Unusual histopathological findings in appendectomy specimens with clinical diagnosis of acute appendicitis: A retrospective cohort analysis

Introduction While appendicitis is considered one of most common acute surgical conditions, several studies have reported abnormal histopathological findings in appendectomy specimens; however, sending all appendices to histopathology is not yet routinely done.Here we report many unusual findings. Those unusual findings played a role not only in confirming acute appendicitis as a cause of the presentation in some cases but also discovering etiologies that mimic it with great impact on its management. Methods Between January 2011 and December 2017, a total of 1510 patients were operated with appendectomy for a primary diagnosis of acute appendicitis. Among them, a total of 72 patients had incidental histopathologic findings in association with acute appendicitis or other pathologies instead of acute appendicitis. A retrospective analysis for those 72 patients was performed with all data being retrieved from the electronic health record system. Results Patients ages ranged between 4 and 71 years with a mean age equal to 23.1 years (SD = 14.2). Majority of patients were women (n = 52; 72.2%). Sixty of the seventy-two cases were seen in patients with negative appendectomies (n = 333) with an overall rate of 18% among this group of patients. The remaining 12 patients had additional findings in histopathology specimens beside acute appendicitis (n = 1131) with an overall rate of 1%. The most commonly reported pathologies were serositis, ovarian cysts, and Enterobius vermicularis in descending frequency. Conclusion Identification of unusual histopathological findings during microscopic examination of resected appendices is more common in female patients and in patients with negative appendectomy. histopathologic assessment of specimens will allow detection of congenital, infectious or malignant pathologies that mimic acute appendicitis clinically even in the absence appendicitis microscopically.


Introduction
Appendicitis is a global disease, and it's without doubt one of the most common major general surgical emergencies [1,2]. Men and women in the United States have approximately 1 in 12 and 1 in 15 lifetime risks of getting appendicitis, respectively.

Materials and methods
Registration and ethics: Research Registry number is stated, in accordance with the declaration of Helsinki. Unique identifying number: researchregistry6963 (https://www.researchregistry.com/browse-th e-registry#home/registrationdetails/60ea0c7a7f4cbf00210ee916/) Ethical approval: The study was approved by the Institutional Review Board (IRB) in Hashemite University. This is a retrospective cohort analysis of the histopathologic findings of patients who were operated with appendectomy for a provisional diagnosis of acute appendicitis in the period between January 2011 and December 2017 in prince Hamza hospital in Amman, Jordan (i.e., a tertiary referral governmental hospital affiliated with the Hashemite University College of Medicine). Patients who went through incidental appendectomy during other surgeries were excluded from the study. A total of 1510 patients was included in the study, 841 (56%) men and 669 (44%) women. Among them, a total of 72 patients proved to have unusual histopathological findings or other pathologic findings other than acute appendicitis.
A critical review of all medical records was performed and all patients' specimens labeled with abnormal findings other than acute appendicitis were reviewed by two experienced pathologists each of them with more than 30 years' experience in the field of pathology.
The main aim of the study is to identify different patterns of unusual histopathological findings in patients with provisional diagnosis of acute appendicitis and to assess their prevalence as well as their clinical significance.
This paper is prepared in compliance with STROCSS 2019 criteria [63]. Data were recorded in a Microsoft Excel (Redmond, WA, USA) spreadsheet and analyzed by SPSS program version 16.0. Statistical significance was assessed using a two-tailed Fisher's exact test (statistical significance was considered for p < 0.05).

Results
Unusual histopathological pathologic findings or other pathologic conditions other than acute appendicitis were found in 72 patients out of 1510 patients with appendectomy for a provisional diagnosis of appendicitis with an overall rate of 4.76%. Out of the seventy-two, twenty patients (27.8%) were males, and fifty-two (72.2%) were females. Patients ages ranged between 4 and 71 years, with a mean of 23.1 years (SD = 14.2).
Sixty of the seventy-two cases were seen in patients with negative appendectomies (n = 333) with an overall rate of 18% among this group of patients. The remaining 12 patients had additional findings in histopathology specimens beside acute appendicitis (n = 1131) with an overall rate of 1%.

