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Increased risk of malignancy for patients older than 40 years with appendicitis and an appendix wider than 10 mm on computed tomography scan: A post hoc analysis of an EAST multicenter study

      Abstract

      Background

      The incidence of underlying malignancy in appendicitis ranges between 0.5% and 1.7%. We sought to identify the subset of patients with appendicitis who are at increased risk of appendiceal malignancy.

      Methods

      Using the Eastern Association for the Surgery of Trauma Multicenter Study of the Treatment of Appendicitis in America: Acute, Perforated, and Gangrenous database, we included all patients from 28 centers undergoing immediate, delayed, or interval appendectomy between 2017 and 2018. Univariate then multivariable analyses were performed to compare patients with and without malignancy and to identify independent demographic, clinical, laboratory, and/or radiological predictors of malignancy. Akaike information criteria for regression models were used to evaluate goodness of fit.

      Results

      A total of 3,293 patients were included. The median age was 38 (27–53) years, and 46.5% were female patients. On pathology, 48 (1.5%) had an underlying malignancy (adenocarcinoma [60.4%], neuroendocrine [37.5%], and lymphoma [2.1%]). Patients with malignancy were older (56 [34.5–67] vs 37 [27–52] years, P < .001), had longer duration of symptoms before presentation (36–41 vs 18–23 hours, P = .03), and were more likely to have a phlegmon on imaging (6.3% vs 1.3%, P = .03). Multivariable analyses showed that an enlarged appendiceal diameter was independently associated with malignancy (odds ratio = 1.06, 95% confidence interval = 1.01–1.12; P = .01). The incidence of malignancy in patients >40 years with an appendiceal diameter >10 mm on computed tomography was 2.95% compared with 0.97% in patients ≤40 years old with appendiceal diameter ≤10 mm. The corresponding risk ratio for that population was 3.03 (95% confidence interval: 1.24–7.42; P = .02).

      Conclusion

      The combination of age >40 and an appendiceal diameter >10 mm is associated with a greater than 3-fold increased risk of malignancy in patients presenting with appendicitis.

