Lymphoid Hyperplasia of the Appendix: A Potential Pitfall in the Sonographic Diagnosis of Appendicitis

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1 Pediatric Imaging Original Research Xu et al. Lymphoid Hyperplasia of the ppendix Pediatric Imaging Original Research Yingding Xu 1 R. rooke Jeffrey 1 Michael. DiMaio 2 Eric W. Olcott 1,3 Xu Y, Jeffrey R, DiMaio M, Olcott EW Keywords: appendicitis, appendix, diagnostic imaging, lymphoid hyperplasia, sonography DOI: /JR Received pril 15, 2015; accepted without revision July 7, Department of Radiology, Stanford University School of Medicine, 300 Pasteur Dr, H1307, Stanford, C ddress correspondence to Eric W. Olcott (eolcott@stanford.edu). 2 Department of Pathology, Stanford University School of Medicine, Stanford, C. 3 Veteran ffairs Palo lto Health Care System, Palo lto, C. JR 2016; 206: X/16/ merican Roentgen Ray Society Lymphoid Hyperplasia of the ppendix: Potential Pitfall in the Sonographic Diagnosis of ppendicitis OJECTIVE. The objective of this study was to test the hypothesis that thickening of the lamina propria, a finding produced by lymphoid hyperplasia, is significantly associated with false-positive sonographic diagnoses of appendicitis in 6- to 8-mm noncompressible appendixes. MTERILS ND METHODS. Sonograms of 119 consecutive patients with suspected appendicitis and 6- to 8-mm noncompressible appendixes were retrospectively blindly evaluated for thickening of the lamina propria (short axis thickness 1 mm). The reference standard for appendicitis was pathologic analysis of resected specimens. Results were compared with the two-tailed Fisher exact test. RESULTS. Thirty-one patients (26.1%) had a thickened lamina propria and 88 (73.9%) did not. Of the 27 pediatric patients with a thickened lamina propria, five (18.5%) had truepositive and 22 (81.5%) had false-positive sonograms for appendicitis; among the 55 pediatric patients without a thickened lamina propria, 27 (49.1%) had true-positive and 28 (50.9%) had false-positive sonograms for appendicitis (p = 0.009). Similar differences in adult patients were not statistically significant. ll five pediatric patients with appendicitis and thickened lamina propria also showed two or more findings of periappendiceal fluid, hyperechoic periappendiceal fat, or mural hyperemia on color Doppler examination, compared with two of 22 similar pediatric patients without appendicitis (p < 0.001). CONCLUSION. Lymphoid hyperplasia may result in a noncompressible appendix 6 8 mm in diameter and may be misdiagnosed as appendicitis in pediatric patients. True-positive diagnoses of appendicitis can be accurately identified by the presence of at least two additional findings from the group of periappendiceal fluid, hyperechoic periappendiceal fat, and mural hyperemia. Identifying the characteristic sonographic appearance of lymphoid hyperplasia may help prevent false-positive misdiagnoses of appendicitis. T he lamina propria is the layer of connective tissue within the digestive tract that lies just superficial to the mucosal epithelium. It extends throughout the gastrointestinal system, including the appendix, and forms the middle layer of the gastrointestinal mucosa. The appendiceal lamina propria normally contains lymphoid follicles, particularly in the pediatric population. These lymphoid follicles may hypertrophy in response to gastrointestinal inflammatory diseases, such as viral gastroenteritis and mesenteric adenitis, leading to thickening of the lamina propria within the appendiceal wall [1 3]. Graded compression sonography has been widely used over the past 3 decades to evaluate patients with right lower quadrant pain and possible acute appendicitis [4, 5]. One of the most useful criteria for the sonographic diagnosis of appendicitis has been the maximum outer diameter of the noncompressible appendix. The normal appendix typically measures less than 6 mm in maximum outer diameter; when the maximum outer diameter increases above 6 mm, the likelihood of appendicitis increases [3, 6 14]. Park et al. [15] have described the sonographic appearance of lymphoid hyperplasia of the appendix, noting characteristic enlargement of the hypoechoic lamina propria to a thickness exceeding 0.8 mm. We anecdotally have noted lymphoid hyperplasia in noncompressible appendixes with sonographically abnormal maximum outer diameters of 6 mm or greater, meeting conventional criteria for acute appendicitis, in patients whose diagnoses were other than appendicitis. ccordingly, we sought to test the hypothesis that thickening of the lamina pro- JR:206, January

