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Predictors of Histological Evidence Suggestive of Risk of Recurrence Following Conservative Management for Appendicular Mass

Caroline M Smith, CK Sinha, James Corbett, Azad B Mathur

Department of Paediatric Surgery, Jenny Lind Children’s Hospital, Norfolk and Norwich University Hospital, Norwich, UK

 

Correspondence:

Caroline Mary Smith

Flat 5, 252 Burgoyne Road,

Sheffield, S6 3QF, UK

Tel: 07545499988

E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.

 

Abstract

Aim

The practice of routine or selective interval appendicectomy (IA) following successful conservative treatment of appendix mass is a matter of debate. Predictors of recurrence may be elucidated by correlating demographic and disease course data with high risk histology obtained at IA.

Material and Methods

Children having undergone IA between 2002 and 2012 were identified. Histology of specimens were reviewed by two clinicians and categorised as low or high risk of recurrence. Demographic and treatment course data was analysed using Fishers exact for nominal and Mann-Whitney U test for continuous data, to demonstrate association with histological risk.

Results

Thirty-nine children were identified, median age 11 years (range 3-15) and weight 37kg (9 -77Kg). We report recurrence of symptoms in 33%. Seventy-two percent had histologically high risk of recurrence. Demographic data was comparable between the two groups. Predictors of high risk included: palpation of a clear abdominal mass on initial exam (PPV 83%), ultrasound findings of a clearly visualised appendix phlegmon (OR 5.25, p=0.038) or faecolith (OR 2.25, p=0.35), recurrence of symptoms and readmission (OR 2.4, 2.3 p=0.3, p=0.29).

Conclusion

Only ultrasound appearance of clearly defined appendix phlegmon reached statistical significance to predict outcome. This information can be used in counselling families following successful conservative treatment of an appendix mass.

Key words: appendix mass, interval appendicectomy, histology, recurrence

 

 

Introduction

Conservative management of the appendix mass at the acute presentation is recommended in children [1]. Whether routine or selective interval appendicectomy should be performed after successful step down management of the appendix mass is a matter of debate. Arguments for routine interval appendicectomy (IA) include: rates of recurrence between 20 and 40%, and the possibility of unsuspected pathology such as carcinoid or granulomatous disease [2-6]. Those supporting selective IA, i.e. interval appendicectomy only if symptoms recur, argue that there is a 3.5% complication rate with laparoscopic appendicectomy and children should not undergo unnecessary surgery [7, 8]. Recurrence of disease is unpleasant for the child with readmission, need for antibioticsand a hospital stay. Ideally it would be possible to predict children at a high risk for recurrence and proceed to IA before the child becomes unwell with acute inflammatory disease, unfortunately we have no such markers.

We hypothesise histological findings at interval appendicectomy provides a model to investigate predictors of recurrence. Children with a normal appendix or an obliterated lumen following conservative management of appendicular inflammation should have a risk equivalent or lower than the general population for recurrence of appendicitis; whereas those with residual inflammation or partial luminal obstruction have a higher risk of developing recurrence [9].

In this study we aim to investigate whether there are predictors of histological outcomes at interval appendicectomy, which may then be investigated as potential predictors of recurrence.

Materials and Methods

Data was analysed retrospectively from case note review. All patients having undergone an elective appendicectomy after previous successful conservative management of an appendix mass at a single institute over a 10 years period between 2002 and 2012 were identified using a prospectively maintained theatre registry.

Management of children with appendix mass at our institute follows a standardised care pathway. In non-toxic, non-peritonitic children with history and examination suspicious for appendix mass, diagnosis is confirmed with abdominal ultrasound. In cases where a mass is felt with on table examination, the child is woken up and conservative management is started. The child is given broad spectrum intravenous antibiotics (cefuroxime and metronidazole or amoxicillin, gentamicin and metronidazole depending on surgeon preference). Intravenous antibiotics were stopped when the child had been pyrexia free for 24 hours and had normalising physiology. All children were changed to the triple antibiotic regimen at 48 hours if symptoms were not settling. The decision to continue oral antibiotics was surgeon specific on discharge. The children were booked for interval appendicectomy as routine on discharge.

Histopathological results were examined carefully and interpreted as ‘high’ and ‘low’ risk for recurrence of appendicitis by two clinicians and consensus agreement achieved in all. Those with normal appendixes or obliterated lumens were considered low risk for recurrence and placed in group one. Those with active, either acute or chronic, inflammation, ongoing suppurative process, faecolith and patchy areas of serosal or subserosal fibrosis were considered high risk and placed in group two.