      Introduction

      Appendectomy for acute appendicitis is one of the most common emergency general surgery procedures in the United States, with an estimated 300,000 procedures performed per year.
      • Mason R.J.
      Surgery for appendicitis: is it necessary?.
      A shift in the treatment practices of patients presenting with complicated appendicitis has been noted in recent years, with many suggesting that an initial nonoperative management is superior to appendectomy in this patient population.
      • Lietzen E.
      • Gronroos J.M.
      • Mecklin J.P.
      • et al.
      Appendiceal neoplasm risk associated with complicated acute appendicitis-a population based study.
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      • Tsao K.
      • Sharp S.W.
      • Ostlie D.J.
      • Holcomb 3rd, G.W.
      • St Peter S.D.
      Resource utilization and outcomes from percutaneous drainage and interval appendectomy for perforated appendicitis with abscess.
      • Sippola S.
      • Gronroos J.
      • Tuominen R.
      • et al.
      Economic evaluation of antibiotic therapy versus appendicectomy for the treatment of uncomplicated acute appendicitis from the APPAC randomized clinical trial.
      • Andersson R.E.
      • Petzold M.G.
      Nonsurgical treatment of appendiceal abscess or phlegmon: a systematic review and meta-analysis.
      • Simillis C.
      • Symeonides P.
      • Shorthouse A.J.
      • Tekkis P.P.
      A meta-analysis comparing conservative treatment versus acute appendectomy for complicated appendicitis (abscess or phlegmon).
      Evidence from randomized-controlled trials show that patients presenting with uncomplicated acute appendicitis may also be managed safely nonoperatively with antibiotics.
      • Lietzen E.
      • Gronroos J.M.
      • Mecklin J.P.
      • et al.
      Appendiceal neoplasm risk associated with complicated acute appendicitis-a population based study.
      ,
      • Sippola S.
      • Gronroos J.
      • Tuominen R.
      • et al.
      Economic evaluation of antibiotic therapy versus appendicectomy for the treatment of uncomplicated acute appendicitis from the APPAC randomized clinical trial.
      ,
      • Salminen P.
      • Paajanen H.
      • Rautio T.
      • et al.
      Antibiotic therapy vs appendectomy for treatment of uncomplicated acute appendicitis: The APPAC randomized clinical trial.
      ,
      • Vons C.
      • Barry C.
      • Maitre S.
      • et al.
      Amoxicillin plus clavulanic acid versus appendicectomy for treatment of acute uncomplicated appendicitis: an open-label, non-inferiority, randomised controlled trial.
      After successful resolution of the index episode, the routine performance of an interval appendectomy in patients successfully managed nonoperatively still remains a subject of much controversy.
      • Sippola S.
      • Gronroos J.
      • Tuominen R.
      • et al.
      Economic evaluation of antibiotic therapy versus appendicectomy for the treatment of uncomplicated acute appendicitis from the APPAC randomized clinical trial.
      • Andersson R.E.
      • Petzold M.G.
      Nonsurgical treatment of appendiceal abscess or phlegmon: a systematic review and meta-analysis.
      • Simillis C.
      • Symeonides P.
      • Shorthouse A.J.
      • Tekkis P.P.
      A meta-analysis comparing conservative treatment versus acute appendectomy for complicated appendicitis (abscess or phlegmon).
      The most common causes of acute appendicitis are thought to be lymphoid hyperplasia and fecalith impaction.
      • Limaiem F.
      • Arfa N.
      • Marsaoui L.
      • Bouraoui S.
      • Lahmar A.
      • Mzabi S.
      Unexpected histopathological findings in appendectomy specimens: A retrospective study of 1627 cases.
      Appendiceal cancer is responsible for 0.5% of all gastrointestinal neoplasms and for about 1% of all colon cancers.
      • Guraya S.Y.
      Do we still need to perform routine histological examination of appendectomy specimens?.
      ,
      • Teixeira Jr., F.J.R.
      • Couto Netto S.D.D.
      • Akaishi E.H.
      • Utiyama E.M.
      • Menegozzo C.A.M.
      • Rocha M.C.
      Acute appendicitis, inflammatory appendiceal mass and the risk of a hidden malignant tumor: a systematic review of the literature.
      The rate of appendiceal cancer in appendicectomy specimens varies between 0.5% and 1.7% in the literature.
      • Guraya S.Y.
      Do we still need to perform routine histological examination of appendectomy specimens?.
      ,
      • Furman M.J.
      • Cahan M.
      • Cohen P.
      • Lambert L.A.
      Increased risk of mucinous neoplasm of the appendix in adults undergoing interval appendectomy.
      Appendiceal tumors are classified into 2 main groups: neuroendocrine tumors (most common primary type–formerly known as carcinoids) and adenocarcinomas.
      • Hatch Q.M.
      • Gilbert E.W.
      Appendiceal neoplasms.
      Adenocarcinomas are very aggressive tumors that may require a right hemicolectomy for an oncologic safe resection.
      • Guraya S.Y.
      Do we still need to perform routine histological examination of appendectomy specimens?.
      Due to the low incidence and lack of sensitive diagnostic tools, the presence of appendiceal malignancy is rarely suspected preoperatively and appendiceal malignancies are usually discovered incidentally on postoperative pathology reports.
      • Lietzen E.
      • Gronroos J.M.
      • Mecklin J.P.
      • et al.
      Appendiceal neoplasm risk associated with complicated acute appendicitis-a population based study.
      ,
      • Kelly K.J.
      Management of appendix cancer.
      • Kalpande S.
      • Pandya J.
      • Sharma T.
      Adenocarcinoma mimicking appendicular lump: a diagnostic dilemma-a case report.
      • Khan K.
      • Patil S.
      • Roomi S.
      • Shiwani M.H.
      Appendicular Neuroendocrine Neoplasm is Associated with Acute Appendicitis - Don't Miss the Boat.
      Even when symptomatic, appendiceal malignancies most commonly present with symptoms indistinguishable from acute appendicitis.
      • Kelly K.J.
      Management of appendix cancer.
      The risk factors for the presence of an underlying malignancy in a patient presenting with acute appendicitis are not well established.
      • Kelly K.J.
      Management of appendix cancer.
      Complicated appendicitis by itself has been associated with an increased risk of underlying malignancy. The risk is even higher in patients presenting with a periappendiceal abscess compared with patients with uncomplicated appendicitis.
      • Lietzen E.
      • Gronroos J.M.
      • Mecklin J.P.
      • et al.
      Appendiceal neoplasm risk associated with complicated acute appendicitis-a population based study.
      Contradictory data exist regarding the risk of appendiceal tumors in patients presenting with an inflammatory mass. Although some studies report similar rates of malignancy in patients presenting with uncomplicated acute appendicitis compared with patients presenting with an inflammatory mass, others report increased tumor rates in the latter.
      • Teixeira Jr., F.J.R.
      • Couto Netto S.D.D.
      • Akaishi E.H.
      • Utiyama E.M.
      • Menegozzo C.A.M.
      • Rocha M.C.
      Acute appendicitis, inflammatory appendiceal mass and the risk of a hidden malignant tumor: a systematic review of the literature.
      ,
      • Carpenter S.G.
      • Chapital A.B.
      • Merritt M.V.
      • Johnson D.J.
      Increased risk of neoplasm in appendicitis treated with interval appendectomy: single-institution experience and literature review.
      Older patients with acute appendicitis have also been found to be at a higher risk for an underlying tumor.
      • Furman M.J.
      • Cahan M.
      • Cohen P.
      • Lambert L.A.
      Increased risk of mucinous neoplasm of the appendix in adults undergoing interval appendectomy.
      ,
      • Wright G.P.
      • Mater M.E.
      • Carroll J.T.
      • Choy J.S.
      • Chung M.H.
      Is there truly an oncologic indication for interval appendectomy?.
      In this study, we sought to use prospectively collected multicenter data to identify the subset of appendicitis patients who are at a particularly increased risk of appendiceal malignancy. We hypothesized that patient characteristics (eg, demographics and comorbidities) and clinical presentation, in addition to laboratory and radiological findings, in cancer patients differ from those of patients presenting with benign appendicitis.

