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Observation Article

Thrombocytosis portends adverse prognostic significance in patients with stage II colorectal carcinoma

[version 1; peer review: 2 approved with reservations]
PUBLISHED 31 Jul 2014
Author details Author details
OPEN PEER REVIEW
REVIEWER STATUS

Abstract

Thrombocytosis portends adverse prognostic significance in many types of cancers including ovarian and lung carcinoma. In this study, we determined the prevalence and prognostic significance of thrombocytosis (defined as platelet count in excess of 400 K/μl) in patients with colorectal cancer. We performed a retrospective analysis of 310 consecutive patients diagnosed at our institution between 2004 and 2013. The patients (48.7% male and 51.3% female) had a mean age of 69.9 years (+/- 12.7 years) at diagnosis. Thrombocytosis was found in a total of 25 patients, with a higher incidence in those with stage III and IV disease (14.4% of patients). Although the mean platelet count increased with the depth of tumor invasion (pT), its values remained within normal limits in the whole patient cohort. No patient with stage I cancer (n=57) had elevated platelet count at diagnosis. By contrast, five of the 78 patients (6.4%) with stage II cancer showed thrombocytosis, and four of these patients showed early recurrence and/or metastatic disease, resulting in shortened survival (they died within one year after surgery). The incidence of thrombocytosis increased to 12.2% and 20.6%, respectively, in patients with stage III and IV disease. The overall survival rate of patients with thrombocytosis was lower than those without thrombocytosis in the stage II and III disease groups, but this difference disappeared in patients with stage IV cancer who did poorly regardless of their platelet count. We concluded that thrombocytosis at diagnosis indicates adverse clinical outcome in colorectal cancer patients with stage II or III disease. This observation is especially intriguing in stage II patients because the clinical management of these patients is controversial. If our data are confirmed in larger studies, stage II colon cancer patients with thrombocytosis should be upstaged and treated as stage III/IV disease patients.

Introduction

Platelets play important roles in hemostasis, immunity and inflammation1. Cancer is often associated with thrombocytosis2. Thrombocytosis was reported as a poor prognostic indicator in many types of cancers including lung cancer3, renal cell carcinoma4 and gynecological cancers5. A positive correlation between the depth of tumor invasion and platelet counts was demonstrated in a gastric cancer study, and thrombocytosis served as an adverse prognostic factor in clinical outcome in gastric cancer patients6. Recent studies have shown that thrombocytosis in cancer may be correlated with serum cytokine levels that stimulate thrombopoiesis. For example, elevated plasma levels of IL-6 and thrombopoietin were reported in ovarian cancer patients5.

Colon cancer is a leading cause of cancer-related death in developed countries (http://seer.cancer.gov/statfacts/html/colorect.html). A significant portion of patients receiving potentially curative resection dies within five years of diagnosis7. Since both chemo- and radiation therapies cause very significant side-effects, it is critical to define reliable prognostic factors to identify patients who might benefit from more aggressive adjuvant treatment options. The prognostic role of thrombocytosis in colorectal cancer patients has not been fully investigated, although there are some reports supporting the negative impact of thrombocytosis on the survival of patients with colorectal cancer8,9.

In this study, the aim was to analyze the association between platelet count at diagnosis or pre-surgery and cancer stage, and to determine the prognostic significance of thrombocytosis in patients with colorectal cancer.

Patients and methods

After approval by the Monmouth Medical Center Institutional Research Review Board (IRB Study # 213-041), the medical records of 310 consecutive colorectal cancer patients who underwent biopsy (47 patients), surgical resection and/or neoadjuvant treatment (263 patients) at our institution between 2004 and 2013 were retrospectively reviewed. The patient cohort included 62 patients with in-situ or stage I disease, 78 patients at stage II, 98 patients at stage III, 34 patients at stage IV, and 38 patients with biopsy diagnosis only (stage could not be determined). The mean age of the patients was 69.9±12.7 years (range = 32 to 98 years). The data gathered included platelet counts, tumor location, histological type, lymph node metastasis, depth of tumor invasion (T), presence or absence of distant metastasis, and survival time.

Pre-operative platelet counts were collected from our Laboratory Information System (LIS), and thrombocytosis was defined as platelet count ≥ 400 × 103/μl. After resection of the tumor, all specimens were histologically examined by a pathologist and the pathological TNM stage was determined according to the American Joint Committee on Cancer, 7th edition. Stage I and II cancers are lymph node negative (N0) whereas stage III is defined by the presence of lymph node metastasis. Patients with distant metastatic disease are classified as stage IV.

Survival data were provided by the Cancer Registry at the Leon Hess Cancer Center, Monmouth Medical Center. All calculations were made using R version 2.15.0 and packages “beeswarm”, “survplot”, “survival” and “stats”. Survival curves were generated using the Kaplan-Meier method. Hazard ratios with 95% confidence intervals were obtained using Cox proportional hazards regression. Long-rank test was used for the analysis of significance.

