Surgery

High serum cancer antigen 125 level indicates perforation in acute appendicitis

a b s t r a c t

Background: The diagnosis of acute appendicitis is sometimes challenging, and prompt evaluation is required be- cause of the risk of complications if not treated appropriately.

Aim: We aimed to evaluate whether cancer antigen 125 (CA-125) has diagnositic accuracy and predictor of the severity in acute appendicitis.

Results: Sixty patients with acute appendicitis were recruited prospectively in this study between May 2014 and March 2015. Blood samples were obtained to measure CA-125 levels before appendectomy. Of the 57 patients, 10 had perforated or gangrenous appendicitis intraoperatively. The CA-125 levels were significantly higher in patients with perforated or gangrenous appendicitis than patients with uncomplicated appendicitis (49.9 vs 10.5 U/mL, P = .000).

Conclusions: Cancer antigen 125 levels in patients with highly suspected or confirmed appendicitis could help cli- nicians determine the severity of the disease.

(C) 2015

  1. Introduction

Acute appendicitis is the most common cause of acute emergent sur- gical condition that needs prompt evaluation and treatment worldwide [1]. Management goals may not be easily obtained because of the diffi- culties in diagnosis of acute appendicitis [2]. Diagnosis is based on both the history and clinical examination and is often supported by the laboratory and imaging modalities. Diagnostic imaging modalities are often unnecessary if the clinical diagnosis is certain. Imaging is espe- cially useful when the clinical presentation is unclear. However, no sin- gle clinical finding or laboratory test is a highly accurate predictor of acute appendicitis. Accurate and prompt evaluation is necessary

? Prospective study, Ethics Committee at Ankara Numune Training and Research Hospi- tal (Ankara, Turkey) (approval no. 811 at 14.04.2014).

?? The work has not been published before and is not currently under consideration for

publication elsewhere.

? The authors have no relevant financial interest in the products or companies de-

scribed in this article.

?? Recently, with the advance of diagnostic imaging studies, nonoperative treatment has

gained the popularity for uncomplicated acute appendicitis. As appendectomy has some surgical complications and Negative appendectomy risk for suspected but not certain cases, antibiotic treatment for patients with uncomplicated acute appendicitis could be an option. Measurement of cancer antigen 125 levels in patients with suspected acute ap- pendicitis in emergency department will help clinicians consider the severity of the dis- ease. In uncomplicated cases, measuring cancer antigen 125 levels consecutively in the follow-up and observing the increasing pattern will warn the clinicians, as complications will ocur.

* Corresponding author at: Department of Colorectal Surgery, General Surgery, Ankara Numune Education and Training Hospital, Sihhiye, 06100, Ankara, Turkey. Tel.: +90 5052918788.

E-mail address: [email protected] (E. Cetinkaya).

because of the risk of perforation and postoperative complications. Be- tween 18% and 34% of the patients can have complicated appendicitis and therefore require Prompt diagnosis, as perforation will often lead to peritonitis, sepsis, and death [3,4].

Several diagnostic markers have been investigated in the diagnosis of acute appendicitis. Some of them are the components of the complete blood count and might be useful in the emergency department for diag- nosing appendicitis, platelet distribution width [5], red cell distribution width (RDW) [6], and white blood cell count. Furthermore, in- flammatory markers such as interleukin 6, chemokine ligand 8, chemo- kine C-C motif ligand 2, serum amyloid A, matrix metalloproteinase 9 and myeloperoxidase [7], C-reactive protein (CRP), and procalcitonin

[8] have been evaluated for use in diagnosing appendicitis.

Cancer antigen 125 (CA-125) is a nonspecific tumor marker, gener- ally used for follow-up of epithelial ovarian cancer in gynecologic oncol- ogy. Levels of this marker can be affected by various pathologic and physiologic conditions, as it is synthesized by the cells from endometri- um, fallopian tube, amniotic cells, lung, and peritoneum [9]. Cancer an- tigen 125 was studied in the in vitro model of peritonitis, and secretion of CA-125 was observed to be secreted by mesothelial cells by the in- flammatory stimulus [10]. As acute appendicitis causes peritoneal irrita- tion, activated peritoneal mesothelium secretes CA-125. In this study, we aimed to evaluate CA-125 levels in the diagnosis and severity of the patients with acute appendicitis.

