Prognostic Relevance of Histological Subtype AC and MC, with most being poorly or undifferentiated tumors (53%, n ¼ 166). Primary MC tumors were more often located in the colon in the case of MC tumor histology. Patients with AC were more likely to have PM and concomitant extra-PM (P < .0001). Further details are shown in Table 1.
differences were found between colonic and rectal tumor localization. The prolonged overall survival in patients with MC colon cancer compared with AC and SC histological subtype remained present after stratification for the presence of extra-peritoneal disease (Table 2).
Overall Survival According to Histological Subtype A significant correlation between survival time and histological subtype was found (Figure 2). In colon cancer patients with MC median survival was 10.9 months versus 7.4 months in AC and 6.6 months in SC (P < .0001). In rectal cancer, the median survival for patients with AC almost equaled MC (respectively, 10.0 and 9.8 months) being significantly longer than the 6.9 months in patients with SC (P < .01). Overall survival for patients with AC was significantly worse in colon than in rectal cancer (P < .01). In patients with MC and SC, no significant
Prognostic Relevance of Histological Subtypes After adjustment for important patient and tumor characteristics, MC was associated with a decreased risk of death compared with AC (hazard ratio [HR], 0.9; 95% CI, 0.79-0.95) in colon cancer patients (Table 3). This association was not observed in patients with rectal cancer (HR, 1.0; 95% CI, 0.74-1.28). An increased risk of death was found for patients with SC histological subtype compared with AC, in colon (HR, 1.2; 95% CI, 1.05-1.42) and in rectal cancer (HR, 2.8; 95% CI, 1.62-3.50).
Figure 2 Overall MS of Patients With Peritoneal Metastases From Colorectal Cancer According to Histological Subtype (n [ 4277): (A) Colon; (B) Rectum
4
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Abbreviations: AC ¼ adenocarcinoma; MC ¼ mucinous carcinoma; SC ¼ signet-ring cell carcinoma.
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Lieke G.E.M. Razenberg et al Table 2 Survival of Patients With PM From AC, MC, or SC Colon or Rectal Cancer, According to the Extent of Metastatic Disease Colon n
Rectum
MS, Months
n
MS, Months
PM-Only AC
959
8.9
150
11.5
MC
468
13.0a
49
9.9
SC
158
7.1
26
P
<.0001
7.7 <.01
Other AC
1631
6.6
269
MC
388
9.5b
53
9.8
SC
107
5.5
20
5.7
P
<.001
9.1
.37
Abbreviations: AC ¼ adenocarcinoma; MC ¼ mucinous carcinoma; MS ¼ median survival; PM ¼ peritoneal metastases; SC ¼ signet-ring cell carcinoma. a Colon, PM-only MC versus AC; P < .01. b Colon, PM-other MC versus AC, P < .001.
Discussion To our knowledge, this is the first nationwide population-based study to focus on histological subtype in CRC patients who present with synchronous PM with regard to prognosis. Our results show that histological subtype of the primary tumor is of prognostic significance in this particular subset of patients. The prevalence of MC and SC in this study on 4277 PM patients was respectively, 22% and 7%. Other studies reported remarkably lower proportions of MC (10%-20%) and SC (0.4%-1%).2,3 This disparity can be explained by differences in patient selection; in the current study we included only patients with synchronous PM from CRC. Previous studies have indeed shown that patients diagnosed with MC or SC have a higher propensity of peritoneal spread in the early course of the disease than do patients with AC.2,3,9 In accordance with previous studies, patients with SC presented at a younger age, were more frequently detected in an advanced stage, and usually had a poorer differentiation grade than patients with AC.10,11
Table 3 Association Between Histological Subtypes and Risk of Death According to Primary Tumor Localization n
HR
2590
1.0
95% CI
P
Colon Adenocarcinomaa Mucinous
856
0.9
0.81-0.98
<.01
Signet-ring cell
265
1.2
1.05-1.42
<.01
Rectum Adenocarcinomaa
418
1.0
Mucinous
102
1.1
0.84-1.47
.84
46
2.4
1.62-3.50
<.0001
Signet-ring cell
Data are adjusted for age, sex, T and N stage, differentiation grade, PM extent, and period of diagnosis and treatment. Abbreviations: HR ¼ hazard ratio; PM ¼ peritoneal metastases a Reference category.