Results

The characteristics (including age, gender, pT stage, tumor differentiation and platelet count) of the patients in our study cohort are shown in Table 1. Of the 310 patients with colorectal cancer, 25 (8.1%) had thrombocytosis at diagnosis or pre-surgery with the highest incidence detected in stage IV patients (20.6%) [Table 2]. Importantly, none of the 57 patients with stage I carcinoma had elevated platelet count. Although the mean platelet count increased with the depth of invasion (pT), it remained within the normal limits in all patients groups (pT1 to pT4) [Figure 1]. Mean platelet counts (×103/µL) were 216±71 (pT1), 252±83 (pT2), 274±109 (pT3), and 291±104 (pT4); this increase was significant at P = 0.001. By contrast, there were no significant differences in thrombocytosis with regard to gender, age, location, or tumor differentiation (data not shown).

Table 1. Patient characteristics.

Number (%)
Total310
Gender
   Male151 (48.7%)
   Female159 (51.3%)
Age69.9±12.7 yearsa
Pathologic category of primary tumor (pT)b
   pTis5 (1.6%)
   pT117 (5.5%)
   pT260 (19.4%)
   pT3137 (44.2%)
   pT444 (14.2%)
   pTx (unclassified)47 (15.2%)
Gradec
   well differentiated42 (13.5%)
   moderately differentiated149 (48.1%)
   poorly differentiated67 (21.6%)
   unclassified52 (16.8%)
Platelet count (×103/µL)
   ≥ 40025 (8.1%)
   < 400285 (91.9%)

a: Data presented as mean ± SD; b: staging according to AJCC Cancer Staging Manual 7th Edition); c: Grading according to WHO grading system

Table 2. Incidence of thrombocytosis in each stage of colorectal cancer.

Number of
cases with
thrombocytosis
Number of
cases without
thrombocytosis
Total
number
of cases
% of
thrombocytosis
Stage 00550.0
Stage I057570.0
Stage II573786.4
Stage III12869812.2
Stage IV7273420.6
Stage X
(unclassified)
137382.6
Overall252853108.1
*Stage IV and III
combined
1911313214.4

Note: There are 403 cases in our data pool. 310 cases were diagnosed as colon cancer among the 321 cases with available platelet counts (82 cases without platelet counts). 11 non-colorectal cancer cases including 5 cases labeled as “appendix” and 6 cases labeled as “not colon cancer” were taken out of the pool.

ffe45b6f-21f6-4ead-bfb8-fe6bddb55fac_figure1.gif

Figure 1. Mean platelet count according to the depth of tumor invasion.

The mean platelet count of patients with pT1, (216±71) × 103/µL is significantly lower than patients with pT4 (291±104) × 103/µL, P = 0.001.

The combined incidence of thrombocytosis in stage III and IV disease was 14.4%. Stage II disease had the lowest incidence (6.4%) and stage IV cancer showed the highest incidence of elevated platelet count (20.6%) [Table 2]. The overall survival of patients with stage I to stage III colorectal cancer with thrombocytosis was significantly lower than those without thrombocytosis [Figure 2]. Although patients with Stage IV carcinoma had the highest prevalence of thrombocytosis, these patients did uniformly poorly and the difference in survival was no longer observed in patients with or without elevated platelet count (not shown). Patients with thrombocytosis (PLT ≥ 400 × 103/μL) at stage I to stage III had a hazard ratio of 2.2 compared to the patients without thrombocytosis (PLT < 400 × 103/μL) as shown in Figure 2.

ffe45b6f-21f6-4ead-bfb8-fe6bddb55fac_figure2.gif

Figure 2. Overall survival plots of patients with stage I to stage III colorectal cancer according the preoperative platelet counts.

Patients were allocated into two groups: with thrombocytosis, PLT ≥ 400 × 103/µL (labeled as Exceeds) and without thrombocytosis) PLT < 400 × 103/µL (labeled as Normal). The patients with thrombocytosis have a hazard ratio of 2.2 compare to the patients without thrombocytosis (P<0.05).