  1. Materials and methods

This study was conducted between May 2014 and March 2015 after obtaining approval from the Ethics Committee at Ankara Numune

http://dx.doi.org/10.1016/j.ajem.2015.07.001

0735-6757/(C) 2015

1466 E. Cetinkaya et al. / American Journal of Emergency Medicine 33 (2015) 14651467

Training and Research Hospital (approval no. 811 at 14.04.2014). Sixty consecutive patients with suspected acute appendicitis were enrolled in the study prospectively. Informed consent was obtained from the participants. Patients were confirmed cases of acute appendicitis with clinical, laboratory, and radiologic findings. Blood samples were collected before surgery to measure CA-125 levels with electro- chemiluminescence immunoassay on an autoanalyzer at our hospital. McBurney incision was applied to the 52 (86.7%) of the patients. Six of the patients had midline, 1 of them had Rockey-Davis, and 1 of them had paramedian incisions. We identified Perforated appendicitis as periappendicular abscess or intraperitoneal dissemination of fecal materi- al and gangrenous appendicitis as ischemia of the appendix wall. Patient’s age, sex, comorbidities, complete blood cell count, Serum electrolytes, bil- irubin, CA-125 levels, onset time of pain, physical findings, surgical find- ings, pathologic findings, and Wound infections were recorded. The specimens were sent to the pathology for diagnosis confirmation.

  1. Statistical analysis

Kolmogorov-Smirnov and Shapiro-Wilk tests were used to assess the normality. Nonparametric data were presented as median values (interquartile range), and parametric data were presented as mean+- SD. The prognostic factors that influenced mortality in univariate analy- ses were determined using the Students t test or Mann-Whitney U and ?2 tests. Factors identified as significant in univariate analyses were in- cluded in multivariate logistic regression analysis.

Receiver operating curve analyses were used to evaluate the mortal- ity Predictive performances and sensitivity, specificity, positive predic- tive value (PPV), and negative predictive value measures of each significant variable, with different cutoff values.

  1. Results

A total of 60 consecutive patients with suspected acute appendicitis were recruited between May 2014 and March 2015. Three of the pa- tients had no intraoperative and histopathologic findings of acute ap- pendicitis and were excluded from the study. Thirty-five patients (61.4%) were men, and 22 patients (38.6%) were women. The median age was 31 (range, 18-60). Overall, 53 of 60 patients had no comorbid- ities. Detected comorbidities were “hypertension, coronary heart dis- ease, deep vein thrombosis, valvular heart disease, epilepsy, and hypothyroidism.” Of the 57 patients, 10 had perforated or gangrenous appendicitis intraoperatively, 5 of the patients were men, and remain- ing were women. No significant difference was observed between the uncomplicated and perforated or gangrenous appendicitis with respect to sex. The diagnosis of perforation was confirmed with ultrasonogra- phy in 3 patients. Computed tomography was performed to 6 of the pa- tients, and 3 of them had perforation. Wound infection was observed in 3 patients; 1 of them was in uncomplicated group, and 2 of them were in perforated or gangrenous appendicitis group. The characteristics of patients with uncomplicated and perforated or gangrenous appendicitis are shown in Table 1.

Median CA-125 levels were significantly higher in patients with per- forated or gangrenous appendicitis than patients with uncomplicated appendicitis (49.9 vs 10.5 U/mL, P = .000). The PPV was 100%. Univar- iate analysis showed that age, platelet count, RDW, and CA-125 levels are significant factors for predicting the perforation or gangrenous ap- pendicitis. Multivariate analysis showed the CA-125 levels to be the sin- gle significant factor for predicting the perforation or gangrenous appendicitis. The area under the receiver operating characteristic curve was 0.855 (95% confidence interval [CI], 0.648-1) (Figure). The cutoff levels of CA-125 for perforated or gangrenous appendicitis was 35U/mL, with the sensitivity and specifity of 60% and 100%, respectively (Table 2).