In the present study, differences in overall survival between the histological subtypes AC, MC, and SC were shown. The poorest median survival (6.8 months after diagnosis) was observed in the subgroup of patients with SC tumors, regardless of tumor localization and the existence of extraperitoneal metastatic disease. The identification of SC as a stage-independent poor prognostic factor has been previously reported in patients with CRC in general.10,12,13 Compared with these studies, the median survival of patients included in the present study was dismal. This confirms the negative influence of PM on survival, compared with other metastatic sites of CRC, such as the liver. The poor prognosis of CRC patients who present with SC differentiation supports the hypothesis that CRC with SC should be regarded as a different clinical entity. Indeed, carcinogenetic factors, tumor growth, and development have been described to be different in SC than in non-SC tumors.10,12 For example, microsatellite instability is more frequently described in SC.12,14 However, the number of SC tumors in these studies were small and therefore these results should be interpreted with caution. The prognostic significance of MC histological subtype is controversial. In some studies MC has been associated with a significantly poorer prognosis than AC, but in other studies no such prognostic significance was found.15-20 None of these studies focused on the specific subgroup of patients with CRC who present with PM as described in our study. In the present study, median survival for colon cancer patients with MC was favorable, compared with patients with AC (10 and 7 months, respectively). No such difference was observed in rectal cancer patients. Obvious reasons for the favorable overall survival in patients with MC colon cancer are not clear. MC has been identified as a distinct colorectal subtype with different molecular, genetic, and pathological characteristics. MC is more frequently associated with high levels of microsatellite instability, BRAF/ p53/16 mutations, downregulation of adhesion molecules, and is characterized by the presence of mucin in > 50% of the lesion.10 It has been suggested that this different tumor biology of MC is responsible for poorer responses to systemic chemotherapy.21 However, in a recent study by Hugen et al no difference in the efficacy of adjuvant chemotherapy was observed between patients with MC and non-MC stage III CRC.17 Furthermore, it can be hypothesized that because of the presence of mucin, peritoneal tumor deposits of MC might be less likely than the more solid tumor deposits to cause bowel obstruction as found in AC. Bowel obstruction resulting in malnourishment and eventually ileus is a frequent cause of death in PM patients. Finally, it was observed that right-sided AC tumors were associated with a poorer prognosis than left-sided AC tumors, which was not the case for MC tumors (data not shown). In the current literature rightsided colon cancers have been associated with different clinical presentations and tumor biology.22 Across all stages right-sided tumors generally have a higher risk of mortality than left-sided tumors, but within stage groups the effect of right-sided tumor localization seems less clear.23 The current study showed that histological subtype influenced the overall survival and should be taken into account in patient counseling and might be important in future patient-tailored treatment decisions. Unfortunately, a significant proportion of PM patients might not be able to receive treatment at all because of
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Prognostic Relevance of Histological Subtype their poor clinical condition that is typical for these patients resulting from bowel obstruction, ascites, and malnourishment. Survival in these patients is very poor and typically averages 3 months.5 Selected patients might be treated with systemic chemotherapy, but responses to conventional 5-fluoropyrimidine-based chemotherapy have been poor, with median survival rates of approximately 6 months.24,25 Since 2001, oxaliplatin-based chemotherapy (capecitabin-oxaliplatin [CAPOX]/fluorouracil-oxaliplatin [FOLFOX]) is recommended as the standard systemic treatment for patients with stage IV CRC in The Netherlands and since 2005 the antivascular agent bevacizumab is recommended as a therapeutic option in combination with first-line chemotherapy. Introduction of these therapeutic options has improved the survival of patients with PM.26 However, the beneficial effect of systemic treatment appears to be limited in patients with PM compared with other metastatic sites, which might explain the poor survival of PM patients as described in the current study.27 Furthermore, patients with PM from CRC might now be offered a multimodality treatment with curative intent including cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC).28,29 Because only selected patients are considered candidates for this highly invasive procedure, most PM patients still depend on palliative systemic treatment options. An important role for histological subtype in treatment decisions has been previously proposed by Pelz et al in patients with PM treated with palliative chemotherapy30 or HIPEC.31 Although in small patient groups, respectively, 59 and 17 patients, they found a negative predictive role for signet cell or poor tumor histology. This was confirmed in a recent study by van Oudheusden and colleagues, who showed limited efficacy of HIPEC in PM patients with SC.32 Of course, because of the nature of this population-based study, our results could also be influenced by study limitations and biases. In the NCR, information on peritoneal tumor burden, microsatellite instability (MSI) status, KRAS/BRAF mutational status, and other established prognostic factors, such as comorbidity is lacking.
Conclusion Mucinous AC and SC were identified in respectively, 22% and 7% of the patients diagnosed with synchronous PM from CRC between 2005 and 2012 in The Netherlands. The results of the current study revealed differences in survival rates and risk of death for AC, MC, and SC histological subtypes and support the hypothesis that SC and MC might be considered as independent tumor entities, with different patient and tumor characteristics and prognoses. The predictive value of the histological subtype in defining optimal treatment strategies should be further clarified.
Clinical Practice Points Mucinous AC and SC are more frequent in CRC patients who
6
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present with PM. However, the role of histological subtype in this particular subset of patients remains unknown. With evolving treatment possibilities for PM of colorectal origin, adequate prognostication and patient selection for treatment becomes increasingly important. The results of this nationwide population-based study reveal differences in overall survival rates and risk of death for AC, MC, and SC histological subtypes.