      Methods

      Data source

      This is a post hoc analysis using data obtained from the Eastern Association for the Surgery of Trauma Multicenter Study of the Treatment of Appendicitis in America: Acute, Perforated, and Gangrenous (MUSTANG) database. The MUSTANG database is a prospectively collected database for all patients presenting with appendicitis between January 2017 and June 2018 in 28 hospitals across the United States. It includes emergency department, imaging, laboratory, intraoperative, and longitudinal outcomes data (up to 1 year after index hospitalization discharge). Patient demographics, clinical presentation of acute appendicitis, Charlson comorbidity index, smoking history, immune status, laboratory inflammatory markers, and radiologic imaging findings were captured and included in our analysis.

      Patient selection

      We included all patients who received a diagnosis of appendicitis, had a computed tomography (CT) scan in the preoperative work-up, and did not have missing information for the results of the pathology report. Our population was divided into 2 cohorts based on the results of the pathology report (benign versus malignant). For the purposes of this study, we defined malignancy as a postoperative pathological diagnosis of adenocarcinoma, neuroendocrine tumor, or lymphoma of the appendix. Mucoceles were not included in the analysis. Patients included in our study did not have to undergo surgical management during index hospitalization. Patients who received an interval appendectomy and were diagnosed with a malignant disease at that point were also included. Multivariable regression models were constructed for the identification of independent predictors of underlying malignancy.

      Statistical analysis

      Continuous data were analyzed using the Mann-Whitney U test. Results are presented as median and interquartile range. Categorical variables were analyzed using Fisher exact test. Results are reported as number of patients and percentages. After univariate analyses, multivariable regression models were constructed, including all available demographic, initial presentation, laboratory, and CT-finding variables, and the best model was selected using the Akaike information criterion. The variance inflation factor was used and no multicollinearity was detected among the variables included in our multivariable regression models. Finally, using clinically and historically relevant cutoffs, we calculated the relative risk for presence of an underlying malignancy in patients from the MUSTANG database. A P value of <.05 was considered statistically significant. All statistical analyses were performed using Stata v15.1 (StataCorp, College Station, TX) and RStudio version 1.2.1335.

      Ethical oversight

      All hospitals participating in this multicenter database were required to get institutional review board approval and data use agreements were signed. Study data were collected and managed using Research Electronic Data Capture electronic data capture tools hosted at the University of Miami.
      • Harris P.A.
      • Taylor R.
      • Thielke R.
      • Payne J.
      • Gonzalez N.
      • Conde J.G.
      Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support.
      All information included in the database were deidentified.