  1. Discussion

In this study, we evaluated CA-125 levels in the patients with acute appendicitis to estimate the severity of the disease. Cancer antigen 125 levels were significantly higher in patients with perforated or gangre- nous appendicitis than patients with uncomplicated appendicitis.

Acute appendicitis is the most common cause of abdominal surgical emergency that requires rapid diagnosis to prevent complications. Diag- nosis is often difficult and often requires supportive imaging and labora- tory testing for confirmation. More recently, literature supports the use of several serum biomarkers for diagnosing appendicitis. In a recent meta-anaysis evaluating diagnostic value of procalcitonin, CRP and WBC in uncomplicated or complicated appendicitis were evaluated, and procalcitonin was found to have greater diagnostic value than CRP and WBC to identify complicated appendicitis. Although procalcitonin had poor diagnostic value for acute appendicitis, it was found to have high accuracy in detecting complicated cases. As the treatment modali- ties change between uncomplicated and complicated patients, it is im- portant to differentiate these 2 conditions. It was mentioned that procalcitonin might be used to select for nonsurgically managed pa- tients [8]. Andersson et al [7] combined inflammatory markers such as interleukin 6, chemokine ligand 8, chemokine C-C motif ligand 2, serum amyloid A, matrix metalloproteinase 9, and myeloperoxidase with appendicitis inflammatory response score to improve the diagno- sis. They found that rebound tenderness had the highest discriminating capacity for all appendicitis among all variables including new inflam- matory markers. Among inflammatory markers, serum amyloid A was the strongest discriminator for all appendicitis. Adding chemokine C-C motif ligand 2 to the appendicitis inflammatory response score was found to increase the discriminating capacity for all and advanced ap- pendicitis. However, they concluded that using any new parameters

Table 1

Characteristics of patients

Uncomplicated cases

Perforated or gangrenous cases

P Univariate

Age (y) 30 (22-37) 43 (24-50) .029?

Sex, men 30 5 .085

Women 17 5

WBC count (x103/mm3) 14.3 (11.7-17.8) 16.75 (12.5-19.5) .367

RDW (%) 12.3 (12.1-13.0) 13.1 (12.5-14.3) .048?

Platelet count (x103/mm3) 230 (191-273) 255.5 (244-383) .026?

CA-125 (U/mL) 10.5 (7.4-13.2) 49.9 (14.1-71.2) .000?

NS: Non-significant.

* P b .05. Figure. Receiver operating characteristic curve analyzed.

E. Cetinkaya et al. / American Journal of Emergency Medicine 33 (2015) 14651467 1467

Table 2

The cutoff level of CA-125 with spesifity and sensivity

Sensivity (% CI)

Specificity (% CI)

PPV

CA-125, N 35 U/mL

60 (26-87)

100 (92-100)

100

with conventional clinical and inflammatory variables does not add use- ful diagnostic information [7].

