Acute Appendicitis Secondary to Metastatic Malignancy - A Review of 78 Cases in Literature

Background: Acute appendicitis is one of the most common causes of acute abdomen presentation to the emergency department. Appendicectomy is one of the most common emergency operations performed. Appendicitis is attributed to lymphoid hyperplasia or faecolith causing obstruction of the appendiceal lumen. Other causes include helminth infection, primary appendiceal tumours, malignancy, and calculi. Metastatic malignancy causing acute appendicitis is very uncommon. In this article, we review the literature that exists reporting acute appendicitis attributed to metastatic diseases of the appendix, the malignancies that were identified


Introduction
Acute appendicitis is one of the most common causes of acute abdomen presentation worldwide and appendicectomy is one of the most common emergency operations performed. The estimated lifetime risk of appendicitis in 7-8% [1]. Appendicitis is caused by a wide array of pathology ranging from infectious diseases to primary and metastatic malignancy. The most common aetiology is lymphoid hyperplasia or a faecolith causing obstruction of the appendiceal lumen resulting in increased intraluminal pressure. Primary appendiceal malignancies is rare, with an incidence of 0.9% -1.5% [2,3]. Metastatic disease resulting in acute appendicitis is extremely rare [4,5], with the majority of data coming from published case reports. The relationship between primary colon and primary ovarian cancer with intraperitoneal secondary metastases has been well established, however other malignancies have also been reported. The relationship has been established, however colorectal and ovarian with secondary appendiceal metastases is still considered rare. The aim of this review article is to identify published literature of acute appendicitis cases secondary to metastatic malignancy and rare non-primary tumours causing acute appendicitis. This study aims to highlight the importance of taking a thorough past medical history and being aware of a patient's previous oncological history prior to performing an emergency appendicectomy.

Methods
This study was performed following the Scale for the Assessment of Narrative Review Articles (SANRA) [6]. A review of existing published literature including case reports, abstracts, and studies were evaluated. PubMed and Google Scholar were used to search for the published articles. The search terms were "(appendicitis due to metastasis) OR (appendicitis secondary to metastatic)) OR (appendicitis as a result of metastasis) OR (appendicitis secondary to metastases). Several cases were identified via the snowball method where references were used to identify additional literature [7]. Right sided colon cancer causing acute appendicitis cases were excluded given a systematic review and meta-analysis has already been performed confirming the incidence of right sided colon cancer in patients aged over 40 presenting with acute appendicitis is 10 times greater than the risk in the general population [8]. Patient's age, gender, time after cancer diagnosis to appendicitis presentation, degree of inflammation, histopathology, and operation were evaluated. Percentage of Complicated was compared with uncomplicated appendicitis. Complicated appendicitis is defined as perforated, peri-appendicular abscess, and gangrenous [9].

Results
78 cases were identified in the literature and included in this review. The most commonly reported metastatic malignancy causing appendicitis were breast, lung, gastric, and prostate. Table  1

Gastric Adenocarcinoma
Thirteen cases of gastric cancer metastasizing to the appendix causing acute appendicitis were identified [41-53]. The age ranged from 32 to 79 years old. There were 5 males and 6 females. Further data for two cases published more than 25 years ago were unable to be located. Six patients had complicated appendicitis compared to five uncomplicated. Six patients had poorly differentiated gastric adenocarcinoma, two patients had moderate to well differentiated Volume 08; Issue 05 J Surg, an open access journal ISSN: 2575-9760 adenocarcinoma, and two had gastric signet ring cell adenocarcinoma.

Prostate Cancer
Eight cases of metastatic prostate cancer resulting in acute appendicitis were found [54-61]. Patients ranged from 62 to 82 years old, with a mean age of 80 years old. Three patients or 37% had complicated appendicitis compare to five or 62% with uncomplicated appendicitis. Most of the patients had Gleason 7 or greater prostate adenocarcinoma.

Cervical
Two patients were found to have metastatic cervical cancer causing acute appendicitis [62,63]. Both cases were stage Ib cervical cancer on initial diagnosis and both had perforated appendicitis.

