Importance of histopathological evaluation of appendectomy specimens

Acute appendicitis is the most common general surgical emergency []. Approximately 7% of individuals in the western countries will suffer from an episode of acute appendicitis during their lifetime, requiring an appendectomy. In developing countries, the incidence is increasing in most urban centers, probably due to the adoption of western diet []. Various etiologies for acute appendicitis have been identified, but luminal obstruction is considered the most critical factor, as it triggers the inflammatory process. Although lymphoid hyperplasia and fecoliths are the most common causative factors of luminal obstruction, other unusual factors have been associated with the condition, including mucocele [], enterobiasis, amebiasis, taeniasis [], endometriosis [], tuberculosis, actinomycosis, adenovirus, other granulomatous diseases [], eosinophilic granuloma [], neurogenic appendicopathy [], diverticulitis [], and appendiceal malignancies, such as carcinoid tumor, gastrointestinal stromal tumor, hyperplastic polyp, tubular adenoma, villous adenoma, neurofibroma, mucinous cystadenoma, adenocarcinoma, mucinous cystadenocarcinoma, lymphoma, and leukemia []. Aberrant findings occur in a small percentage of appendices, but can have major consequences []. The diagnosis of appendicitis is largely clinical and appendectomy is the treatment of choice. Delayed diagnosis of appendicitis could lead to complications which increase morbidity and mortality. Despite advances in technology and imaging modalities, there are difficulties in the clinical diagnosis of acute appendicitis. Histopathological examination still remains the gold standard method for the confirmation of appendicitis []. The practice of sending appendectomy specimens for histopathological analysis varies among hospitals. Arguments against the practice include the rarity of incidental pathologies that may reflect on treatment and also the financial implications of routine histopathological assessments. Whereas it is recognized that many resected specimens in general surgery needs no histopathology, there are as yet no guidelines as to whether appendiceal specimens should be sent routinely for histopathology. Opponents of screening argue that not sending the specimens is justified by the rarity of aberrant findings combined with the low clinical significance and the significant costs of specimen processing. However, a number of published papers have found aberrant incidental findings to be more common []. Selective histopathology for appendiceal specimens might induce the risk of missing significant pathologies, which may have an impact on patient management. Further, histopathological examination of appendiceal specimens may ascertain other diagnoses such as parasitic infections, endometriosis, and granulomatosis []. This study was designed to investigate the occurrence and distribution of unusual histopathological findings encountered in appendectomy specimens of patients who had undergone surgery to treat an initial diagnosis of acute appendicitis. Patients and methods The clinicopathological data of 460 cases who underwent appendectomies for presumed acute appendicitis between October 2012 and October 2016 for a clinical suspicion of inflamed appendix were collected. The study met the criteria of the IRB/Ethics committee approval statement and all patients were write a consent. Patients were included in the study fulfilled the following criteria: over 16 years of age and appendectomy indicated to treat an initial diagnosis of appendicitis. Evaluation of histopathological reports of appendectomy specimens was done. The study was approved by the Ethical Committee of Al-Azhar University. Patient’s medical records included sex, age, and histopathological diagnosis. Pathological reports were evaluated and revised by a senior pathologist. Appendectomy specimens were fixed in 10% phosphate buffered formaldehyde solutions, embedded in paraffin, and sections were prepared for microscopy after staining with hematoxylin and eosin. In neuroendocrine tumor cases, immunohistochemical analysis will be performed with antibodies targeting chromogranin A and synaptophysin. Appendectomy specimens were subjected to microscopic examination, with representative sections (including the tip and two cross sections from the body and the base of the appendix). Extra sections will be examined in cases of normal, suspected granulomatous, or tumoral appendices. Negative appendectomy was defined as a specimen that microscopically contains no pathology [no evidence of inflammation (acute or chronic), tumors, parasitic infestation, and any other pathological abnormalities]. Obliteration due to fibrosis and lymphoid hyperplasia of the appendix were included as abnormal findings. The slides that contain unusual histopathological findings were reevaluated by an experienced pathologist. On the basis of the histopathological findings the appendectomy specimens will be classified as either positive or negative for appendicitis features. Positive specimens contain fecoliths, worms, neurogenous hyperplasia, appendiceal neuroma, granulomatous inflammation, foreign body reaction, endometriosis, mucocele, cystadenoma, or appendiceal tumors. Specimens were considered negative if proved to be microscopically normal, with no clue of inflammation. Follow-up was done concerning all patients to determine survival and morbidity in the postoperative period. For the present study, the follow-up of the patients was calculated as months from the date of appendectomy until the final clinical informations were reported in the database, or up to December 2016. Patients’ confidentiality were maintained. Results were analyzed using SPSS, version 18. A P values of less than 0.05 were considered statistically significant.