Clinical Colorectal Cancer Month 2015
This finding supports the hypothesis that SC and MC might be
considered as independent tumor entities, with different patient and tumor characteristics and prognoses. The predictive value of the histological subtype in definition of optimal treatment strategies should be further clarified.
Acknowledgments The authors thank the registration personnel of the NCR for their dedicated data collection.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. S.R. Hamilton, L.A. Aaltonen. WHO Classification of tumours: pathology and genetics of tumours of the digestive system. International Agency for Research on Cancer (IARC) Press, Lyon, 2000. 2. Sim HL, Tan KY, Poon PL, Cheng A. Primary rectal Signet ring cell carcinoma with peritoneal dissemination and gastric secondaries. World J Gastroenterol 2008; 14:2118-20. 3. Winder T, Lenz HJ. Mucinous adenocarcinomas with intra-abdominal dissemination: a review of current therapy. Oncologist 2010; 15:836-44. 4. Goere D, Allard MA, Honore C, Dumont F, Elias D. Incidence and prognosis of synchronous colorectal carcinomatosis. Future Oncol 2013; 9:541-9. 5. Lemmens VE, Klaver YL, Verwaal VJ, Rutten HJ, Coebergh JW, de Hingh IH. Predictors and survival of synchronous peritoneal carcinomatosis of colorectal origin: a population-based study. Int J Cancer 2011; 128:2717-25. 6. The Union for International Cancer Control (UICC). TNM Classification of Malignant Tumours. 7th ed. New York: Wiley-Blackwell; 2009. 7. Fritz AG, Percy C, Jack A, et al. International Classification of Diseases for Oncology. 3rd ed. Geneva: World Health Organization; 2000. 8. Elias D, Glehen O, Pocard M, et al. A comparative study of complete cytoreductive surgery plus intraperitoneal chemotherapy to treat peritoneal dissemination from colon, rectum, small bowel, and nonpseudomyxoma appendix. Ann Surg 2010; 251:896-901. 9. Hugen N, van de Velde CJ, de Wilt JH, Nagtegaal ID. Metastatic pattern in colorectal cancer is strongly influenced by histological subtype. Ann Oncol 2014; 25:651-7. 10. Nitsche U, Zimmermann A, Spath C, et al. Mucinous and signet-ring cell colorectal cancers differ from classical adenocarcinomas in tumor biology and prognosis. Ann Surg 2013; 258:775-83. 11. Pande R, Sunga A, Levea C, et al. Significance of signet-ring cells in patients with colorectal cancer. Dis Colon Rectum 2008; 51:50-5. 12. Hartman DJ, Nikiforova MN, Chang DT, et al. Signet ring cell colorectal carcinoma: a distinct subset of mucin-poor microsatellite-stable signet ring cell carcinoma associated with dismal prognosis. Am J Surg Pathol 2013; 37:969-77. 13. Chew MH, Yeo SA, Ng ZP, et al. Critical analysis of mucin and signet ring cell as prognostic factors in an Asian population of 2,764 sporadic colorectal cancers. Int J Colorectal Dis 2010; 25:1221-9. 14. Koczka CP, Goodman A. Metastatic signet ring colon cancer in a Caribbean young adult and review of the literature. Eur J Gastroenterol Hepatol 2012; 24:731-4. 15. Numata M, Shiozawa M, Watanabe T, et al. The clinicopathological features of colorectal mucinous adenocarcinoma and a therapeutic strategy for the disease. World J Surg Oncol 2012; 10:109. 16. Kang H, O’Connell JB, Maggard MA, Sack J, Ko CY. A 10-year outcomes evaluation of mucinous and signet-ring cell carcinoma of the colon and rectum. Dis Colon Rectum 2005; 48:1161-8. 17. Hugen N, Verhoeven RH, Radema SA, et al. Prognosis and value of adjuvant chemotherapy in stage III mucinous colorectal carcinoma. Ann Oncol 2013; 24: 2819-24. 18. Green JB, Timmcke AE, Mitchell WT, Hicks TC, Gathright JB Jr, Ray JE. Mucinous carcinomaejust another colon cancer? Dis Colon Rectum 1993; 36:49-54. 19. Nozoe T, Anai H, Nasu S, Sugimachi K. Clinicopathological characteristics of mucinous carcinoma of the colon and rectum. J Surg Oncol 2000; 75:103-7. 20. Secco GB, Fardelli R, Campora E, et al. Primary mucinous adenocarcinomas and signet-ring cell carcinomas of colon and rectum. Oncology 1994; 51:30-4. 21. Catalano V, Loupakis F, Graziano F, et al. Mucinous histology predicts for poor response rate and overall survival of patients with colorectal cancer and treated with first-line oxaliplatin- and/or irinotecan-based chemotherapy. Br J Cancer 2009; 100:881-7. 22. Weiss JM, Pfau PR, O’Connor ES, et al. Mortality by stage for right- versus leftsided colon cancer: analysis of Surveillance, Epidemiology, and End ResultseMedicare data. J Clin Oncol 2011; 29:4401-9. 23. Meguid RA, Slidell MB, Wolfgang CL, Chang DC, Ahuja N. Is there a difference in survival between right- versus left-sided colon cancers? Ann Surg Oncol 2008; 15: 2388-94. 24. Jayne DG, Fook S, Loi C, Seow-Choen F. Peritoneal carcinomatosis from colorectal cancer. Br J Surg 2002; 89:1545-50.