Endometroid
Three endometroid causes of acute appendicitis were identified. One patient had metastatic endometrial adenocarcinoma [64]. All three had uncomplicated appendicitis, and one had an open ileocecectomy [65] as the cecum was found to be oedematous and inflamed.

Discussion
Internationally, acute appendicitis is the one of the most common reasons for acute abdomen presentation to the emergency room, and one of the most common reasons for emergency surgery. Appendicitis is usually diagnosed clinically where patients typically present with migratory periumbilical to right iliac fossa pain with biochemical results showing leukocytosis, neutrophilia, and elevated c-reactive protein. In equivocal findings imaging is often performed with computed tomography scans having a sensitivity and specificity of 98% in identifying the pathology [86] the other option would be proceeding to diagnostic laparoscopy [87]. The gold standard treatment for appendicitis is appendicectomy for source control. In our study, 46% of the patients had complicated appendicitis. Whilst small numbers, this suggests that the incidence of complicated appendicitis due to metastatic malignancy is higher compared to incidence of appendiceal perforation in nonmalignant appendicitis. A prospective cohort study of 1486 patients by Korner et al found the overall appendix perforation rate was 19%, with elderly and small children having the greatest number of perforated appendix [88]. The pathogenesis of appendicitis is described as an appendiceal outlet obstruction due to infection, calculi, appendicoliths, lymphoid hyperplasia, and tumours with subsequent increased luminal pressure of the appendix. This causes small vessel thrombosis, reduced lymphatic flow, ischemia and resultant accumulation of bacteria. Eventually, if not treated early, the appendix wall may rupture due to necrosis [89] . Several randomized controlled trials have investigated conservative management of acute uncomplicated appendicitis with antibiotics [90][91][92][93]. One of these, the Appendicitis Acuta (APPAC) trial enrolled 530 patients aged 18 to 60 years with CT confirmed acute uncomplicated appendicitis. In this trial, patients were randomized into two groups: antibiotic vs surgical management. In the antibiotic group, patients received IV ertapenem for 3 days, then 7 days of levofloxacin and metronidazole. The authors found most patients who received antibiotic for uncomplicated appendicitis at the 1 year did not require an appendicectomy [90]. However, managing patients conservatively presenting with acute appendicitis with a background of malignancy is perilous as an appendicitis due to metastatic or recurrent malignancy may be missed. For example, in one of our cases, a 70-year-old male with history of T3N1M0 Gleason 7 prostatic adenocarcinoma presented with contained perforated appendicitis and was managed conservatively with iv antibiotics. Six weeks later he represented with a symptomatic appendiceal mucocele with histology showing metastatic prostatic adenocarcinoma infiltration [60].
In our review, the malignancies with greatest number to metastasize to appendix causing acute appendicitis are breast, lung, gastric, and prostate. The most common site of distant metastases (from most common to least) in invasive breast carcinoma is bone, lung, brain, and liver [94]. Interestingly, there was a greater number of invasive ductal carcinoma metastasis to appendix compared to Invasive Lobular Carcinoma (ILC). In a study by Dixon et al., when compared with ductal carcinomas, lobular carcinomas showed greater tendency for peritoneal, retroperitoneal, and gastrointestinal tract [95,96]. However, from our review of case reports there was greater number of spread to the appendix by invasive ductal carcinoma. For lung cancer, there was a large number of Small Cell Lung Cancer (SCLC) that metastasized to the appendix causing appendicitis. This is in congruent with published data demonstrating SCLC is highly metastatic, and 70% of patients by the time of diagnosis would have had metastatic disease [97]. The most common sites of gastric cancer metastasis are liver, peritoneum, lung, and bone [98]. Prior to proceeding with surgical resection in gastric cancer, a diagnostic laparoscopy is performed to exclude peritoneal metastasis because curative surgery for gastric cancer is only performed if there is no evidence of metastases [99]. In prostate cancer, the greatest distribution of metastatic sites are bone, distant lymph nodes, liver, and thorax [100].

Conclusion
Acute appendicitis secondary to metastatic malignancy is extremely uncommon. The percentage of complicated appendicitis in acute appendicitis due to metastatic malignancy is greater than the percentage of complicated appendicitis not due to metastatic malignancy. It is important to be cognizant of a patient's previous malignancy history when considering management for acute appendicitis.