Among the 460 patients, 265 (57.7%) were men and 195 (42.3%) were women with a sex ratio (male/female) of 1.4. The mean age was 27.6 years with a range from 16 to 62 years (Table 1). Distribution of patients according to the age group is summarized in Table 1. All patients were diagnosed clinically with acute appendicitis on the basis of physical, laboratory, and ultrasound examination (in selected cases). All patients underwent open appendectomy. All patients with incidental unexpected pathological diagnoses were diagnosed clinically with acute appendicitis, and none of them had preoperative suggestion of any other pathology. Appendix appeared normal intraoperatively in 28/460 (6%) cases, grossly inflamed in 365/460 (79.3%), gangrenous in 32/460 (7%), perforated with localized peritonitis in 30/460 (6.6%), and perforated with generalized peritonitis in 5/460 (1.1%). Histopathology documents normal appendix in 7/421 (1.7%) of classic cases and 16/39 (41%) of cases with unusual pathological findings, acute appendicitis in 310/421 (73.7%) of classic cases and 23/39 (59%) of cases with unusual pathological findings, acute gangrenous appendicitis in 32/421 (7.6%) of classic cases and 0/39 (0%) of cases with unusual pathological findings, acute gangrenous perforation in 30/421 (7.1%) of classic cases and 0/39 (0%) of cases with unusual pathological findings, lymphoid hyperplasis in 15/421 (7.1%) of classic cases and 0/39 (0%) of cases with unusual pathological findings, chronic appendicitis in 27/421 (7.1%) of classic cases and 0/39 (0%) of cases with unusual pathological findings. Appendix was normal in 23/460 (5%) cases, 7/421 (1.7% of appendicitis cases), and 16/39 (41% of unexpected pathological cases) [including 13 (56.5%) women and 10 (53.5%) men]. It was significantly higher in female patients (P=0.02) and in the 20-year to less than 30-year age group (P=0.02) with the female : male ratio of 1.3 : 1. Primary cause of acute abdominal pain could be found in other associated pathological findings. Changes consistent with acute inflammation (acute appendicitis, acute suppurative appendicitis, gangrenous appendicitis, perforated appendicitis with peritonitis, lymphoid hyperplasia, and chronic appendicitis) encountered in 437/460 (95% of all cases), 414/421 (98% of appendicitis cases), and 23/39 (59% of unexpected pathological cases). Incidental unexpected pathological diagnoses were noted in 39/460 (8.5%) cases of appendectomy specimens, 16/39 (41%) were associated with noninflamed appendix, and 23/39 (59%) were associated with inflamed appendix. Histological examination of the surgical specimen showed unusual pathological findings in 39/460 (8.5%) cases. Unexpected pathological findings included Enterobius vermicularis in 19/39 (48.7%) cases (Fig. 1), mucinous neoplasms 3/39 (7.7%), neuroendocrine tumor 1/39 (2.6%) (Figs 2 and 3), tuberculosis 1/39 (2.6%) (Fig. 4), granulomatous inflammation 12/39 (30.8%) (Fig. 5), bilharziasis 1/39 (2.6%) (Fig. 6), and endometriosis 2/39 (5%) (Fig. 7). Histopathological findings of appendectomy specimens with unexpected pathological diagnoses are shown in Table 2. Among the 19 appendices with E. vermicularis, 11 (57.9%) cases were associated with acute inflammation and eight (42.1%) cases were within normal limits. In 12 cases of granulomatous inflammation, five (41.7%) cases were associated with acute inflammation, and seven (58.3%) cases were within normal limits. In addition, most of the cases 333/460 (72.4%) showed a picture of nonobstructive acute appendicitis in which inflammation started either in the mucous membrane or in the lymph follicles and terminated either as resolution, ulceration, suppuration, or fibrosis. Ulceration of the mucosa with infiltration by acute inflammatory cells mainly formed of neutrophils and pus cells was found. The inflammatory cellular infiltrate reached the submucosa and muscularis propria. One hundred and four (22.6%) cases showed obstructive acute appendicitis. The obstruction was considered to be either because of parasites in the lumen, which was in the form of E. vermicularis or other causes as fecolith, and food particles in the appendicular