Lieke G.E.M. Razenberg et al 25. Sadeghi B, Arvieux C, Glehen O, et al. Peritoneal carcinomatosis from nongynecologic malignancies: results of the EVOCAPE 1 multicentric prospective study. Cancer 2000; 88:358-63. 26. Klaver YL, Lemmens VE, Creemers GJ, Rutten HJ, Nienhuijs SW, de Hingh IH. Population-based survival of patients with peritoneal carcinomatosis from colorectal origin in the era of increasing use of palliative chemotherapy. Ann Oncol 2011; 22:2250-6. 27. Klaver YL, Simkens LH, Lemmens VE, et al. Outcomes of colorectal cancer patients with peritoneal carcinomatosis treated with chemotherapy with and without targeted therapy. Eur J Surg Oncol 2012; 38:617-23. 28. Kuijpers AM, Mirck B, Aalbers AG, et al. Cytoreduction and HIPEC in the Netherlands: nationwide long-term outcome following the Dutch protocol. Ann Surg Oncol 2013; 20:4224-30.
29. Glehen O, Mohamed F, Gilly FN. Peritoneal carcinomatosis from digestive tract cancer: new management by cytoreductive surgery and intraperitoneal chemohyperthermia. Lancet Oncol 2004; 5:219-28. 30. Pelz JO, Chua TC, Esquivel J, et al. Evaluation of best supportive care and systemic chemotherapy as treatment stratified according to the retrospective peritoneal surface disease severity score (PSDSS) for peritoneal carcinomatosis of colorectal origin. BMC Cancer 2010; 10:689. 31. Pelz JO, Stojadinovic A, Nissan A, Hohenberger W, Esquivel J. Evaluation of a peritoneal surface disease severity score in patients with colon cancer with peritoneal carcinomatosis. J Surg Oncol 2009; 99:9-15. 32. van Oudheusden TR, Braam HJ, Nienhuijs SW, et al. Poor outcome after cytoreductive surgery and HIPEC for colorectal peritoneal carcinomatosis with signet ring cell histology. J Surg Oncol 2015; 111:237-42.
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The Prognostic Relevance of Histological Subtype in Patients With Peritoneal Metastases From Colorectal Cancer: A Nationwide Population-Based Study Lieke G.E.M. Razenberg,1,2 Yvette R.B.M. van Gestel,2 Valery E.P.P. Lemmens,2 Johannes H.W. de Wilt,3 Geert-Jan Creemers,1 Ignace H.J.T. de Hingh4 Abstract The prognostic relevance of commonly identified histological subtypes in patients with peritoneal metastases from colorectal cancer (adenocarcinoma, mucinous adenocarcinoma, and signet-ring cell carcinoma) is currently unclear. This study involved 4277 patients diagnosed with synchronous peritoneal metastases from colorectal cancer between 2005 and 2012 in The Netherlands. Histological subtype was identified as an important prognostic factor in patients with synchronous peritoneal metastases from colorectal cancer. Background: With evolving treatment possibilities for peritoneal metastases (PM) from colorectal cancer (CRC), adequate prognostication and patient selection for treatment becomes increasingly important. We investigated the prognostic relevance of commonly identified histological subtypes in PM of CRC (adenocarcinoma [AC], mucinous AC [MC], and signet-ring cell carcinoma [SC]), which is currently unclear. Patients and Methods: This study involved 4277 patients diagnosed with synchronous PM from CRC between 2005 and 2012 in The Netherlands. KaplaneMeier analysis and log-rank testing were performed to estimate survival. Subsequently a Cox proportional hazard model was used to calculate hazard ratios for the risk of death. Results: Most of the CRC patients were diagnosed with AC (n ¼ 3008; 70%), whereas MC and SC were found in 958 (22%) and 311 (7%) patients, respectively. SC was associated with the highest risk of death in colon and rectal cancer, with median survival rates of respectively, 6.6 and 6.9 months. For MC, median survival varied from 10.9 months in colon and 9.8 months in rectal cancer (P > .05). In colon cancer, MC was associated with a significantly lower risk of death compared with AC (hazard ratio, 0.9; 95% confidence interval, 0.79-0.95). In rectal cancer, no such effect was observed. AC was associated with a significantly poorer survival rate in the case of primary colonic tumor localization (7.4 months in colon vs. 10.9 months in rectal cancer). Conclusion: Histological subtype is an important prognostic factor in patients with synchronous PM of colorectal origin. This knowledge will aid clinicians in counseling of patients and clinical decision-making regarding possible treatment options. Clinical Colorectal Cancer, Vol. -, No. -, --- ª 2015 Elsevier Inc. All rights reserved. Keywords: Adenocarcinoma, Colorectal cancer, Mucinous adenocarcinoma, Signetering-cell carcinoma, Synchronous peritoneal metastases
1
Department of Oncology, Catharina Hospital, Eindhoven, The Netherlands Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, The Netherlands 3 Department of Surgery, Radboud University Medical Centre, Nijmegen, The Netherlands 4 Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands 2