      Results

      A total of 3,293 patients were included; 48 (1.5%) had confirmed appendiceal malignancy, specifically adenocarcinoma (n = 29), neuroendocrine tumors (n = 18), and B-cell lymphoma (n = 1) of the appendix. In both the benign and malignant cohorts, the majority of the patients, 3,207 (98.8%) and 47 (97.9%), respectively, underwent appendectomy during their index hospitalization. Most patients underwent a laparoscopic appendectomy (92.7%). Table I summarizes the demographics, clinical presentation, and laboratory data of the patient population. In summary, patients with an underlying malignancy were older (median age 56 [34.5–67] vs 37 [27–52] years old, P < .001), had longer duration of symptoms (median duration 36–41 vs 18–23 hours, P = .03), and were less likely to present with nausea (58.3% vs 73.8%, P = .02), vomiting (22.9% vs 49.3%, P = .01), anorexia (34.8% vs 51.8%, P = .01), and migration of the pain to the right lower quadrant (59.6% vs 74.9%, P = .03). Charlson’s comorbidity index was also significantly higher in patients with malignant appendicitis (1.5 [0–3] vs 0 [0–1], P < .001). On physical examination, patients with malignancy were less likely to present with a Rovsing’s sign (17.6% vs 36.7%, P = .02). Owing to the aforementioned differences regarding clinical presentation, the interquartile range of Alvarado scores of patients with an underlying malignancy was lower, even though the median score was the same compared to benign appendicitis (median score 6 [4.5–6] vs 6 [5–7], P = .001).
      Table IDemographics, clinical presentation, and laboratory between patients presenting with a benign versus malignant appendicitis
      VariablesBenign (n = 3,245)Malignancy (n = 48)P value
      Age (y), median [IQR]37 [27–52]56 [34.5–67]< .001
      Mann-Whitney U test.
      Male sex, (%)1,724 (53.1)21 (43.8).24
      Fisher exact test.
      BMI (kg/m2), median [IQR]28 [24.2–31.9]25.9 [23.85–31.25].51
      Mann-Whitney U test.
      Duration of symptoms (h), median [IQR]18–23 [12–17, 48–53]36–41 [12–17, >96].03
      Mann-Whitney U test.
      Nausea, (%)2,395 (73.8)28 (58.3).02
      Fisher exact test.
      Vomiting, (%)1,401 (49.3)11 (22.9).01
      Fisher exact test.
      Anorexia, (%)1,638 (51.8)16 (34.8).01
      Fisher exact test.
      Diarrhea, (%)561 (17.4)9 (18.8).85
      Fisher exact test.
      Migration to RLQ, (%)2,400 (74.9)28 (59.6).03
      Fisher exact test.
      Prior episodes, (%)273 (8.6)3 (6.5).79
      Fisher exact test.
      Charlson comorbidity index, median [IQR]0 [0–1]1.5 [0–3]< .001
      Mann-Whitney U test.
      Prior abdominal surgery, (%)719 (22.2)17 (35.4).04
      Fisher exact test.
      Steroids, (%)57 (1.8)2 (4.2).21
      Fisher exact test.
      Chemotherapy, (%)17 (0.5)1 (2.1).23
      Fisher exact test.
      Other immunosuppression, (%)52 (1.6)1 (2.1).54
      Fisher exact test.
      Tobacco, (%).11
      Fisher exact test.
       Current594 (18.3)7 (14.6)
       Former462 (14.3)13 (27.1)
       Never2183 (67.4)28 (58.3)
      Temperature (Celsius), median [IQR]36.9 [36.6–37.2]36.7 [36.5–37.3].12
      Mann-Whitney U test.
      Heart rate (bpm), median [IQR]86 [74–97]97 [81–103].01
      Mann-Whitney U test.
      Systolic blood pressure (mmHg), median [IQR]131 [118–142]134 [124–151].03
      Mann-Whitney U test.
      RLQ tenderness, (%)3,177 (97.9)45 (93.8).08
      Fisher exact test.
      Diffuse tenderness, (%)467 (14.7)10 (21.3).21
      Fisher exact test.
      RLQ rebound tenderness, (%)919 (28.7)10 (21.3).33
      Fisher exact test.
      Diffuse rebound tenderness, (%)63 (2.0)0 (0)1.00
      Fisher exact test.
      Rovsing’s sign, (%)925 (36.7)6 (17.6).02
      Fisher exact test.
      Obturator sign, (%)329 (14.4)4 (12.9)1.00
      Fisher exact test.
      Psoas sign, (%)340 (14.8)5 (15.6).80
      Fisher exact test.
      Alvarado score, median [IQR]6 [5–7]6 [4.5–6].001
      Mann-Whitney U test.
      Clinical AAST appendicitis severity, (%)1.00
      Fisher exact test.
       Grades 1,2, and 33,157 (98.0)48 (100)
       Grade 415 (0.5)0 (0)
       Grade 551 (1.6)0 (0)
      White blood cell (K/uL), median [IQR]13.4 [10.6–16.1]12.9 [11.0–15.1].33
      Mann-Whitney U test.
      Polymorphonuclear cells, (%)80.7 [73.2–85.8]80.4 [71.3–86.5]1.00
      Mann-Whitney U test.
      AAST, American Association for the Surgery of Trauma; BMI, body mass index; IQR, interquartile range; RLQ, right lower quadrant.
      Mann-Whitney U test.
      Fisher exact test.
      Table II shows the differences in the CT findings between patients with malignant versus benign appendicitis. The presence of a phlegmon was significantly associated with the presence of underlying malignancy (6.3% vs 1.3%, P = .03). Intraoperative findings and patients’ mortality are summarized in Table III. Briefly, patients with an underlying malignancy were more likely to have a perforated appendicitis with phlegmon or abscess (14.6% vs 4.7%, P = .01) and were more likely to have an abdominal abscess (12.5% vs 2.7%, P = .002). No differences were noted regarding the duration of the surgical procedure and in-hospital mortality.
      Table IICT findings between patients presenting with a benign versus malignant appendicitis
      VariablesBenign (n = 3,245)Malignancy (n = 48)P value
      Local inflammatory changes, (%)2,762 (85.1)36 (75.0).07
      Fisher exact test.
      Contrast non-filling of appendix, (%)107 (3.3)4 (8.3)0.08
      Fisher exact test.
      Appendiceal wall necrosis, (%)193 (5.9)4 (8.3)0.53
      Fisher exact test.
      Air in appendiceal wall, (%)45 (1.4)0 (0)1.00
      Fisher exact test.
      Periappendiceal fluid, (%)543 (16.7)6 (12.5)0.56
      Fisher exact test.
      Contrast extravasation, (%)2 (0.1)0 (0)1.00
      Fisher exact test.