PatientLocationLocation1GenderPlateletsLymphocytesAbsolute lymphocytesMSIStageGradeDate of SpecimenColumnVital StatusDate of Last contactDate of first encounterDate of diagnosisAge at diagnosis
1ColonF22411NoneT4N12Jan-04DeadFeb-04Jan-04Dec-0381
2Right ColonF197111NoneT2N0Well differentiatedJan-04DeadFeb-09Jan-04Nov-0381
3Left colonF213231NoneT3N2Moderately differentiatedJan-04DeadMar-07Jan-04Jan-0435
4Terminal ileum & colonRight colonM152542NoneT3N0Well to moderately differentiatedJan-05DeadNov-05Feb-05Feb-0558
5Ascending colonRight colonF263121NoneNoneNoneJan-04DeadMar-04Jan-04Jan-0491
6Transverse colonF25880NoneT3N2Poorly differentiatedFeb-04DeadSep-04Feb-04Dec-0384
7Liver with metsM298252NoneNoneNoneFeb-04Mets to liver - only specimenDeadMay-05Feb-04Feb-0479
8ColonM426121NoneNonePoorly differentiated signet ring adenocarcinomaFeb-04Signet ringAliveAug-04Feb-04Feb-0472
9AscendingRight colonFNoneNoneNoneNoneNoneModerately to poorly differentiatedFeb-04Sigmoid biopsy is only specimenAliveAug-11Feb-04Feb-0468
10ColonM332181NoneNoneCarcinoma in situ2/5/2004 and 6/11/2004AliveMar-13Mar-04Feb-0449
11SigmoidLeft colonM254376NoneNoneNoneApr-04DeadNov-04Apr-04Mar-0472
12Transverse and Descending ColonLeft colonM27421NoneIntramucosal carcinomaNoneApr-04DeadDec-10Apr-04Apr-0481
13Right ColonM28491NoneT3N0Well to moderately differentiatedApr-04DeadOct-07Apr-04Apr-0483
14Descending ColonLeft colonFNoneNoneNoneNoneNoneModerately differentiated found in 2008 specimenApr-04DeadMay-09Apr-04Apr-0480
15NoneF19351NoneNoneNoneApr-04No cancerAliveOct-12Apr-04Mar-0478
16Right ColonM344232NoneT4N1V12Feb-04DeadJun-04Apr-04Apr-0489
17Right ColonF308151NoneT3N0Poorly differentiatedMay-04DeadMar-05Apr-04Apr-0487
18Right ColonM17351NoneT3N02May-04focal mucinous differentiationAliveNov-12May-04May-0457
19Right ColonF279162NoneT3N12Jun-04AliveSep-06Jun-04Jun-0474
20ColonMNoneNoneNoneNoneT3N02Jul-04AliveDec-12Jun-04Jun-0462
21Sigmoid colonLeft colonMNoneNoneNoneNoneNoneNoneJun-04AliveDec-12Jun-04May-0457
22Sigmoid colonLeft colonM443102NonepT4N2M1Poorly differentiatedJul-04DeadFeb-06Jun-04Jul-0477
23Ascending colonRight colonF364332NoneT3N2M12Jun-04DeadJul-07Jun-04Jun-0462
24Left colonM262101NoneT3N0Well to focally moderately differentiatedJun-04DeadDec-07Jun-04Jun-0481
25ColonLeft colonF242151NoneT3N0M1CarcinoidJul-04Carcinoid TumorDeadFeb-06Jul-04Jul-0477
26SigmoidMNoneNoneNoneNoneT4N0Well differentiatedJul-04MucinousAliveDec-12Jul-04Jul-0472
27Hepatic flexureRight colonFNoneNoneNoneNoneNoneNoneJul-04AliveMay-09Jul-04Jul-0474
28RectosigmoidM220182NoneNoneNoneJul-04CarcinoidAliveJan-12Jul-04Jul-0465
29RectosigmoidF174101NoneT3N0MXModerately to poorly differentiatedAug-04AliveApr-13Jul-04Jul-0468
30Ascending colonRight colonFNoneNoneNoneNoneNoneNoneAug-04Biopsy - only specimenAliveMar-12Aug-04Aug-0457
31SigmoidLeft colonF402162NoneT4bN2M1Well to moderately differentiatedAug-04AliveNov-12Aug-04Jul-0481
32Right colonM225121NoneT1N0Well differentiatedOct-04AliveMay-13Sep-04Sep-0460
33ColonM32651NoneT3N1Moderately differentiatedSep-04DeadJun-09Sep-04Sep-0481
34SigmoidLeft colonM196352NoneNoneNoneSep-04DeadSep-08Sep-04Sep-0465
35Right colonM38020NoneT3N2Moderately differentiatedSep-04DeadJun-05Sep-04Aug-0484
36Cecum and ascendingRight colonM64631NoneT3N0, T3N1Moderately diffentiatedSep-04with mucinous differentiatedAliveDec-12Sep-04Sep-0444
37Left colonF381182NoneT1Moderately differentiatedOct-04AliveNov-12Oct-04Aug-0468
38Right colonF21171NoneT3N0Moderately differentiatedOct-04focal mucinous component (20%)DeadMay-11Oct-04Sep-0478
39Right colonM258111NoneT4N2M1Poorly differentiatedNov-04DeadAug-06Nov-04Oct-0478