Submitted: Feb 12, 2015; Revised: May 26, 2015; Accepted: May 29, 2015 Address for correspondence: Ignace H.J.T. de Hingh, MD, PhD, Department of Surgery, Catharina Hospital, Michelangelolaan 2, 5623 EJ, Eindhoven, The Netherlands Fax: þ31-40-2443370; e-mail contact: [email protected]
1533-0028/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clcc.2015.05.011
Introduction Colorectal carcinomas are histologically classified according to the World Health Organization classification system.1 Adenocarcinoma (AC) is the most frequently diagnosed histological subtype, followed by mucinous AC (MC), and signet-ring cell carcinoma (SC). The histological subtype has been suggested to play a role in the development and natural course of patients with colorectal cancer (CRC).2,3 The prognostic significance of histological subtype is not clear in the specific subset of CRC patients who presenting with
Clinical Colorectal Cancer Month 2015
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Prognostic Relevance of Histological Subtype peritoneal metastases (PM). The limited data available are derived from few studies with insufficient statistical power because of the low prevalence of MC and SC. Peritoneal dissemination is a well known manifestation of metastatic CRC, which is present in approximately 7% of CRC patients at the time of diagnosis.4 Recently, several risk factors for the development of PM have been identified, including right-sided tumor, advanced T-stage, advanced N-stage, poor differentiation grade, and younger age at diagnosis.5 In the current era of evolving treatment options for patients with PM, identification of prognostic factors is essential to provide adequate counseling on prognosis and accurate patient selection for treatment. Therefore, the current nationwide population-based study on the clinicopathological characteristics and prognosis of patients with synchronous PM from primary colorectal tumors of different histological subtypes was performed.
Patients and Methods Data and Patients All patients newly diagnosed with cancer in The Netherlands are registered by the Netherlands Cancer Registry (NCR). The NCR covers the entire Dutch population of approximately 16 million inhabitants. Data on patient and tumor characteristics are collected from medical records by specially trained registry staff, using the registration and coding manual of the NCR. Pathologists enter histopathological and cytopathological reports of the diagnosed cancers in the nationwide Dutch Pathology Network, which subsequently submits the data to the NCR. In the NCR, the tumor, node, metastases (TNM) system is used for stage classification of the
primary tumor.6 In case of missing pathological data, clinical TNM stage is used. Anatomical site of the tumor is registered according to the International Classification of Diseases for Oncology (ICD-O).7 Data on location of distant metastases were available in the NCR in 8 of 9 regions since 2005. Since 2007 data on site of metastases were available in all 9 regions and complete in approximately 95% of all patients with metastasized disease. In total, 4623 patients were diagnosed with synchronous PM from CRC between 2005 and 2012, representing 4.6% of the total CRC group and 21.2% of the synchronous metastasized CRC group. Most (96%) of these patients were diagnosed with either AC (ICD-O: 8140, 8144, 8120, 8255, 8261, 8263, 8560), MC (ICD-O: 8480, 8481, 8470), or SC (ICD-O: 8490). The remaining subgroup (n ¼ 169), mostly consisted of patients with small cell carcinoma, undifferentiated carcinoma, carcinoid, neuroendocrine carcinoma, and other even less frequent histological subtypes and was excluded. In addition, patients with primary appendiceal cancer (ICD-O: C18.1; n ¼ 177) were excluded because they reflect a distinct entity with a different prognosis.8 Tumor localization was further divided into colonic (ICD-O: C18, excluding C18.1) and rectal cancers (ICD-O: C19-20). The final database included 4277 CRC patients with PM (Figure 1).
Statistical Analysis Differences in patient and tumor characteristics between the different histological subtypes were compared and analyzed using a 2-sided c2 test. Survival time was defined as the time between diagnosis of CRC and death or lost to follow-up. Patients still alive at the end of follow-up (January 1, 2014) and those who emigrated were
Figure 1 Number of Patients With Synchronous PM of Colorectal Origin Diagnosed Between 2005 and 2012 in The Netherlands
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Abbreviations: AC ¼ adenocarcinoma; MC ¼ mucinous carcinoma; PM ¼ peritoneal metastases; SC ¼ signet-ring cell carcinoma.