      Regional soft tissue swelling, (%)206 (6.3)6 (12.5).13
      Fisher exact test.
      Diffuse abdominal/pelvic inflammation, (%)14 (0.4)0 (0)1.00
      Fisher exact test.
      Free intraperitoneal fluid or air, (%)324 (10.0)5 (10.4).81
      Fisher exact test.
      Perforated appendicitis, (%)164 (5.1)5 (10.4).10
      Fisher exact test.
      Phlegmon, (%)41 (1.3)3 (6.3).03
      Fisher exact test.
      Cecal inflammation, (%)255 (7.7)6 (12.5).27
      Fisher exact test.
      Appendicolith, (%)1,040 (32.0)12 (25.0).35
      Fisher exact test.
      CT diameter (mm), median [IQR]12 [10–14]12.5 [11–16].06
      Mann-Whitney U test.
      Image AAST appendicitis severity, (%).59
      Fisher exact test.
       Grade 12212 (72.1)32 (71.1)
       Grade 292 (3.0)1 (2.2)
       Grade 3482 (15.7)5 (11.1)
       Grade 4220 (7.2)6 (13.3)
       Grade 561 (2.0)1 (2.2)
      AAST, American Association for the Surgery of Trauma; IQR, interquartile range.
      Fisher exact test.
      Mann-Whitney U test.
      Table IIIOperative data between patients presenting with a benign versus malignant appendicitis
      VariablesBenign (n = 3,245)Malignancy (n = 48)P value
      Initial operative approach, (%).10
      Fisher exact test.
       Laparoscopic single incision8 (0.2)0 (0)
       Laparoscopic 3 incision3,143 (98.0)44 (93.6)
       Open approach49 (1.5)3 (6.4)
       Other6 (0.2)0 (0)
      Final operative approach, (%).28
      Fisher exact test.
       Laparoscopic single incision8 (0.2)0 (0)
       Laparoscopic 3 incision3,003 (93.7)42 (89.4)
       Open, midline incision93 (2.9)2 (4.3)
       Open, RLQ incision78 (2.4)2 (4.3)
       Open, other incision7 (0.2)0 (0)
       Other17 (0.5)1 (2.1)
      Conversion to open from laparoscopic, (%)129 (4.0)1 (2.1).51
      Fisher exact test.
      Intraoperative findings, (%)
       Normal appearing appendix53 (1.6)0 (0)1.00
      Fisher exact test.
       Acutely inflamed, intact2,318 (71.4)29 (60.4).11
      Fisher exact test.
       Perforated with local contamination290 (8.9)5 (10.4).62
      Fisher exact test.
       Perforated with phlegmon or abscess153 (4.7)7 (14.6).01
      Fisher exact test.
       Perforated with generalized purulence128 (3.9)2 (4.2).71
      Fisher exact test.
       Gangrenous appendix, intact142 (4.4)1 (2.1).72
      Fisher exact test.
       Gangrenous appendix, local contamination105 (3.2)1 (2.1)1.00
      Fisher exact test.
       Gangrenous with phlegmon or abscess59 (1.8)3 (6.3).06
      Fisher exact test.
       Gangrenous with generalized purulence53 (1.6)1 (2.1).55
      Fisher exact test.
       Abscess87 (2.7)6 (12.5).002
      Fisher exact test.
       Serous abdominal/pelvic fluid188 (5.8)1 (2.1).52
      Fisher exact test.
       Purulent abdominal/pelvic fluid321 (9.9)4 (83.3)1.00
      Fisher exact test.
       Other159 (4.9)3 (6.3).51
      Fisher exact test.
      Intraoperative adverse event, (%)39 (1.2)2 (4.17).12
      Fisher exact test.
      Operative duration (min), median [IQR]57 [41–76]56 [36–76].41
      Mann-Whitney U test.
      Mortality (in-hospital), (%)5 (0.2)0 (0)1.00
      Fisher exact test.
      Mortality (30 d), (%)3 (0.1)1 (2.1).06
      Fisher exact test.
      IQR, interquartile range; RLQ, right lower quadrant.
      Fisher exact test.
      Mann-Whitney U test.
      The results of the multivariable regression analysis are shown in Table IV. In summary, only appendiceal diameter on CT imaging was identified as an independent predictor for the presence of underlying malignancy (odds ratio = 1.06, 95% confidence intervals: 1.01–1.12, P = .01). For every millimeter increase in the appendiceal diameter on CT imaging, the odd of underlying malignancy increased by 6%. Based on previously published work on the topic of malignancy in patients presenting with acute appendicitis, we dichotomized the age variable using the cutoff of 40 years old.
      • Furman M.J.
      • Cahan M.
      • Cohen P.
      • Lambert L.A.
      Increased risk of mucinous neoplasm of the appendix in adults undergoing interval appendectomy.
      ,
      • Carpenter S.G.
      • Chapital A.B.
      • Merritt M.V.
      • Johnson D.J.
      Increased risk of neoplasm in appendicitis treated with interval appendectomy: single-institution experience and literature review.
      ,
      • Wright G.P.
      • Mater M.E.
      • Carroll J.T.
      • Choy J.S.
      • Chung M.H.
      Is there truly an oncologic indication for interval appendectomy?.
      The incidence of appendiceal cancer in patients ≤40 years old with an appendiceal diameter ≤10 mm was 0.97%. On the other hand, the incidence of appendiceal cancer in patients >40 years old with an appendiceal diameter >10 mm was 2.95%. The corresponding risk ratio for the presence of cancer in a patient >40 years old with >10 mm appendiceal diameter compared to a patient ≤40 years old with ≤10 mm appendiceal diameter presenting with acute appendicitis was 3.03 with 95% confidence intervals (1.24–7.42) (Fig 1).
      Table IVIndependent predictors for the presence of underlying malignancy in patients presenting with acute appendicitis
      MultivariableOdds ratio95% CIP value
      Age1.020.99–1.06.15
      Charlson comorbidity index1.120.87–1.41.35
      Duration of symptoms (every 5 h increase)1.060.99–1.13.06
      CT presence of appendicolith0.490.19–1.08.10
      CT contrast nonfilling of appendix2.820.80–7.66.06
      CT perforated appendix0.350.02–1.80.32
      CT phlegmon3.480.51–13.91.12
      CT diameter, mm1.061.01–1.12.01
      AIC = 343.9
      AIC, Akaike information criterion; CI, confidence interval.
      Figure thumbnail gr1
      Fig 1Incidence of malignancy and risk ratio for patients >40 years old with an appendiceal diameter >10 mm. RR, relative risk.