Data collection included all considered predictive factors for the development of recurrent appendicitis after conservatively managed appendix mass. These included patient demographics (age, sex, weight of child, presenting symptoms, length of pre-presentation symptoms); inflammatory markers and positive blood cultures; ultrasound findings at presentation (presence of phelgmon, abscess, faecolith, lymph nodes, localised ileus); treatment parameters (intravenous and oral antibiotic choice, intravenous and oral antibiotic duration, inpatient duration) and post conservative treatment disease course (recurrence of symptoms, need for readmission, percentage weight gain between initial presentation and readmission for IA).

Data was analysed using open source software. Comparative analysis was carried out by histological group. Mann-Whitney U was used for non parametric continuous data, Fishers exact for ordinal and binomial data. The study was registered with the hospital audit board and approved for ethics.

Results

Descriptive

Thirty nine children were identified having undergone an interval appendicectomy following successful management of an appendix mass; 69% were male. Median age was 11 years (range 3-15). Median weight was 36.7kg (range 10.9 -77.3).

The average length of symptoms prior to presentation was 6 days (range 2-21). Median white cell count was 18.1 (range 8.1 – 33.2), in 5 children there was no elevation. C-reactive protein levels were elevated above 30 in all children, with a median rise of 378%. In 12 (31%) children blood cultures were sent, all of which returned as negative.

Diagnosis of appendix mass was made with combination of clinical exam and ultrasound in 90% of cases. In two cases, examination prior to appendicectomy at general anaesthetic revealed a mass where an ultrasound was not performed preoperatively. One child with a limp was diagnosed with appendix mass following MRI hip.

Ultrasound abdominal findings were as follows: appendix phlegmon 74%, peri-appendicular collection 37%, faecolith 31%, localised small bowel dilatation and ileus 8%, localised florid inflammation 6% and lymphoid hyperplasia 6%. No child underwent computer tomography. In 28 children response was seen on first line antibiotics. In 11 (28%) children antibiotics were changed to the Gentamycin regimen after 48 hours due to ongoing symptoms. One child required laparoscopic drainage of an intraabdominal collection during initial admission. There were no percutaneous drainages. Median duration of IV antibiotic course was 5 days (range 2-12). The median length of course of oral antibiotics was 5 days (range 0-14). Four children received no oral antibiotics following stopping intravenous treatment. Median inpatient duration was 5 days (range 2-16).

There was recurrence of symptoms in 13 children (33%). Three children were readmitted with one child requiring two readmissions. Readmission was for pyrexia or pain. All settled with intravenous antibiotics ranging from 2 to 4 days. The median time to interval appendicectomy was 73 days (range 31-178); 13% were performed open and 87% laparoscopically. There was one conversion from laparoscopic to open and one intraoperative complication where a serosal tear was made. Median time to discharge post interval appendicectomy was 1 day (range 1-2 days). One child developed a postoperative intraperitoneal collection which responded to antibiotics.

Histological findings of appendixes removed at interval appendicectomy are shown in Table I. Those children with normal histological appearances or obliterated lumens were placed in group one (28%). All other findings placed the children in group two (72%).

Table I. Showing histological findings in 39 excised appendixes taken at interval appendicectomy following successful conservative management of appendix mass.

Histological Findings

Frequency

(n=39)

Percentage %

Chronic inflammation

9

23

Normal appendix

8

21

Active acute inflammation

7

18

Serosal / Sub serosal fibrosis

5

13

Acute on chronic inflammation

3

8

Obliterated lumen

2

5

Granulomatous change

2

5

Faecolith

1

3

Carcinoid

1

3

Lymphoid hyperplasia, with evidence of perforation at tip

1

3


Demographic data including gender, age, weight and delay to interval appendicectomy was comparable between groups one and two. Median time to IA in the group showing low risk for recurrence was 78.5 days, opposed to 70 in group two (p=0.11). The percentage normal or obliterated lumens were similar in IAs performed in under 70 days or those over 70 days (28% vs 24%, p=0.53).

Comparative Analysis

All clinical examination findings were positively predictive of histological evidence of ongoing pathology (group 2), with palpation of the appendix mass abdominal mass on initial exam having the strongest PPV at 83%; but none reached statistical significance in differentiating between group one and two.