2 Xu et al. pria (i.e., lymphoid hyperplasia) is associated with an increased likelihood of false-positive sonographic diagnoses of appendicitis among patients with 6- to 8-mm noncompressible appendixes. We also analyzed additional sonographic findings that may be seen in appendicitis and, therefore, could be useful in differentiating patients with only lymphoid hyperplasia from those with appendicitis namely, periappendiceal fluid, periappendiceal hyperechoic fat, and mural hyperemia within the appendix [14, 16 19]. Materials and Methods This study was performed in compliance with the HIP. The requirement for informed consent was waived by the institutional review board of Stanford University School of Medicine, owing to the retrospective nature of the study. Patient Sample n electronic search engine operating on the institutional radiology information system identified all patients referred for sonographic examination of the appendix from February 2012 through ugust 2013 whose appendiceal maximum outer diameters measured 6 8 mm, inclusive. Sonographic Technique t our institution, sonography is the preferred first-line imaging modality for the evaluation of patients with suspected appendicitis. Patients are referred for sonography unless they exhibit body mass index greater than 30, findings indicating peritonitis, or evidence of perforation; individuals with any of these clinical features are triaged to undergo CT. The appendiceal sonography protocol at our institution includes supine scanning with lineararray transducers, beginning with the patient indicating the point of maximal pain, whenever possible, and continuing with real-time evaluation from the hepatorenal fossa through the colon and the appendix [12, 20 22]. oth static images and cine clips are routinely acquired. ll sonographic examinations are performed by one of six licensed sonographers in our laboratory, each with a minimum of 5 years of experience. Each examination is supervised by attending physicians, fellows, or residents in our Department of Radiology, with additional images acquired as deemed necessary. Instrumentation includes Logiq 9 (GE Healthcare) and Sequoia System 512 (Siemens Healthcare) ultrasound scanners. Fig year-old boy with normal lamina propria layer., Sagittal sonographic image shows echogenic fecal matter in appendiceal lumen (L). Immediately adjacent to lumen is hypoechoic lamina propria (between long arrows). Note normal echogenic submucosal layer (between short arrows). TIP = appendiceal tip., Transverse sonographic image shows normal hypoechoic lamina propria (long arrow) adjacent to central lumen and echogenic submucosal layer (short arrow). Lamina propria measured 0.6 mm in shortaxis thickness. Calipers mark appendiceal diameter. Review of Imaging Studies One expert radiologist blindly reviewed all imaging studies, without knowledge of the original clinical sonography reports or the pathologic results related to individual examinations. Lymphoid hyperplasia was considered present when the sonographic thickness of the lamina propria on shortaxis views was greater than or equal to 1.0 mm, according to the observations of Park et al. [15]. In addition, the presence or absence of periappendiceal fluid, hyperechoic periappendiceal fat, and mural hyperemia was determined. Periappendiceal fluid was defined as extraluminal fluid within the right lower quadrant. Hyperechoic fat was defined as periappendiceal adipose tissue with a globular appearance, measuring at least 1.0 cm in thickness, with echogenicity greater than that of other regions of fat within the FOV. Mural hyperemia was considered present when color or power Doppler examination revealed linear flow on longitudinal views or curvilinear flow on transverse views. Diagnostic Reference Standards ll examinations were considered sonographically positive for appendicitis, given their findings of noncompressible appendixes with 6- Fig year-old boy with lymphoid hyperplasia, with false-positive sonogram and misdiagnosis of acute appendicitis., Transverse sonographic image shows enlarged appendix with thickened hypoechoic lamina propria (long arrow) reflecting lymphoid hyperplasia. ppendix measured 7.6 mm in maximum outer diameter (between calipers), and lamina propria layer measured 2.0 mm in short axis thickness. Note echogenic luminal contents (short arrow)., Histologic section of this appendix after appendectomy (H and E stain, 40) shows marked hypertrophy of lymphoid follicles (F) within lamina propria (LP). Owing to thickened lamina propria, submucosal layer (between long white arrows) and muscularis externa (between short white arrows) are attenuated. Note mucosal epithelium (long black arrow), adjacent to appendiceal lumen, and subserosa (between short black arrows). 190 JR:206, January 2016

3 TLE 1: Correlation etween Thickening of the Lamina Propria and ppendicitis in Patients With Noncompressible ppendixes Lymphoid Hyperplasia of the ppendix Finding Pediatric Patients a to 8-mm maximum outer diameters [3, 6 14]. These examinations were defined as true-positives and false-positives when histologic evaluation of subsequently resected specimens revealed, or did not reveal, respectively, evidence of appendicitis. Review of Medical Records The original clinical report generated at the time of the clinical examination was reviewed for each patient with lymphoid hyperplasia evident on retrospective review of the original sonographic images. Clinical interpretations in our institution are rendered by staff radiologists, each with 5 to more than 35 years of experience. Each such patient s disposition, including the use of CT or surgical intervention after sonography, was determined from the electronic medical record. Statistical nalysis The unpaired t test was used to compare