      Discussion

      In this multi-institutional study of appendicitis, we show that patients older than 40 years with an appendiceal diameter greater than 10 mm are 3 times more likely to have an underlying malignancy compared with patients younger than 40 with a diameter less than 10 mm. To our knowledge, this is the first time in the literature that appendiceal diameter on imaging has been identified as an independent predictor of appendiceal cancer in patients presenting with appendicitis. We believe that the diameter is larger in patients with underlying malignancy due to the chronic and gradual obstruction of the appendiceal lumen from the tumor mass, although further research is necessary to prove this hypothesis.
      Appendiceal cancer is rare; however, its true incidence may be underestimated owing to the limited preoperative diagnostic abilities. As a result, some patients may have a missed diagnosis when treated nonoperatively. The rate of appendiceal cancer is reported to be increasing within the past decade.
      • Siddharthan R.V.
      • Byrne R.M.
      • Dewey E.
      • Martindale R.G.
      • Gilbert E.W.
      • Tsikitis V.L.
      Appendiceal cancer masked as inflammatory appendicitis in the elderly, not an uncommon presentation (Surveillance Epidemiology and End Results (SEER)-Medicare Analysis).
      Previous studies have failed to identify radiologic factors that can predict the presence of an underlying malignancy in patients presenting with acute appendicitis.
      • Kunduz E.
      • Bektasoglu H.K.
      • Unver N.
      • Aydogan C.
      • Timocin G.
      • Destek S.
      Analysis of appendiceal neoplasms on 3544 appendectomy specimens for acute appendicitis: Retrospective cohort study of a single institution.
      ,
      • Schwartz J.A.
      • Forleiter C.
      • Lee D.
      • Kim G.J.
      Occult appendiceal neoplasms in acute and chronic appendicitis: A single-institution experience of 1793 appendectomies.
      Over the past years, there has been growing interest in managing both complicated and uncomplicated appendicitis nonoperatively.
      • Khan K.
      • Patil S.
      • Roomi S.
      • Shiwani M.H.
      Appendicular Neuroendocrine Neoplasm is Associated with Acute Appendicitis - Don't Miss the Boat.
      Nonoperative management of acute appendicitis without an interval appendectomy would lead to worse outcomes in patients with underlying malignancy.
      • Loftus T.J.
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      • et al.
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      • Sciarretta J.D.
      • Pahlkotter M.
      • Muertos K.
      • Onayemi A.
      • Davis J.M.
      The understated malignancy potential of nonoperative acute appendicitis.
      The literature that identifies interval appendectomy as a risk factor for an appendiceal tumor may be simply reflecting the shift in the management of acute appendicitis with higher rates of nonoperative management.
      • Furman M.J.
      • Cahan M.
      • Cohen P.
      • Lambert L.A.
      Increased risk of mucinous neoplasm of the appendix in adults undergoing interval appendectomy.
      ,
      • Carpenter S.G.
      • Chapital A.B.
      • Merritt M.V.
      • Johnson D.J.
      Increased risk of neoplasm in appendicitis treated with interval appendectomy: single-institution experience and literature review.
      ,
      • Wright G.P.
      • Mater M.E.
      • Carroll J.T.
      • Choy J.S.
      • Chung M.H.
      Is there truly an oncologic indication for interval appendectomy?.
      ,
      • Schwartz J.A.
      • Forleiter C.
      • Lee D.
      • Kim G.J.
      Occult appendiceal neoplasms in acute and chronic appendicitis: A single-institution experience of 1793 appendectomies.
      Although several authors have argued against the routine performance of interval appendectomies in patients with complicated appendicitis that experience complete resolution of symptoms, due to the high rates of complications and low risk of recurrence, our data suggests that we would be overlooking the risk of an underlying malignancy when opting out of interval appendectomies, especially in patients older than 40 years with an appendiceal lumen wider than 10 mm on CT.
      • Andersson R.E.
      • Petzold M.G.
      Nonsurgical treatment of appendiceal abscess or phlegmon: a systematic review and meta-analysis.
      ,
      • Furman M.J.
      • Cahan M.
      • Cohen P.
      • Lambert L.A.
      Increased risk of mucinous neoplasm of the appendix in adults undergoing interval appendectomy.
      ,
      • Bagi P.
      • Dueholm S.
      Nonoperative management of the ultrasonically evaluated appendiceal mass.
      • Hoffmann J.
      • Lindhard A.
      • Jensen H.E.
      Appendix mass: conservative management without interval appendectomy.
      • Nitecki S.
      • Assalia A.
      • Schein M.
      Contemporary management of the appendiceal mass.
      • Tekin A.
      • Kurtoglu H.C.
      • Can I.
      • Oztan S.
      Routine interval appendectomy is unnecessary after conservative treatment of appendiceal mass.
      • Talan D.A.
      Cancer of the appendix and nonoperative treatment of appendicitis shared decision making.
      Previous studies have identified various factors associated with malignancy, including age.
      • Furman M.J.
      • Cahan M.
      • Cohen P.
      • Lambert L.A.
      Increased risk of mucinous neoplasm of the appendix in adults undergoing interval appendectomy.
      ,
      • Carpenter S.G.
      • Chapital A.B.
      • Merritt M.V.
      • Johnson D.J.
      Increased risk of neoplasm in appendicitis treated with interval appendectomy: single-institution experience and literature review.
      ,
      • Wright G.P.
      • Mater M.E.
      • Carroll J.T.
      • Choy J.S.
      • Chung M.H.
      Is there truly an oncologic indication for interval appendectomy?.
      Some suggested that underlying malignancies should also be suspected in all patients who present with an inflammatory mass or an abscess.
      • Teixeira Jr., F.J.R.
      • Couto Netto S.D.D.
      • Akaishi E.H.
      • Utiyama E.M.
      • Menegozzo C.A.M.