Cancer antigen 125 is a nonspecific marker generally known as tumor antigen, although it is shown in the normal epithelium of the fe- male genital tract; gastric; colonic mucosal cells; and mesothelium of the peritoneum, pleura, and pericardium [11]. Cancer antigen 125 levels are not only raised in ovarian cancers, but increased concentrations of this marker is also found in patients with liver cirrhosis, Hepatocellular carcinoma, peritonitis, pregnancy, Pelvic inflammatory disease, during menstrual cycles, and after abdominal surgery [10]. This suggests that activated peritoneal mesothelium secretes CA-125. Acute appendicitis is an Inflammatory process begining from the appendiceal wall and followed by localized ischemia, and, if not treated appropriately, perfo- ration, abscess formation, or generalized peritonitis could occur. As acute appendicitis is a condition that involves the mesothelium of vis- ceral and parietal peritoneum, CA-125 levels will elevate. With this mechanism of action, we hypothesized that CA-125 could be used as a diagnostic marker in patients with complicated or uncomplicated acute appendicitis. In this study, we measured CA-125 serum levels be- fore surgery in patients with acute appendicitis. Cancer antigen 125 levels were significantly higher in patients with complicated acute ap- pendicitis than uncomplicated patients. The cutoff value for the diagno- sis of complicated acute appendicitis was 35 U/mL, with the sensitivity, specifity, and PPVs of 60%, 100%, and 100%, respectively. So, we consider that CA-125 performed well as a diagnostic marker for evaluating sever- ity of appendicitis.

Wound infection was observed in 3 patients in our study; 1 of them

was in uncomplicated group and 2 of them were in perforated or gan- grenous appendicitis group. The percentage of the wound infection was approximately 2% and 20% in uncomplicated and perforated or gan- grenous appendicitis, respectively. Therefore, if we could predict the occurence of perforation preoperatively, broad spectrum antibiotics could be initiated immediately.

Computed tomography is an optimum method for diagnosing acute appendicitis and differentiating perforated from nonperforated acute appendicitis. It is found to have higher sensitivity, specificity, and accu- racy than the use of scoring systems for diagnosing appendicitis [12]. Al- though computed tomography has improved the accuracy of diagnosis, exposure to radiation is the main disadvantage of this technique. In our study, the diagnosis of perforation was confirmed with ultrasonography in 3 patients. Computed tomography was performed to 6 of the patients, and 3 of them had perforation. But CA-125 levels were signicantly higher in perforated cases than uncomplicated cases. Our results indicate that measuring CA-125 levels might be a good predictor for evaluating the severity of the disease, potentially better than diagnostic imaging.

Appendectomy has been the mainstay treatment of acute appendici- tis. Recently, with the advanced of diagnostic imaging studies, nonoper- ative treatment has gained the popularity for uncomplicated acute appendicitis. In the literature, there have been studies that compare an- tibiotic treatment vs appendectomy as a primary Treatment modality for uncomplicated appendicitis. As appendectomy has some surgical com- plications and negative appendectomy risk for suspected but not con- firmed cases, antibiotic treatment for patients with uncomplicated acute appendicitis could be an option. In a recent meta-analysis, Varadhan et al [13] compared the antibiotic treatment with appendec- tomy for uncomplicated patients including 4 randomized controlled tri- als. In the antibiotic treatment group, meta-analysis of complications showed a relative risk of reduction of 31% compared with appendecto- my group. No significant difference was found in length of hospital stay and incidence of complicated appendicitis between the 2 groups.

The incidence of PErforation in antibiotic treatment group was 8% lower than the reported rates of perforation in the literature. Although there have been differences between the study design, methodology, and results between the studies, Varadhan et al [13] concluded that an- tibiotic treatment for uncomplicated acute appendicitis can be a safe treatment modality. Similarly, in another meta-analysis, Liu et al [14], compared these 2 treatment modalities; no significant difference was found in the terms of complication and hospital stay. The main advan- tages of antibiotic treatment for uncomplicated acute appendicitis are shorter time to return to the work and lower Medical cost than appen- dectomy [14]. Because of the advantages of antibiotic treatment in the eligible patients with uncomplicated acute appendicitis, it may be rec- ommended as an alternative to surgery. With the help of diagnostic im- aging techniques and laboratory studies, uncomplicated appendicitis can be identified. In the present study, we found that CA-125 levels were significantly higher in patients with perforated or gangrenous ap- pendicitis than uncomplicated cases. Before the time of surgery, it will be obtained from the patients with suspected acute appendicitis. Pa- tients could be selected for Nonoperative management if the serum levels indicated uncomplicated appendicitis. Cancer antigen 125 has been shown to increase as early as 6 hours after the inflammatory stim- ulation in in vitro studies [10]; in clinical, practice it will be better to measure CA-125 levels on 2 consecutive times to determine the diagno- sis and severity of the diasease [15].