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Lieke G.E.M. Razenberg et al censored. Crude survival estimates were calculated with the KaplaneMeier method and presented up to 36 months. Median survival was presented in months with corresponding 95% confidence intervals (CIs). Differences in survival proportions between the histological subtypes were calculated with a log-rank test. Univariable Cox regression analysis was performed to identify relevant and prognostic patient and tumor characteristics for the risk of death. Subsequently, multivariable Cox regression analyses were carried out to estimate independent hazard ratios on the risk of death for the histological subtypes. All analyses were performed with SAS/STAT statistical software (SAS system 9.3; SAS Institute, Cary, NC).
Results Between January 2005 and December 2012, a total of 4277 patients were diagnosed with synchronous PM from AC, MC, or SC CRC in The Netherlands.
Clinical Features of Histological Subtypes Sex was distributed equally between the histological subsets. In the SC group, the proportion of patients diagnosed at a younger age (< 60 years) was greater and advanced T and N stages were more frequently present in patients with SC tumors. Moreover, differentiation grade was unfavorable for patients with SC compared with
Table 1 General Characteristics of Patients Diagnosed Between 2005 and 2012 in The Netherlands With Synchronous PM of Colorectal Origin (n [ 4277)
Characteristic
Adenocarcinoma (n [ 3008; 70%)
Mucinous (n [ 958; 22%)
n
n
%
Signet-Ring Cell (n [ 311; 7%)
%
n
%
P .18
Sex Male
1521
51
483
50
174
56
Female
1487
49
475
50
137
44
615
20
215
22
92
30
60-70
903
30
269
28
91
29
>70
1490
50
474
50
128
41
2005-2006
574
19
209
22
57
18
2007-2008
722
24
252
26
80
26
2009-2010
810
27
237
25
81
26
2011-2012
902
30
260
27
93
30
2590
86
856
89
265
85
418
14
102
11
46
15
59
2
8
1
5
1
Age, Years <60
<.01
Period .22
Localization Colon Rectum
<.05
T Stage T1,2 T3
764
25
257
27
58
19
T4
1369
46
488
51
182
59
816
27
205
21
66
21
N0
403
13
140
15
27
8
N1
794
26
218
23
58
19
N2
979
33
355
37
134
43
Nx
832
28
245
25
92
30
1112
37
290
30
10
3
728
24
223
23
166
53
1168
39
445
47
135
44
PM only
1109
39
517
54
184
59
PM with systemic metastases
1899
61
441
46
127
41
T0,X
<.0001
N Stage <.0001
Differentiation Grade Well/moderate Poor/undifferentiated Unknown
<.0001
Extent of Metastatic Disease <.0001
Abbreviation: PM ¼ peritoneal metastases.
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Prognostic Relevance of Histological Subtype AC and MC, with most being poorly or undifferentiated tumors (53%, n ¼ 166). Primary MC tumors were more often located in the colon in the case of MC tumor histology. Patients with AC were more likely to have PM and concomitant extra-PM (P < .0001). Further details are shown in Table 1.
differences were found between colonic and rectal tumor localization. The prolonged overall survival in patients with MC colon cancer compared with AC and SC histological subtype remained present after stratification for the presence of extra-peritoneal disease (Table 2).
Overall Survival According to Histological Subtype A significant correlation between survival time and histological subtype was found (Figure 2). In colon cancer patients with MC median survival was 10.9 months versus 7.4 months in AC and 6.6 months in SC (P < .0001). In rectal cancer, the median survival for patients with AC almost equaled MC (respectively, 10.0 and 9.8 months) being significantly longer than the 6.9 months in patients with SC (P < .01). Overall survival for patients with AC was significantly worse in colon than in rectal cancer (P < .01). In patients with MC and SC, no significant
Prognostic Relevance of Histological Subtypes After adjustment for important patient and tumor characteristics, MC was associated with a decreased risk of death compared with AC (hazard ratio [HR], 0.9; 95% CI, 0.79-0.95) in colon cancer patients (Table 3). This association was not observed in patients with rectal cancer (HR, 1.0; 95% CI, 0.74-1.28). An increased risk of death was found for patients with SC histological subtype compared with AC, in colon (HR, 1.2; 95% CI, 1.05-1.42) and in rectal cancer (HR, 2.8; 95% CI, 1.62-3.50).
Figure 2 Overall MS of Patients With Peritoneal Metastases From Colorectal Cancer According to Histological Subtype (n [ 4277): (A) Colon; (B) Rectum
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Abbreviations: AC ¼ adenocarcinoma; MC ¼ mucinous carcinoma; SC ¼ signet-ring cell carcinoma.
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Lieke G.E.M. Razenberg et al Table 2 Survival of Patients With PM From AC, MC, or SC Colon or Rectal Cancer, According to the Extent of Metastatic Disease Colon n
Rectum
MS, Months
n
MS, Months
PM-Only AC
959
8.9
150
11.5
MC
468
13.0a
49
9.9
SC
158
7.1
26
P
<.0001
7.7 <.01
Other AC
1631
6.6
269
MC
388
9.5b
53
9.8
SC
107
5.5
20
5.7
P
<.001
9.1
.37
Abbreviations: AC ¼ adenocarcinoma; MC ¼ mucinous carcinoma; MS ¼ median survival; PM ¼ peritoneal metastases; SC ¼ signet-ring cell carcinoma. a Colon, PM-only MC versus AC; P < .01. b Colon, PM-other MC versus AC, P < .001.