Discussion
Appendicitis is the most common surgical emergency that mostly affects adolescents although it can hit any age [35]. The primary pathology is luminal obstruction which increases the intra-luminal pressure within the appendix, and leads to ischemia. Bacteria translocate causing inflammation, Infarction and perforation can happen after [36]. Many usual and unusual etiologies may lead to appendiceal lumen obstruction. An overview of reported histopathological findings is discussed in our paper.

Serositis
Also called peri-appendicitis, is an inflammation of the serosal surface of the appendix, which is always associated with an intraabdominal pathology [37]. It is difficult to be diagnosed clinically. The disease course depends on early recognition and treatment of the underlying cause. among our patients, it was the most reported histopathology findings in patients with negative appendectomy, and it was more prevalent among women. Among all patient who had appendectomy (n = 1510), 18 patients (12 females, 6 males) with mean age of 26.5 and age range 6-69 years had a diagnosis of serositis without evidence of underlying appendicitis. Jadhav V and Singhal V [10] reported 5 patients who had serositis in 199 appendices. Peri-appendicitis actually has been found in many other studies [38,39].

Ruptured ovarian corpus luteal cyst
Most of ruptured ovarian cysts could be asymptomatic or even present with minimal symptoms mimicking acute appendicitis, which can be controlled medically. in some cases, it may develop complications and require surgical intervention.
Among the 72 patients, 16 female patients with mean age of 23.1 years and age range 11-48 years were diagnosed with ruptured ovarian cyst during appendectomy with an overall rate of 1.05%. only 2 patients had associated acute appendicitis, 10 of the cysts were hemorrhagic and 6 were simple, non-hemorrhagic corpus luteal cysts. Although the association of a ruptured ovarian cyst and acute appendicitis is unlikely but it can happen. Tanaka [40] reported three patients who showed ruptured ovarian cysts in association with acute appendicitis.

Enterobius vermicularis
Formerly known as Oxyuris vermicularis is an extremely common among population, which runs in families. It is commonly asymptomatic with high cure rate but common recurrences.A total of 12 patients including 9 females and 3 males were diagnosed with E. vermicularis on the final histopathology for appendectomy with an overall prevalence of 0.79%. Patients ages range from 4 to 21 years, with a mean of 13 years. 3 patients (2 females and one male patients) had E. vermicularis with acute appendicitis. its association with appendicitis was first reported in the late 19 th century. Previous reports of E. vermicularis incidence in appendectomy specimens have ranged from 0.2% to 41.8%. In this study the incidence (i.e., 0.79%) was very close to 0.81% reported by Yabanoglu [9] (12/1466) and 0.6% by Emre (2013) [57]. Qasaimeh et al. [61] reported a prevalence of 2.2% in their study on 3984 appendices in northern Jordan. Rates of inflammation in appendices infected with E. vermicularis were ranged from 13% to 37% [5], in the present study it was 25% (3 out of 12 case) that is similar to other published studies.

Carcinoid tumor
The little understood slow-motion cancer is the most common tumor of the appendix. Appendix is the site of around 12% of carcinoid tumors, and it usually discovered as an incidental finding of histopathological examination following appendectomy.
Since the misdiagnosis of its symptoms, carcinoid tumor is usually diagnosed biochemically or histologically. Although it can behave aggressively, localized carcinoids have excellent prognosis with a 5-year survival rate of 98% [43].
Appendiceal carcinoid was diagnosed in 4 patients; three females (16, 17 and 28 years old) and one male (27 years). only male patient had a diagnosis of acute appendicitis in association with the carcinoid while all women had no histopathological evidence of appendicitis. All carcinoid tumors were localized in the distal part of the appendix, of which 3 cases were approximately 4 mm in diameter while the 4th one reached 10 mm all tumors were of the insular type, and were invading muscularis propria without involvement of the serosa.
Literature review by Shrestha (2012) [62] showed incidence of carcinoid tumor ranging from 0.1% to 1.05%, mostly found incidentally during microscopic examination. In the present study, the incidence was 0.26% which lies within the range of other reports [62].