40CecumF16091NoneT3N1Moderately differentiatedNov-04AliveJul-12Nov-04Oct-0481
41SigmoidLeft colonM17921NoneT2N0Well differentiatedNov-04DeadJul-10Nov-04Oct-0481
42ColonF443142NoneT4bN2MXWell differentiatedDec-04DeadFeb-05Dec-04Dec-0465
43Rectosigmoid colonM169162NoneT1N1Well differentiatedDec-04AliveJan-13Dec-04Nov-0457
44Right colonFNoneNoneNoneNoneT3N0Moderately to poorly differentiatedJan-05AliveApr-12Jan-05Jan-0586
45Cecum and ascendingRight colonF323222NoneNoneNoneFeb-05AliveSep-10Feb-05Feb-0576
46AppendixF302282NoneNoneNoneJan-05Appendix with mucinous cysadenomaAliveDec-12Feb-05Jan-0561
47Right colonF336161NoneT2N0Well differentiatedFeb-05AliveDec-12Feb-05Feb-0574
48Colon, terminal ileumRight colonM282141NoneT3N0Well to moderately differentiatedMar-05DeadDec-10Mar-05Mar-0579
49ColonM20431NoneNoneNoneMar-05Leiomyosarcoma, not adenocarcinomaAliveOct-12Mar-05Mar-0567
50Ascending colonRight colonM135152NoneT1N0MXWell differentiatedApr-05AliveNov-12Apr-05Mar-0567
51ColonM198101NoneT3N2MXWell to moderately differentiatedApr-05AliveNov-12Apr-05Apr-0562
52Right colonFNoneNoneNoneNoneNoneNoneMar-05AliveSep-12Apr-05Mar-0571
53Proximal transverse colonM497101NoneT3N1Moderately differentiatedMay-05AliveNov-12May-05Apr-0560
54Right colonMNoneNoneNoneNoneT3N2MXPoorly differentiatedJun-05AliveJun-13May-05May-0580
55Sigmoid colonLeft colonF164101NoneT3N0Moderately differentiatedJun-05AliveOct-12Jun-05May-0577
56Right colonM262171NoneT3N1Poorly differentiatedJun-05DeadApr-06Jun-05Mar-0570
57Hepatic flexure/ascendingRight colonM137111NoneNoneNoneJun-05DeadOct-07Jun-05Jun-0590
58Right colonM49491NoneT4N2Moderately differentiatedJun-05AliveNov-10Jun-05May-0579
59Right colonM26281NoneT3N1Moderately differentiatedJun-05AliveAug-12Jun-05Jun-0553
60Right colonM16351NoneT1Well differentiatedFeb-05DeadJun-05Feb-05Feb-0590
61Sigmoid colonF39471NoneT3N2Moderately differentiatedJul-05DeadMar-11Jun-05Jun-0551
62Ascending colonRight colonF362182NoneT3N0Jun-05extensive areas of mucinous differentiationAliveDec-12Jun-05May-0583
63Right colonM175191NoneT2N0Well differentiatedJun-05AliveAug-12Jun-05Jun-0573
64CecumRight colonMNoneNoneNoneNoneT2N1Well differentiatedJul-05AliveAug-12Jun-05Jun-0585
65Left colonF37341NoneT3N0Moderately differentiatedJul-05DeadJan-08Jul-05Jul-0567
66Ileocecal valveRight colonF319241NoneNoneNoneJul-05Biopsy only - Intramucosa carcinomaDeadApr-06Jul-05Jul-0595
67Right colonM20471NoneT2N02Jul-05AliveOct-11Jul-05Jun-0568
68ColonF18930NoneT1Well to moderately differentiatedAug-05with focal mucinous differentiationAliveNov-12Aug-05Jun-0559
69ColonM23041NoneT3N0 and T3N1Moderately differentiatedAug-05AliveMay-13Aug-05Aug-0580
70TransverseF353121NoneT2N2MXWell to moderately differentiatedAug-05DeadNov-06Aug-05Apr-0596
71Right ColonM16870NoneT3N1Moderately differentiatedAug-05AliveMar-10Aug-05Jul-0590
72Left colonF14421NoneT4N1Moderately differentiatedAug-05AliveSep-10Aug-05Aug-0553
73Left extended sigmoidLeft colonM26140NoneT3N2MXWell to moderately differentiatedSep-05DeadApr-10Aug-05Aug-0556
74Liver metsM455111NoneNoneNoneAug-05DeadSep-05Aug-05Aug-0584
75Right colonM36211NoneT3N2M1Sep-05DeadOct-05Aug-05Sep-0570
76Right colonF22961NoneT3N0Moderately differentiatedSep-05AliveJan-13Aug-05Aug-0537
77Right colonF26331NoneT3N1V1Moderately differentiatedSep-05DeadJan-11Sep-05Sep-0585
78Ascending colonRight colonM143172NoneT2N1MXModerately to poorly differentiatedSep-05Focal mucinous differentiationAliveJan-13Sep-05Sep-0553
79Right colonM179331NoneT3N0Moderately differentiatedSep-05Tubular adenomaAliveAug-12Sep-05Sep-0556
80Right colon, cecumF86NoneDeadNov-05Sep-05Sep-0581
81SigmoidLeft colonM377141NoneNoneWell differentiatedOct-05DeadNov-05Oct-05Oct-0578