Discussion To our knowledge, this is the first nationwide population-based study to focus on histological subtype in CRC patients who present with synchronous PM with regard to prognosis. Our results show that histological subtype of the primary tumor is of prognostic significance in this particular subset of patients. The prevalence of MC and SC in this study on 4277 PM patients was respectively, 22% and 7%. Other studies reported remarkably lower proportions of MC (10%-20%) and SC (0.4%-1%).2,3 This disparity can be explained by differences in patient selection; in the current study we included only patients with synchronous PM from CRC. Previous studies have indeed shown that patients diagnosed with MC or SC have a higher propensity of peritoneal spread in the early course of the disease than do patients with AC.2,3,9 In accordance with previous studies, patients with SC presented at a younger age, were more frequently detected in an advanced stage, and usually had a poorer differentiation grade than patients with AC.10,11
Table 3 Association Between Histological Subtypes and Risk of Death According to Primary Tumor Localization n
HR
2590
1.0
95% CI
P
Colon Adenocarcinomaa Mucinous
856
0.9
0.81-0.98
<.01
Signet-ring cell
265
1.2
1.05-1.42
<.01
Rectum Adenocarcinomaa
418
1.0
Mucinous
102
1.1
0.84-1.47
.84
46
2.4
1.62-3.50
<.0001
Signet-ring cell
Data are adjusted for age, sex, T and N stage, differentiation grade, PM extent, and period of diagnosis and treatment. Abbreviations: HR ¼ hazard ratio; PM ¼ peritoneal metastases a Reference category.
In the present study, differences in overall survival between the histological subtypes AC, MC, and SC were shown. The poorest median survival (6.8 months after diagnosis) was observed in the subgroup of patients with SC tumors, regardless of tumor localization and the existence of extraperitoneal metastatic disease. The identification of SC as a stage-independent poor prognostic factor has been previously reported in patients with CRC in general.10,12,13 Compared with these studies, the median survival of patients included in the present study was dismal. This confirms the negative influence of PM on survival, compared with other metastatic sites of CRC, such as the liver. The poor prognosis of CRC patients who present with SC differentiation supports the hypothesis that CRC with SC should be regarded as a different clinical entity. Indeed, carcinogenetic factors, tumor growth, and development have been described to be different in SC than in non-SC tumors.10,12 For example, microsatellite instability is more frequently described in SC.12,14 However, the number of SC tumors in these studies were small and therefore these results should be interpreted with caution. The prognostic significance of MC histological subtype is controversial. In some studies MC has been associated with a significantly poorer prognosis than AC, but in other studies no such prognostic significance was found.15-20 None of these studies focused on the specific subgroup of patients with CRC who present with PM as described in our study. In the present study, median survival for colon cancer patients with MC was favorable, compared with patients with AC (10 and 7 months, respectively). No such difference was observed in rectal cancer patients. Obvious reasons for the favorable overall survival in patients with MC colon cancer are not clear. MC has been identified as a distinct colorectal subtype with different molecular, genetic, and pathological characteristics. MC is more frequently associated with high levels of microsatellite instability, BRAF/ p53/16 mutations, downregulation of adhesion molecules, and is characterized by the presence of mucin in > 50% of the lesion.10 It has been suggested that this different tumor biology of MC is responsible for poorer responses to systemic chemotherapy.21 However, in a recent study by Hugen et al no difference in the efficacy of adjuvant chemotherapy was observed between patients with MC and non-MC stage III CRC.17 Furthermore, it can be hypothesized that because of the presence of mucin, peritoneal tumor deposits of MC might be less likely than the more solid tumor deposits to cause bowel obstruction as found in AC. Bowel obstruction resulting in malnourishment and eventually ileus is a frequent cause of death in PM patients. Finally, it was observed that right-sided AC tumors were associated with a poorer prognosis than left-sided AC tumors, which was not the case for MC tumors (data not shown). In the current literature rightsided colon cancers have been associated with different clinical presentations and tumor biology.22 Across all stages right-sided tumors generally have a higher risk of mortality than left-sided tumors, but within stage groups the effect of right-sided tumor localization seems less clear.23 The current study showed that histological subtype influenced the overall survival and should be taken into account in patient counseling and might be important in future patient-tailored treatment decisions. Unfortunately, a significant proportion of PM patients might not be able to receive treatment at all because of