Transmural infarction
Any serious infection within the peritoneum can progress to intestinal infarction which is a life-threatening condition, therefore, early diagnosis and therapy is a must and occasionally surgery is essential. many complications of acute appendicitis occur even after appendectomy. in particular, thrombophlebitis of the porto-mesenteric veins could occur and progress to intestinal infarction. this is usually uncommon with the antibiotic use and the surgical management; however, it should always be considered [44].Transmural infarction was found in 3 males, 28 y old with negative appendectomy and two 32 y and 71 y old males with acute appendicitis.

Entameba Histolytica
Even it is rare to be a cause of acute appendicitis, E. histolytica must be kept in physician's mind to avoid misdiagnosis and unfavorable prognosis. It is diagnosed by histopathological examination with PAS stain postoperatively and a fecal culture. The treatment is usually appendectomy with oral metronidazole [45]. E. histolytica was seen in two young male patients (16 and 17-year-old), in both the appendix was not inflamed. Yabanoglu et al. [9] reported 4 cases of Entameba Histolytica in 1466 appendices, one of which was associated with acute appendicitis.

Primary adenocarcinoma (PAA)
PAA is very rare tumor, first described in 1882 with fewer than 300 cases recorded between 1882 and 2004 [3]. One case of primary adenocarcinoma of the appendix (PAA) of the colonic type was reported in the distal appendix of a 39 years old female patient with evident direct continuity of the carcinoma with the normal appendicular mucosa confirming that this is PAA and not arising from the caecum, with no evidence of acute appendicitis. This case represents an incidence of 1 in 1510 cases (0.06%) which lie within the range reported by others (0.01% in Miguel Leon Arellano 2016 [46] and 0.08% in Collins (1955) [47,48]. Elective treatment of right hemicolectomy was carried out for the patient few days after the initial diagnosis.

Ruptured ectopic pregnancy
One 34-year-old female patient had ruptured ectopic pregnancy at time of appendectomy that was proved negative for AA. Although it's rare for ectopic pregnancy and acute appendicitis to occur at the same time, there few cases were reported about simultaneous AA with ruptured ectopic pregnancy [41,49].

Endometriosis
Appendiceal endometriosis, which has 2.8% prevalence in patients with endometriosis [50] has assimilated symptoms to acute appendicitis. Because of endometrial tissue response to hormonal changes, symptoms of appendiceal endometriosis overlap with menstrual cycle. In one case, appendiceal endometriosis was reported in a 24 years old female patient.

Strength and limitations
To the best of our knowledge, this is the first study that describes specifically unusual patterns of histopathological findings in patients with a presumptive diagnosis of acute appendicitis in Jordan. It has been performed in a tertiary hospital where large number of cases were retrospectively critically reviewed to confirm these unusual findings. Our findings were largely consistent with many reports from other world countries.

Conclusion
Identification of unusual histopathological findings during microscopic examination of resected appendices is more common in female patients and in patients with negative appendectomy. taking in consideration cases presented here in as well as in the literature, histopathologic assessment of specimens will allow detection of congenital, infectious or malignant pathologies that mimic acute appendicitis clinically even in the absence appendicitis microscopically. The clinical significance of identifying these unusual findings will impact the clinical outcome of affected patients for example by requiring further surgical interventions, adding chemotherapy for malignant changes or adding anthelmintic treatment.

Funding statement
The Authors received no financial support for the research, authorship and/or publication of this article.

Ethical approval
The statement of ethical approval was obtained from the Institutional Review Board (IRB) committee at Hashemite University AND Prince Hamza Hospital.

Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.

Research registration number
Unique Identifying number or registration ID: researchregistry6963.

Guarantor
The corresponding author is the guarantor for the work and he has the responsibility of access to the data, and controlling the decision to publish.

Provenance and peer review
Not commissioned, externally peer-reviewed.

Consent
Consent waived by the IRB.

Author contribution
Hamzeh

Declaration of competing interest
The authors declare no potential conflicts of interest with respect to the research, authorship and/or publication of this research.