An ultrasound finding of a clearly visualised appendix phlegmon had an odds ratio of 5.25 (95% CI 1.02-27) of a histologically high risk outcome (p=0.038), whereas an ultrasound finding of lymphoid hyperplasia had an OR of 0.34 (95%CI 0.02-6.65) of histological high risk, i.e. predicted low risk histology findings. A finding of faecolith was associated with increased risk of inflammation at IA, but did not reach statistical significance in discriminating group one from group two. In two cases where faecolith was seen on ultrasound, a normal appendix was found on subsequent histology.

There was no association between length of intravenous antibiotic course and outcomes (p=0.526). It is noted that change to the Gentamycin based regimen decreased the OR to 0.27 of high risk histological of recurrence. There was no association between children receiving oral antibiotics following their IV course or course length or type of oral antibiotics and histological risk group.

Inpatient stay did not vary between groups and neither did weight change predict histological high risk. Initial inflammatory marker levels also did not associate with histological group. Recurrence of symptoms and requirements for readmission increased the odd ratio of findings of high histological specimen to 2.3 (95% CI 0.11 – 50.2), see Table II.

Table II. Showing odds ratio (OR) of grade 2 histological findings at interval appendicectomy following conservative management of appendix mass.  Fisher’s exact used for calculation of p value (p>0.05 considered significant).

Proposed predictors of high risk histological grade

OR

p

Requirements for change of IV antibiotics to triple regimen

0.27

0.087

Recurrence of symptoms

2.44

0.30

Required readmission

2.31

0.29

Discussion

Approximately 9% - 13.5% children with appendicitis present with an appendix mass developing after progression of complicated appendicitis [9, 10]. Conservative management, with broad spectrum antibiotics and percutaneous abscess drainage is recommended [3]. Surgery is avoided due to a risk of intraoperative complications reported as high as 56% [1].

Previous studies have looked for risk factors for clinical recurrence of symptoms following successful conservative initial management and found faecolith [11], female sex, presence of abscess at diagnosis [8] and delay of resolution of symptoms over 6 days [12] to predict recurrence of appendicitis.

We hypothesise histological appearances at IA are an objective marker of risk of recurrence. Previous studies have shown that normal and obliterated appendixes are likely to have low risk of recurrence of appendicitis [5]. In addition a group from the Gunma University Hospital found fibrosis and infiltration by inflammatory cells in three-quarters of appendix specimens taken at IA, and hypothesised that these findings may lead to stagnation of intraluminal contents and lead to increased risk of recurrence [9].

In 28% of our specimens showed normal or obliterated lumens suggesting low risk of recurrence. In 72% there was evidence of fibrosis or inflammation suggesting higher risk of recurrence of appendicitis.

Our data showed an association between recurrence of symptoms and histological grade (32% group two vs 18% group one) but this did not reach statistical significance. Similarly presence of faecolith on ultrasound was higher in group two but did not reach statistical significance (39% vs 18%). It is of interest in our study presence of faecolith on ultrasound did not associate with recurrence of symptoms.

We have found predictors of ongoing inflammation of the appendix or other pathological findings at interval appendicectomy (group two) to be a palpable abdominal appendix mass at time of initial presentation, ultrasound appearances of a clearly defined appendix phlegmon, recurrence of symptoms and requirement for readmission, albeit only ultrasound findings reached statistical significance due to small numbers in our study. Predictors of a normal or obliterated appendix (group two) included ultrasound findings of lymphoid hyperplasia and change of antibiotics to a triple regimen. This may suggest Gentamycin is a superior antibiotic for intra-abdominal infection.

We recognise the limitations in the retrospective methodology of this paper and small numbers, leading to underpowering of the associations shown. We also recognise the timing of IA may influence histological findings but median time from admission to interval appendicectomy was 79 vs 70 days for group two and one respectively, with no statistically significant difference.

Conclusion

We report recurrence of symptoms in one third of cases after successfully treated appendix mass. Three quarters of histological findings at IA suggest ongoing appendix pathology which predicts increased risk of recurrence of appendicular inflammation. The only statistically significant predictor at presentation, of ongoing appendix pathology at IA, is a clearly visualised appendix phlegmon on ultrasonography. This information may be used in combination with surgeon preference to council families as to the likelihood of recurrence and the need for progression to interval appendicectomy.

Acknowledgements

Please we thank Claire Roberts for help with the administrative aspects of this paper.



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Proposed predictors of high risk histological grade

OR

p

Requirements for change of IV antibiotics to triple regimen

0.27

0.087

Recurrence of symptoms

2.44

0.30

Required readmission

2.31

0.29