82Large intestine, 20 cmF290251NoneNoneNoneOct-05AliveNov-12Oct-05Oct-0541
83SigmoidM24581NoneT3N02Oct-05AliveMar-13Oct-05Sep-0560
84Left colonF32721NoneT3N0Moderately differentiatedOct-05AliveNov-12Oct-05Sep-0573
85Proximal transverse colonM136272NoneNoneNoneDec-05Intramucosal carcinomaDeadApr-08Oct-05Oct-0598
86Right colonF294241NoneT3N0Moderately to poorly differentiatedOct-04AliveNov-12Oct-05Sep-0574
87Left colonF231252NoneNoneNoneOct-05Carcinoid tumorAliveDec-12Oct-05Sep-0566
88Right colonM22881NoneT2N0Moderately differentiatedNov-0570% mucinous differentiationAliveNov-12Nov-05Nov-0576
89ColonM357121NoneT2N0Well differentiatedDec-05AliveNov-12Dec-05Dec-0550
90AppendixM264161NoneNoneNoneDec-05Superficially invasive mucinous adenocarcinomaAliveMay-12Dec-05Dec-0551
91Sigmoid, Right ColonMNoneNoneNoneNoneT4N2MXWell to moderately differentiatedJan-06mucinous (colloid)DeadJan-07Jan-06Jan-0666
92Right colon/cecumF188131NoneT2N0Well differentiatedJan-06AliveOct-11Jan-06Jan-0682
93TransverseF458141NoneT3N1Moderately differentiatedJan-06AliveNov-12Jan-06Jan-0683
94ColonF276131NoneT2N1MXWell differentiatedFeb-06with mucin production/colloid carcinomaAliveDec-12Feb-06Nov-0550
95Left colonF57722NoneT3N1Moderately differentiatedMar-06DeadJun-06Mar-06Feb-0673
96Left colonF35371NoneT3N0MXWell to moderately differentiatedMar-06DeadSep-07Mar-06Mar-0689
97Metastatic to ovaries, abdominal wall, omentumF51730NoneNoneNoneMar-06DeadJul-06Mar-06Mar-0654
98Left colonF23450NoneT3N1MXModerately differentiatedApr-06DeadAug-11Apr-06Apr-0648
99RectosigmoidM21640NoneT3N2Jun-06DeadFeb-08Apr-06Apr-0650
100Left colonFNoneNoneNoneNoneT4N1Jun-06DeadMar-09May-06May-0659
101SigmoidLeft colonM19030NoneT2N0Moderately differentiatedJul-06AliveOct-11May-06May-0672
102Transverse colonF27641NoneT3N0MXWell to moderately differentiatedMay-06AliveFeb-13May-06May-0682
103Right colonMNoneNoneNoneNoneT2N0Jun-06mucinousAliveDec-12Jun-06May-0638
104Transverse and left colon/splenic flexureLeft colonM344121NoneT3N2Poorly differentiatedJun-06DeadJun-06Jun-06Jun-0677
105SigmoidLeft colonF226201NoneT2N0 Moderately differentiatedJun-06Two tumors in 2008, T2N0 and T1N), moderately and well to moderately differentiatedAliveNov-12Jun-06Jun-0673
106Right colon/cecumF31361NoneT4N2Poorly differentiatedMar-06AliveNov-12Jun-06Jun-0669
107Right colonF202131NoneT3N0Moderate differentiatedJul-06AliveNov-12Jul-06Jun-0669
108CecumRight colonF36911NoneNoneNoneJul-06focally mucinous - biopsy onlyDeadJan-07Jul-06Jul-0681
109SigmoidLeft colonNoneNoneNoneNoneT1N1MXWell differentiatedAug-06mucinous differentiationAliveJun-12Jul-06Jul-0661
110Right colon/cecumF296202NoneT3N0Well to moderately differentiatedJul-06with mucinous featuresAliveNov-12Jul-06Jun-0686
111Hepatic flexure/ascendingRight colonM168181NoneNoneNoneJul-06not a resection specimen - massDeadJun-08Jul-06Jul-0685
112Right colonFNoneNoneNoneNoneT2N0MXWell differentiatedAug-06mucinous/ colloidAliveJan-13Aug-06Aug-0665
113Cecum and appendixRight colonM30451None(T3/T4)NXMXWell differentiatedSep-06appendiceal originAliveNov-11Aug-06Sep-0668
114CecumRight colonM220141NoneT3N1MXWell differentiatedAug-06AliveFeb-13Aug-06Jul-0667
115ColonMNoneNoneNoneNoneT4N2Moderately differentiatedAug-06DeadNov-08Aug-06Aug-0658
116Right colonF29891NoneT3N0MXModerately differentiatedSep-06AliveNov-12Sep-06Aug-0681
117SigmoidLeft colonF27951NoneT4N2Oct-06DeadJun-08Sep-06Oct-0673
118Ascending colonRight colonF21081NoneT3N1Moderately differentiatedOct-06AliveMar-13Oct-06Sep-0657
119Transverse colonF321172NoneT3N22 and 3 / 3Oct-06DeadDec-07Oct-06Oct-0674
120RectalF89485NoneT1NOModerately differentiatedOct-06AliveNov-12Oct-06Oct-0681