wall. Perforation occurred most commonly at the site of impacted fecolith or parasite. The escaping purulent contents caused periappendicitis in the form of inflammation of tissues around the appendix with the formation of abscess (localized or generalized peritonitis). This occurred in 30/460 (6.6%) and 5/460 (1.1%), respectively. Twenty-seven (5.8%) cases showed chronic appendicitis in the form of transmural infiltration by chronic inflammatory cells in the form of lymphocytes, eosinophils, plasma cells, and macrophages. The mucosa found ulcerated, especially when the parasite was seen. The submucosa showed congested vascular spaces and one case showed granuloma formation around a calcified Schistosoma ovum. Other pathological findings associated with appendicitis or other unusual pathological findings of the appendix were 18/460 (3.98%) cases. Ruptured ovarian cyst found in 9/460 (2%) cases, perforated duodenal ulcer 3/460 (0.66%), Meckel’s diverticulum 1/460 (0.22%), disturbed ectopic pregnancy 3/460 (0.66%), and cecal adenocarcinoma 2/460 (0.44%) (Table 3).

Opponents of screening argue that not sending appendectomy specimens is justified by the rarity of aberrant findings combined with the low clinical significance and the significant costs of specimen processing []. However, a number of published papers have found aberrant incidental findings to be more common. Selective histopathology for appendiceal specimens might induce the risk of missing significant pathologies, which may have an impact on patient management []. Further, histopathological examination of appendiceal specimens may ascertain other diagnoses such as parasitic infections, endometriosis, and granulomatosis. As nonsurgical treatment of appendicitis is currently being advocated as an alternative to surgery [], questions regarding histopathological examination of the specimen in patients having appendectomy are important. Swank et al. [] review showed that the incidence of an unexpected diagnosis, particularly of a benign or malignant neoplasm, is low. The diagnosis was made intraoperatively in only a few cases; in particular, diagnosis of parasitic infection, endometriosis, and granulomatosis. The presence of neoplasia was also frequently missed intraoperatively, although the variation among the studies was high. Some authors claim to have diagnosed all aberrant findings intraoperatively [], but most articles recommend routine histopathology owing to the unreliability of intraoperative diagnosis []. Swank et al. [] included 19 articles from a wide variety of countries. Parasitic infection and tuberculosis were more common in the studies from Asia, Africa, and the Middle East [] and were not found at all in some of the western studies []. In contrast, endometriosis and Crohn’s disease were more frequent in western countries. In the present study, unexpected pathological findings were detected in 39/460 (8.5%) cases. They included E. vermicularis in 19/39 (48.7%) cases, mucinous neoplasms 3/39 (7.7%), neuroendocrine tumor 1/39 (2.6%), tuberculosis 1/39 (2.6%), granulomatous inflammation 12/39 (30.8%), bilharziasis 1/39 (2.6%), and endometriosis 2/39 (5%). The sensitivity of the intraoperative findings to detect aberrant diagnoses was subjected to great variation. This may have been caused in part by the very low frequency of neoplasms in some studies []. One author claimed that all neoplasms were macroscopically suspicious, but did not state whether the suspicion was raised by the surgeon or the histopathologist []. One of the articles dismissing the need for routine histopathological examination suggested opening all specimens at the time of surgery for macroscopic examination [], while others took the view that opening the specimens would interfere with histopathological examination []. Swank et al. [] found malignant neoplasm in 0.2% of all cases. Other pathologies included parasitic infection, endometriosis, granulomatosis, lymphoid hyperplasia, diverticulosis, diverticulitis, and subserosal cyst as primary diagnosis in 0.0–14% of the cases. The consequences of finding a benign neoplasm were described in four articles reviewed by Swank et al. []. This