      • Rocha M.C.
      Acute appendicitis, inflammatory appendiceal mass and the risk of a hidden malignant tumor: a systematic review of the literature.
      ,
      • Mallinen J.
      • Rautio T.
      • Gronroos J.
      • et al.
      Risk of appendiceal neoplasm in periappendicular abscess in patients treated with interval appendectomy vs follow-up with magnetic resonance imaging: 1-year outcomes of the Peri-Appendicitis Acuta randomized clinical trial.
      In other reports, female sex, appendiceal perforation, underlying Crohn’s disease, longer duration of symptoms, and lower admission hemoglobin have been suggested as risk factors.
      • Sadot E.
      • Keidar A.
      • Shapiro R.
      • Wasserberg N.
      Laparoscopic accuracy in prediction of appendiceal pathology: oncologic and inflammatory aspects.
      • West N.E.
      • Wise P.E.
      • Herline A.J.
      • Muldoon R.L.
      • Chopp W.V.
      • Schwartz D.A.
      Carcinoid tumors are 15 times more common in patients with Crohn's disease.
      • Todd R.D.
      • Sarosi G.A.
      • Nwariaku F.
      • Anthony T.
      Incidence and predictors of appendiceal tumors in elderly males presenting with signs and symptoms of acute appendicitis.
      Similar to our study, Pickhardt et al investigated 65 patients presenting with appendicitis who had an underlying neoplasm.
      • Pickhardt P.J.
      • Levy A.D.
      • Rohrmann Jr., C.A.
      • Kende A.I.
      Primary neoplasms of the appendix manifesting as acute appendicitis: CT findings with pathologic comparison.
      The authors described that patients with appendiceal malignancy tend to have a diameter larger than 15 mm. Using that cutoff, they found that the sensitivity of CT scan for the diagnosis of underlying malignancy was 86%.
      • Pickhardt P.J.
      • Levy A.D.
      • Rohrmann Jr., C.A.
      • Kende A.I.
      Primary neoplasms of the appendix manifesting as acute appendicitis: CT findings with pathologic comparison.
      Our study is different, because we compared patients with underlying malignancy to a control group of patients with acute appendicitis but without underlying malignancy, and we identified CT diameter larger than 10 mm as the an independent predictor for malignancy.
      Another area of debate among surgeons is colonoscopy after nonoperative management of acute appendicitis. Since most malignancies present in patients older than 40, patients managed nonoperatively should be offered a screening postoperative colonoscopy.
      • Andersson R.E.
      • Petzold M.G.
      Nonsurgical treatment of appendiceal abscess or phlegmon: a systematic review and meta-analysis.
      ,
      • Teixeira P.G.
      • Demetriades D.
      Appendicitis: changing perspectives.
      ,
      • Sylthe Pedersen E.
      • Stornes T.
      • Rekstad L.C.
      • Martinsen T.C.
      Is there a role for routine colonoscopy in the follow-up after acute appendicitis?.
      Furthermore, synchronous colonic cancer is reported to occur in up to 3% of patients with appendiceal tumor.
      • Cerame M.A.
      A 25-year review of adenocarcinoma of the appendix. A frequently perforating carcinoma.
      ,
      • Whitfield C.G.
      • Amin S.N.
      • Garner J.P.
      Surgical management of primary appendiceal malignancy.
      Considering all the above, some authors also suggest the use of colonoscopy in all patients older than 40 presenting with acute appendicitis irrespective of surgical or nonoperative management.
      • Lai H.W.
      • Loong C.C.
      • Tai L.C.
      • Wu C.W.
      • Lui W.Y.
      Incidence and odds ratio of appendicitis as first manifestation of colon cancer: a retrospective analysis of 1873 patients.
      ,
      • Narayanswami J.
      • Smith D.A.
      • Enzerra M.
      • Rahnemai-Azar A.A.
      • Kikano E.
      • Ramaiya N.H.
      “-Omas” presenting as “-itis”: acute inflammatory presentations of common gastrointestinal neoplasms.
      Based on the results of our study, we have identified a specific subgroup of patients older than 40 years with an appendiceal diameter larger than 10 mm who would particularly benefit from colonoscopy and an interval appendectomy, when managed nonoperatively.
      Our study has a few limitations. First, our patient population size is small, especially those with malignancy. However, the reported incidence of appendiceal malignancy in our patient population was in accordance with the literature.
      • Guraya S.Y.
      Do we still need to perform routine histological examination of appendectomy specimens?.
      ,
      • Furman M.J.
      • Cahan M.
      • Cohen P.
      • Lambert L.A.
      Increased risk of mucinous neoplasm of the appendix in adults undergoing interval appendectomy.
      Second, we did not find age as a continuous variable to be associated independently with underlying malignancy. Failure to achieve significance in the multivariable regression and due to our small population size, we decided not to use specific age cutoffs in our multivariable regression models and to use historic data for the age from the literature. Third, mucoceles were not included in the analysis; although not malignant per se, failure to remove can have devastating consequences to the patient. However, this study also has the strength of being a prospectively collected database including patients from 28 rural and urban centers across the United States with geographic representation of all areas that can help in the generalizability of our results. The most important addition to the existing literature includes the identification of a specific subset of older patients with enlarged appendiceal diameter as one at a particularly high risk for malignancy and thus warranting a more aggressive follow-up and surgical approach.
      In conclusion, the combination of age >40 years and an appendiceal diameter >10 mm is associated with a greater than 3-fold increased risk of malignancy in patients presenting with appendicitis. Such findings are important for patient counseling and perhaps suggest that those patients, when managed nonoperatively, should undergo screening colonoscopy and an interval appendectomy.