121Supraclavicular l.n.M245221NoneNonePoorly differentiatedNov-06DeadAug-10Oct-06Oct-0671
122Right colonF56671NoneT3N0Poorly differentiatedNov-06AliveDec-12Nov-06Oct-0669
123Transverse colon neuroendocrineF32671NoneT3N2M1 with liver mets3/3, moderately differentiated neuroendocrineJan-073/3 and moderately differentiated disparityDeadJan-07Dec-06Dec-0665
124Transverse colonF114181NoneNoneNoneDec-06Intramucosal carcinomaAliveNov-12Dec-06Nov-0663
125RectosigmoidF243241NoneT2N1Moderately differentiatedDec-06AliveJun-12Dec-06Dec-0672
126Left colonFNoneNone NoneNoneT3N1Poorly differentiatedFeb-07DeadJan-10Feb-07Feb-0778
127Right colonM103161NoneT2N0Moderately differentiatedFeb-07Focal mucinous componentAliveNov-12Feb-07Feb-0786
128RectosigmoidF17161NoneNo infoNoneMar-07Tattoos onlyAliveNov-12Mar-07Dec-0674
129Right colonF41161NoneT3N1MxModerately to poorly differentiatedMar-07focal mucinous and signet ring differentiationDeadMar-07Mar-07Jan-0790
130Sigmoid colonLeft colonM18930NoneHigh grade dysplasiaNoneMar-07TA with high grade dysplasia onlyAliveApr-12Mar-07Jan-0769
131RectosigmoidM240172NoneT2N0Moderately differentiatedJun-07AliveNov-12Apr-07Apr-0745
132Ascending colonRight colonF516217NoneT3N2Moderately differentiatedApr-07AliveJul-12Apr-07Mar-0744
133Right colonM32391NoneT2N02 focal 3May-07AliveNov-12Apr-07Apr-0768
134Right colonF126162NoneT2N2N/AMay-07AliveApr-12May-07May-0764
135AppendixF251111NoneN/AN/AMay-07AliveJan-13Apr-07Apr-0766
136Right colon, hepatic flexureM150352NoneT3N2Moderately differentiatedApr-07AliveMay-13Apr-07Apr-0772
137ColonF313101NoneT3N0MXWell differentiatedMay-07AliveAug-12May-07Apr-0768
138Right colonM282102NoneT2N0Well differentiatedMay-07AliveNov-11May-07May-0752
139Right colonM10771NoneHigh grade dysplasiaN/AJun-07AliveNov-12Jun-07Jun-0759
140Transverse colonM342242NoneT3N02,3Jun-07DeadJul-07Jun-07Jun-0767
141Right colonM2831710NoneT4N2Jul-07DeadAug-07Jul-07Jul-0772
142Right colonF36461NoneT3N0Moderately differentiatedAug-07AliveDec-12Aug-07Aug-0759
143Left colonM508263NoneT3N12Aug-07DeadJul-11Aug-07Jul-0773
144CecumRight colonF255381NoneT3N0Poorly differentiatedSep-07DeadNov-07Sep-07Sep-0787
145SigmoidLeft colonFNoneNoneNoneNoneT2N0Moderately differentiatedNov-07DeadJan-10Sep-07Sep-0775
146RectosigmoidF39881NoneT2N0Moderately differentiatedSep-07AliveMay-12Sep-07Sep-0779
147Left colonFNoneNoneNoneNoneT1N0MXWell to moderately differentiatedNov-07AliveApr-13Oct-07Aug-0772
148Right colonMNoneNoneNoneNoneT3N12Nov-07DeadJan-10Nov-07Nov-0786
149Rectal sigmoidF336101NoneT3N2MXwell differentiatedNov-07AliveNov-12Nov-07Nov-0768
150SigmoidLeft colonM246121NoneNoneModerately differentiatedNov-07DeadApr-08Nov-07Nov-0752
151Rectal sigmoidF155111NoneT2N1well to moderately differentiatedDec-07AliveJun-13Nov-07Nov-0770
152Transverse colonM325292NoneT2N0MXWell differentiatedDec-07AliveNov-12Nov-07Nov-0763
153Right colonFNoneNoneNoneNoneT3N0MXModerately diffentiatedJan-08DeadJun-09Dec-07Dec-0781
154RectosigmoidM5181118NoneT4N1High gradeDec-07DeadJul-11Dec-07Dec-0764
155Right colonF207622NoneT3N1Intermediate to poorly differentiatedDec-07AliveJun-13Dec-07Dec-0764
156Right colonM343111NoneT3N0Moderately differentiatedDec-07AliveOct-12Dec-07Nov-0779
157Right colonFNoneNoneNoneNoneTisN01Jan-08AliveJun-13Jan-08Jan-0861
158RectosigmoidM2245NoneNoneT3N22,3Jan-08AliveMay-13Jan-08Dec-0744
159Right colonF19781NoneT4N1Poorly differentiatedFeb-08DeadApr-08Feb-08Feb-0864
160Transverse colonM21081NoneT3N0Moderately differentiatedFeb-08AliveNov-12Feb-08Jan-0865
161Left colonMNoneNoneNoneNoneT3N1Moderately differentiatedFeb-08DeadJun-11Feb-08Feb-0882
162Right colonF238352NoneT3N0MXModerately differentiatedFeb-08DeadJun-09Feb-08Feb-0869