led to a change in management in the form of a right colectomy to gastroenterological follow-up. Collins found a high frequency of parasitic infection (17%) with other pathologies, including fibrosis (8%), fecolith (44%), melanosis (15%), and foreign body (4%) []. Swank et al. [] in their review article found that no study mentioned the intraoperative diagnosis and how this varied from the eventual histopathological features (as the present study did). As a result, no specificity data could be calculated. In the present study, negative appendectomy rate of 6% falls within the acceptable range of 3–20% []. The present study showed women to have higher rates of negative appendectomy frequently occurring within the younger age group of 16–30 years []. Edino et al. [] and Marudanayagam et al. [] also presented similar finding which showed a high incidence in the age group of 10–19 and 11–30 years, respectively. Similar to other studies, [] other pathologies such as perforated duodenal ulcer, ruptured ovarian cyst, Meckel’s diverticulitis, and disturbed ectopic pregnancy as the causes of acute abdominal pain in negative appendectomy were encountered. Bahar et al. [] from Egypt stated that high result of negative appendectomy rate (normal appendix) is higher than accepted standard in their study (37.5%) and is more in female patients. Also, the high result of appendicular malignancy (2.2%) in their study is histologically surprise so they recommended routine histological examination of appendix after appendectomy. Abdellatif et al. [] from Egypt examined fecolith and successfully detected eggs of Ascaris lumbricoides (1%), Ascaris duodenale (1%), and Hymenolepis nana (1%) in their examined appendectomies, whereas histopathological examination of the appendix failed to detect them. This confirmed the value of the combination of histopathological and fecolith examinations for laboratory diagnosis of the parasitic etiology of appendicitis. Their record of A. lumbricoides is nearly similar to the 0.79% obtained by other Egyptian researchers [] and is contradictory to the 18% result obtained by Indian researchers []. Interestingly, Manal et al. discovered the association between H. nana and acute appendicitis which is a novel finding as no available literature reported a similar result. Manal et al. [] concluded that infections of the appendix by schistosomiasis and enterobiasis is important in the pathogenesis of appendicitis in Egypt; thus, early diagnosis as well as treatment of these infestations are indicated to avoid the development of appendicitis, with subsequent appendectomy. The current study aims to determine the occurrence and type of unusual factors in acute appendicitis cases or in cases that mimicked the clinical presentation of acute appendicitis. Appendiceal endometriosis may be the first indication of underlying pelvic endometriosis, which is an important cause of infertility []. Granulomatous appendicitis may be the first indication of tuberculosis, an important risk of patients living in tuberculosis-endemic regions, or of Crohn’s disease. Incidental diagnosis of parasites in appendectomy specimens may allow for initiation of antihelminth treatment. Most appendix carcinoids and mucinous neoplasms are diagnosed incidentally during surgery for acute appendicitis. Certainly, early diagnosis of cancer and initiation of treatment is extremely beneficial to patient survival. Thus, even when appendectomy specimens show normal macroscopic features, histopathological analyses may provide clinically useful insights into the patient’s condition and help to improve patient outcome by revealing a previously unrecognized disease.

From the available evidence, it is not possible to conclude whether routine histopathology is justified or not. The incidence of unexpected findings is low, intraoperative diagnosis is insufficient, and the benefit of histopathology has not been adequately studied. Until more reliable data become available, histopathological examination of the removed appendix should continue to be carried out. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

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