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Prognostic Relevance of Histological Subtype their poor clinical condition that is typical for these patients resulting from bowel obstruction, ascites, and malnourishment. Survival in these patients is very poor and typically averages 3 months.5 Selected patients might be treated with systemic chemotherapy, but responses to conventional 5-fluoropyrimidine-based chemotherapy have been poor, with median survival rates of approximately 6 months.24,25 Since 2001, oxaliplatin-based chemotherapy (capecitabin-oxaliplatin [CAPOX]/fluorouracil-oxaliplatin [FOLFOX]) is recommended as the standard systemic treatment for patients with stage IV CRC in The Netherlands and since 2005 the antivascular agent bevacizumab is recommended as a therapeutic option in combination with first-line chemotherapy. Introduction of these therapeutic options has improved the survival of patients with PM.26 However, the beneficial effect of systemic treatment appears to be limited in patients with PM compared with other metastatic sites, which might explain the poor survival of PM patients as described in the current study.27 Furthermore, patients with PM from CRC might now be offered a multimodality treatment with curative intent including cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC).28,29 Because only selected patients are considered candidates for this highly invasive procedure, most PM patients still depend on palliative systemic treatment options. An important role for histological subtype in treatment decisions has been previously proposed by Pelz et al in patients with PM treated with palliative chemotherapy30 or HIPEC.31 Although in small patient groups, respectively, 59 and 17 patients, they found a negative predictive role for signet cell or poor tumor histology. This was confirmed in a recent study by van Oudheusden and colleagues, who showed limited efficacy of HIPEC in PM patients with SC.32 Of course, because of the nature of this population-based study, our results could also be influenced by study limitations and biases. In the NCR, information on peritoneal tumor burden, microsatellite instability (MSI) status, KRAS/BRAF mutational status, and other established prognostic factors, such as comorbidity is lacking.
Conclusion Mucinous AC and SC were identified in respectively, 22% and 7% of the patients diagnosed with synchronous PM from CRC between 2005 and 2012 in The Netherlands. The results of the current study revealed differences in survival rates and risk of death for AC, MC, and SC histological subtypes and support the hypothesis that SC and MC might be considered as independent tumor entities, with different patient and tumor characteristics and prognoses. The predictive value of the histological subtype in defining optimal treatment strategies should be further clarified.
Clinical Practice Points Mucinous AC and SC are more frequent in CRC patients who
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present with PM. However, the role of histological subtype in this particular subset of patients remains unknown. With evolving treatment possibilities for PM of colorectal origin, adequate prognostication and patient selection for treatment becomes increasingly important. The results of this nationwide population-based study reveal differences in overall survival rates and risk of death for AC, MC, and SC histological subtypes.
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This finding supports the hypothesis that SC and MC might be
considered as independent tumor entities, with different patient and tumor characteristics and prognoses. The predictive value of the histological subtype in definition of optimal treatment strategies should be further clarified.
Acknowledgments The authors thank the registration personnel of the NCR for their dedicated data collection.
Disclosure The authors have stated that they have no conflicts of interest.
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Lieke G.E.M. Razenberg et al 25. Sadeghi B, Arvieux C, Glehen O, et al. Peritoneal carcinomatosis from nongynecologic malignancies: results of the EVOCAPE 1 multicentric prospective study. Cancer 2000; 88:358-63. 26. Klaver YL, Lemmens VE, Creemers GJ, Rutten HJ, Nienhuijs SW, de Hingh IH. Population-based survival of patients with peritoneal carcinomatosis from colorectal origin in the era of increasing use of palliative chemotherapy. Ann Oncol 2011; 22:2250-6. 27. Klaver YL, Simkens LH, Lemmens VE, et al. Outcomes of colorectal cancer patients with peritoneal carcinomatosis treated with chemotherapy with and without targeted therapy. Eur J Surg Oncol 2012; 38:617-23. 28. Kuijpers AM, Mirck B, Aalbers AG, et al. Cytoreduction and HIPEC in the Netherlands: nationwide long-term outcome following the Dutch protocol. Ann Surg Oncol 2013; 20:4224-30.
29. Glehen O, Mohamed F, Gilly FN. Peritoneal carcinomatosis from digestive tract cancer: new management by cytoreductive surgery and intraperitoneal chemohyperthermia. Lancet Oncol 2004; 5:219-28. 30. Pelz JO, Chua TC, Esquivel J, et al. Evaluation of best supportive care and systemic chemotherapy as treatment stratified according to the retrospective peritoneal surface disease severity score (PSDSS) for peritoneal carcinomatosis of colorectal origin. BMC Cancer 2010; 10:689. 31. Pelz JO, Stojadinovic A, Nissan A, Hohenberger W, Esquivel J. Evaluation of a peritoneal surface disease severity score in patients with colon cancer with peritoneal carcinomatosis. J Surg Oncol 2009; 99:9-15. 32. van Oudheusden TR, Braam HJ, Nienhuijs SW, et al. Poor outcome after cytoreductive surgery and HIPEC for colorectal peritoneal carcinomatosis with signet ring cell histology. J Surg Oncol 2015; 111:237-42.
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