163SigmoidLeft colonF28791MSh2, MLH1, MSH6 presentT2N12Feb-08AliveMay-13Feb-08Jan-0854
164Sigmoid and rectumLeft colonM427232NoneT4N0Moderately to poorly differentiatedFeb-08DeadMar-09Feb-08Feb-0873
165CecumRight colonM28181NoneT1N0MXModerately differentiatedJan-08DeadApr-08Feb-08Feb-0871
166Metastatic - PortahepatisMDeadDec-09Feb-08Feb-0860
167Metastatic to liverF246111NoneMets to liverN/AMar-08DeadDec-09Mar-08Feb-0861
168Ascending and Proximal Transverse ColonRight colonM34031NoneT3N0Moderately differentiatedMar-08DeadApr-08Mar-08Mar-0880
169Left colonM298182NoneT2N0Moderately differentiatedApr-08AliveNov-12Apr-08Mar-0871
170Right colonF37061NoneT2N02Apr-08AliveFeb-12Apr-08Mar-0885
171Right colonM302322NoneTisN0well differentiatedApr-08AliveNov-12Apr-08Mar-0874
172AppemdixM19291NoneNonewell differentiatedApr-08AliveJun-11Apr-0849
173Left colonM29461NoneT2N2Moderately differentiatedApr-08AliveNov-12Apr-08Apr-0846
174CecumMNoneNoneNoneNoneT4N1Moderately differentiatedApr-08AliveNov-12Apr-08Apr-0878
175Right colonM189211NoneT3N0MX2May-08DeadAug-10May-08May-0887
176Right colonM519162NoneT3N2M1moderately diffentiatedMay-08AliveFeb-13May-08Apr-0869
177Right colonM207131NoneT3pN0MXwell to moderately differentiatedJun-08AliveOct-12May-08Jun-0881
178AppendixF232292NoneT4pN0MXwell differentiatedJun-08AliveApr-13Jun-08Jun-0852
179ColonM29650NoneT3pN2Mxwell to moderately differentiatedJun-08DeadSep-09Jun-08Jan-0871
180ColonFNoneNoneNoneNoneT4N22Jul-08AliveApr-13Jul-08Jul-0860
181RectosigmoidM21081NoneT3N0Poorly differentiatedJul-08DeadDec-11Jul-08May-0864
182Right colonF255172NoneT4N2MxModerately to poorly differentiatedAug-08DeadAug-08Jul-08Mar-0853
183Right colonM379151Partial loss of MSH6 (60%), MSH2 and MLH1 presentT2N2M1Poorly differentiatedAug-08DeadNov-08Aug-08Jul-0873
184Right colonF300272NoneT3N0Poorly differentiatedSep-08DeadDec-09Sep-08Aug-0865
185Right colonF193111NoneT2Well to moderately differentiatedSep-08DeadNov-11Sep-08Sep-0881
186RectosigmoidF24751NoneT3N1Well differentiatedSep-08AliveMar-13Sep-08Sep-0864
187SigmoidLeft colonMNoneNoneNoneNoneT3N0Moderately differentiatedNov-08AliveMay-13Oct-08Oct-0870
188Left colonM363221NoneT2N0Moderately differentiatedNov-08AliveNov-12Nov-08Nov-0847
189SigmoidLeft colonF226201NoneT2N0Moderately differentiatedJun-06AliveNov-12Nov-08Oct-0875
190ColonM27391No MSI by PCRT2N0Moderately differentiatedDec-08AliveDec-12Dec-08Oct-0847
191Right colonF212111NoneTisN0Well differentiatedDec-08AliveDec-11Dec-08Oct-0860
192Hepatic flexureRight colonMNoneNoneNoneNoneT1NoneDec-08AliveMay-12Dec-08Dec-0880
193Transverse colonF249131NoneT3N0MXWell to moderately differentiatedDec-08AliveNov-11Dec-08Dec-0887
194Ascending colonRight colonF22620Focal absence of MSH6, no MSH2 or MLH1T3N2Moderately differentiatedDec-08AliveNov-12Dec-08Nov-0878
195Right colonF224141Focally absent MLH1 and MSH6, MSH2 presentT3N1Moderately to poorly differentiatedDec-08AliveJun-13Dec-08Dec-0865
196Right colonM300231MSH2 and MLH1 present, MSH6 not testedT3N2Poorly differentiatedJan-09AliveMay-13Jan-09Jan-0973
197Large intestine MNoneNoneNoneNoneT2pN0MXWell to moderately differentiatedFeb-09AliveJan-13Jan-09Jan-0987
198Left colonF305191NoneT2N0Moderately differentiatedJan-09AliveOct-11Jan-09Jan-0979
199ColonF41711NoneT4N0High grade anaplastic suggesting neuroendocrineFeb-09DeadMay-09Jan-09Jan-0982
This is a portion of the data; to view all the data, please download the file.
Dataset 1.Data of thrombocytosis in colon cancer patients.
This data set contains the medical records of patients diagnosed with colon cancer at the Monmouth Medical Center between 2004 and 2013.