In conclusion, measurement of CA-125 levels in patients with

suspected acute appendicitis has the potential to be used to assess the severity of the disease. Future studies may indicate that, in uncompli- cated appendicitis, CA-125 levels could potentially be used during follow-up evaluating for rising trends to warn clinicians of impending complications.

  1. Limitations

Our study has some limitations; the sample size was small, and the study was conducted in a single center.

References

  1. Williams GR. Presidential address: a history of appendicitis. With anecdotes illus- trating its importance. Ann Surg 1983;197(5):495-506.
  2. Pittman-Waller VA, Myers JG, Stewart RM, Dent DL, Page CP, Gray GA, et al. Appen- dicitis: why so complicated? Analysis of 5755 consecutive appendectomies. Am Surg 2000;66(6):548-54.
  3. Ricci MA, Trevisani MF, Beck WC. Acute appendicitis. A 5-year review. Am Surg 1991;57:301-5.
  4. Chamisa I. A clinicopathological review of 324 appendices removed for acute appendicitis in Durban, South Africa: a retrospective analysis. Ann R Coll Surg Engl 2009;91:688-92.
  5. Dinc B, Oskay A, Dinc SE, Bas B, Tekin S. New parameter in diagnosis of acute appen- dicitis: platelet distribution width. World J Gastroenterol 2015;21(6):1821-6.
  6. Narci H, Turk E, Karagulle E, Togan T, Karabulut K. The role of red cell distribution width in the diagnosis of acute appendicitis: a retrospective case-controlled study. World J Emerg Surg 2013;8:46.
  7. Andersson M, Ruber M, Ekerfelt C, Hallgren HB, Olaison G, Andersson RE. Can new inflammatory markers improve the diagnosis of acute appendicitis? World J Surg 2014;38(11):2777-83.
  8. Yu CW, Juan LI, Wu MH, Shen CJ, Wu JY, Lee CC. Systematic review and meta- analysis of the diagnostic accuracy of procalcitonin, C-reactive protein and white blood cell count for suspected acute appendicitis. Br J Surg 2013;100(3):322-9.
  9. Zeimet AG, Marth C, Offner FA, Obrist P, Uhl-Steidl M, Feichtinger H, et al. Human peritoneal mesothelial cells are more potent than ovarian cancer cells in producing tumor marker CA-125. Gynecol Oncol 1996;62(3):384-9.
  10. Zeillemaker AM, Verbrugh HA, Hoynck van Papendrecht AA, Leguit P. CA 125 secre- tion by peritoneal mesothelial cells. J Clin Pathol 1994;47(3):263-5.
  11. Kabawat SE, Bast Jr RC, Bhan AK, Welch WR, Knapp RC, Colvin RB. Tissue distribution of a coelomic-epithelium-related antigen recognized by the monoclonal antibody OC125. Int J Gynecol Pathol 1983;2(3):275-85.
  12. Liu W, Wei Qiang J, Xun Sun R. Comparison of multislice computed tomography and Clinical scores for diagnosing acute appendicitis. J Int Med Res 2015;43(3):341-9.
  13. Varadhan KK, Neal KR, Lobo DN. Safety and efficacy of antibiotics compared with ap- pendicectomy for treatment of uncomplicated acuteappendicitis: meta-analysis of Randomised controlled trials. BMJ 2012;344:e2156 [1-15].
  14. Liu ZH, Li C, Zhang XW, Kang L, Wang JP. Meta-analysis of the Therapeutic effects of antibiotic versus appendicectomy for the treatment of acute appendicitis. Exp Ther Med 2014;7(5):1181-6.
  15. Basaran A. CA-125 for diagnosis of acute appendicitis: new possibility for an old tumor marker. Colorectal Dis 2010;12(2):155-6.