      Conflict of interest/Disclosure

      The authors declare that they have no conflicts of interest or disclosures.

      Funding/Support

      None.

      EAST Appendicitis Study Group (alphabetically by center)

      Baystate Medical Center – Reginald Alouidor, MD, FACS; Kailyn Kwong Hing, MD
      Beaumont Hospital – Victoria Sharp, DO; Thomas Serena, D.O.
      Boston Medical Center – George Kasotakis, MD, MPH; Sean Perez, BS
      Carilion Clinic – Stacie L. Allmond, DO; Bruce Long, MD
      Cooper University Hospital – Nadine Barth, MD; Janika San Roman, MPH
      Denver Health – Ryan A. Lawless, MD, FACS; Alexis L. Cralley, MD
      Emory University – Rondi Gelbard, MD; Crystal Szczepanski, MSN, NP-C, ACNP-BC
      Essentia Health – Steven Eyer, MD, FACS; Kaitlyn Proulx, PA
      Geisinger Medical Center – Jeffrey Wild, MD, FACS; Katelyn A. Young, BS
      Inova Fairfax – Erik J. Teicher, MD, FACS; Elena Lita, BS
      Intermountain Medical Center – David Morris, MD; Laura Juarez, PA-C
      Loma Linda University – Richard D. Catalano, MD; David Turay, MD, PhD
      Marshfield Clinic – Daniel C. Cullinane, MD; Jennifer C. Roberts, MD
      Massachusetts General Hospital – Ahmed I. Eid, MD
      Mayo Clinic – Mohamed Ray-Zack, MD; Tala Kana’an, MBBS
      Medical City Plano – Victor Portillo, MD; Morgan Collom, DO
      Medical College of Wisconsin – Chris Dodgion, MD; Savo Bou Zein Eddine, MD
      North Shore Medical Center – Maryam B. Tabrizi, MD; Ahmed Elsayed Mohammed Elsharkawy
      Ohio State University Wexner Medical Center – David C. Evans, MD, FACS; Daniel E. Vazquez, MD, FACS
      St. Vincent Hospital Indianapolis – Jonathan Saxe, MD; Lewis Jacobson, MD
      Oregon Health Sciences University – Brandon Behrens, MD; Martin Schreiber, MD
      University of Arizona, Tucson – Bellal Joseph, MD; Muhammad Zeeshan, MD
      University of California, Irvine – Jeffry Nahmias, MD, MHPE; Beatrice Sun, BS
      University of Florida, Jacksonville – Marie Crandall, MD, MPH, FACS; Jennifer Mull, MSN, RN, CCRC
      University of Maryland – Jason D. Pasley, DO, FACS; Lindsay O’Meara
      University of Southern California – Ali Fuat Kann Gok, MD; Jocelyn To, BS
      Walter Reed National Military Medical Center – Carlos Rodriguez, DO; Matthew Bradley, MD

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