Discussion

It was noted more than 100 years ago that thrombocytosis is often seen in patients with malignant diseases. Indeed, thrombocytosis correlates with both worse disease free survival and shortened overall survival in patients with ovarian cancer3, and worsens overall survival in patients with gastric cancer (reviewed in 10). The prognostic significance of thrombocytosis in colorectal cancer, however, remains controversial11, although the majority of literature suggests a negative impact of thrombocytosis on the survival of patients with colorectal cancer8,9.

In the present study, we identified a mild, T stage-dependant increase in mean platelet counts in patients with colorectal carcinoma that reached statistical significance when comparing T1 to T4; however, the mean platelet count remained within the normal limits in the whole patient cohort. Importantly, thrombocytosis was more common among patients with advanced disease: its prevalence increased from 6.4% in stage II to 20.6% in stage IV cancer patients. Our data are comparable to those reported in the literature (12.1–13.9%;6,7).

In our study, thrombocytosis showed adverse prognostic significance in patients with stage I to stage III colorectal carcinoma; this was no longer apparent in patients with stage IV disease, presumably because these patients did poorly regardless of the platelet count.

Probably the most intriguing observation of our study is the fairly uniformly dismal clinical outcome of stage II patients with thrombocytosis (five out of 78 patients): four of these five patients did very poorly (they died within a year) and the fifth was lost to follow-up. We suspect that these cases might represent stage III/IV cases misclassified as stage II due to false negative lymph node examination. At present, the National Comprehensive Cancer Network guidelines do not recommend routine administration of adjuvant chemotherapy to stage II colorectal cancer patients whose cancer was completely resected12. If our data are confirmed in future larger studies, stage II colorectal cancer patients with thrombocytosis should be upstaged and treated clinically as stage III/IV.

The molecular mechanisms underlying thrombocytosis in cancer patients are incompletely understood. Recently, plasma levels of IL-6 and thrombopoietin were found to significantly correlate with platelet counts in ovarian cancer patients. Indeed, silencing of the IL-6 and thrombopoietin genes markedly abrogated thrombocytosis (and halted tumor progression) in a mouse model of epithelial ovarian cancer5. These findings are promising because an anti-IL-6 agent (siltuximab) has already been approved by the United States Food and Drug Administration (FDA) to treat patients with Castleman’s disease (http://www.cancer.org//cancer/new/fda-approves-sylvant-siltuximab-for-castleman-disease). Another series of study showed that immobilized platelets support human colon carcinoma cell tethering, rolling, and firm adhesion under dynamic flow conditions in colon cancer cell lines, suggesting a role of platelets in hematogenous dissemination of tumor cells in colorectal cancer13. Taken together, these studies imply that inhibition of thrombocytosis may represent a potential novel target in cancer therapy.

In summary, thrombocytosis appears to herald adverse clinical outcome in patients with stage II and III colorectal carcinoma. We suggest that elevated platelet count may identify a subset of patients with stage II colon cancer who could benefit from close follow-up and aggressive adjuvant therapy.

Data availability

F1000Research: Dataset 1. Data of thrombocytosis in colon cancer patients, 10.5256/f1000research.4856.d3337114

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Guo T, Krzystanek M, Szallasi Z and Szallasi A. Thrombocytosis portends adverse prognostic significance in patients with stage II colorectal carcinoma [version 1; peer review: 2 approved with reservations] F1000Research 2014, 3:180 (https://doi.org/10.12688/f1000research.4856.1)
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ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
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Reviewer Report 06 Oct 2014
Judit Moldvay, Department of Pulmonology, Semmelweis University, Budapest, Hungary 
Approved with Reservations
VIEWS 16
It is an interesting work providing new information on the issue of thrombocytosis in colon cancer patients. It contains relevant clinicopathologic parameters, however, there is no data on ethnicity, smoking habits, inflammatory processes, comorbidities, or medications of the studied patients, ... Continue reading
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Moldvay J. Reviewer Report For: Thrombocytosis portends adverse prognostic significance in patients with stage II colorectal carcinoma [version 1; peer review: 2 approved with reservations]. F1000Research 2014, 3:180 (https://doi.org/10.5256/f1000research.5184.r6229)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 13 Oct 2014
    Arpad Szallasi, Department of Pathology, Monmouth Medical Center, Long Branch, NJ, NJ 07740, USA
    13 Oct 2014
    Author Response
    Whereas we share some of the reservations of the referee, we would like to point out that this is an Observational Study and not a full report. We believe that ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 13 Oct 2014
    Arpad Szallasi, Department of Pathology, Monmouth Medical Center, Long Branch, NJ, NJ 07740, USA
    13 Oct 2014
    Author Response
    Whereas we share some of the reservations of the referee, we would like to point out that this is an Observational Study and not a full report. We believe that ... Continue reading
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14
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Reviewer Report 14 Aug 2014
Ioannis A. Voutsadakis, Medical Oncology, Sault Area Hospital, Ontario, Canada 
Approved with Reservations
VIEWS 14
This is an interesting retrospective study of an extensive series of colorectal cancer patients and authors are to be congratulated on undertaking this academic endeavour. Nevertheless there are several points that need to be addressed. A major concern is that ... Continue reading
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CITE
HOW TO CITE THIS REPORT
Voutsadakis IA. Reviewer Report For: Thrombocytosis portends adverse prognostic significance in patients with stage II colorectal carcinoma [version 1; peer review: 2 approved with reservations]. F1000Research 2014, 3:180 (https://doi.org/10.5256/f1000research.5184.r5655)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 13 Oct 2014
    Arpad Szallasi, Department of Pathology, Monmouth Medical Center, Long Branch, NJ, NJ 07740, USA
    13 Oct 2014
    Author Response
    We are grateful for the referee for his thoughts in making this a better MS. Whereas we agree with most of the reservations of the referee, we would like to ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 13 Oct 2014
    Arpad Szallasi, Department of Pathology, Monmouth Medical Center, Long Branch, NJ, NJ 07740, USA
    13 Oct 2014
    Author Response
    We are grateful for the referee for his thoughts in making this a better MS. Whereas we agree with most of the reservations of the referee, we would like to ... Continue reading

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VERSION 2 PUBLISHED 31 Jul 2014
Comment
Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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