means, the exact binomial test was applied to proportions, and the two-tailed Fisher exact test was used for two-by-two comparisons of imaging findings. The Stata software platform (version 2.1, StataCorp) was used for all analyses. Results Patient Sample total of 119 patients (64 female and 55 male) were identified who had been referred to sonography for suspected appendicitis during the study period and had 6- to 8-mm noncompressible appendixes. These 119 individuals included 37 adults and 82 pediatric patients; the latter are defined at our institution as those younger than 19 years (Table 1). dult Patients b ll Patients c Thickening of lamina propria No appendicitis 22 (81.5) 4 (100.0) 26 (83.9) ppendicitis 5 (18.5) 0 (0.0) 5 (16.1) Total No thickening of lamina propria No appendicitis 28 (50.9) 20 (60.6) 48 (54.5) ppendicitis 27 (49.1) 13 (39.4) 40 (45.5) Total Note Except for total, data are number (%) of patients. Fisher exact test was used to calculate p values. a p = b p = c p = Sonographic ppearance of the Lamina Propria The review of sonographic images identified patients with a normal lamina propria (Fig. 1), as well as those with a thickened lamina propria (Figs. 2 5). Of the 119 patients included in the study, 31 (26.1%; 95% CI, %) had thickening of the lamina propria and 88 (73.9%; 95% CI, %) did not. Of the 31 patients with thickening of the lamina propria, four (12.9%; 95% CI, %) were adults and 27 (87.1%; 95% CI, %) were pediatric patients. The mean maximum outer diameters for patients with a thickened lamina propria and patients with a normal lamina propria were 6.4 mm (95% CI, mm) and 6.8 mm (95% CI, mm), respectively. Sonographic Findings and Clinical Follow-Up Of all 31 patients with thickening of the lamina propria, five (16.1%) had histologyproven acute appendicitis (true-positives for appendicitis) and 26 (83.9%) did not (falsepositives for appendicitis) (Table 1); of all Fig. 3 5-year-old girl who underwent appendectomy after false-positive sonography. Sonographic image obtained during compression shows enlarged noncompressible appendix. Pathologic analysis revealed lymphoid hyperplasia with no appendicitis. Note marked thickening of hypoechoic laminal propria (between long white arrows), which measured 1.7 mm. Note also echogenic submucosal layer (short white arrow) and thin bright central echo of fecal matter (black arrow) within lumen. Maximum outer diameter of appendix (between calipers) measured 6.4 mm. 88 patients without a thickened lamina propria, 40 (45.5%) had histology-proven acute appendicitis (true-positives for appendicitis) and 48 (54.5%) did not (false-positives for appendicitis) (p = 0.005). When these data are stratified by age group, statistically significant differences are evident between pediatric patients but not between adult patients. Regarding pediatric patients, of the 27 with thickening of the lamina propria, five (18.5%) had histology-proven acute appendicitis (true-positives) and 22 (81.5%) did not (false-positives) (Table 1); of the 55 pediatric patients without a thickened lamina propria, 27 (49.1%) had histology-proven acute appendicitis (true-positives) and 28 (50.9%) did not (false-positives). This difference in the proportion of false-positives, 50.9% in the absence of a thickened lamina propria versus 81.5% in the presence of a thickened lamina propria, was statistically significant (p = 0.009). Regarding adults, a similar trend was observed, with increased false-positives in the presence of a thickened lamina propria; however, the numbers of adult patients was small TLE 2: Characteristics of Pediatric Patients With ppendicitis on Histologic Examination and Thickening of the Lamina Propria on Sonography Patient No. ge (y) Maximum Outer Diameter (mm) Sonographic Features Periappendiceal Fluid Hyperechoic Periappendiceal Fat Mural Hyperemia Yes Yes Yes No Yes Yes Yes No Yes Yes No Yes Yes Yes No JR:206, January

4 Xu et al. and this difference did not reach statistical significance (Table 1). ll five patients (100.0%) with appendicitis and thickening of the lamina propria were pediatric patients and all five had at least two additional sonographic findings among the group of periappendiceal fluid, hyperechoic periappendiceal fat, and mural hyperemia (Table 2 and Figs. 4 5), whereas only two comparable patients without appendicitis did so; both of the latter were pediatric patients, constituting 7.7% (p < 0.001) of the 26 comparable pediatric or adult patients without appendicitis and 9.1% (p < 0.001) of the 22 comparable pediatric patients without appendicitis. mong these 22 comparable pediatric patients without appendicitis, one had periappendiceal fluid, another had hyperechoic periappendiceal fat, four others had mural hyperemia, and the remainder had none of the three additional findings. The five pediatric patients with appendicitis and a thickened lamina propria were not otherwise sonographically distinguishable from comparable pediatric patients without appendicitis, with no statistically significant difference in mean maximum outer diameter values (Table 3). Review of the original sonography reports for the 26 patients with a thickened lamina propria, whose sonograms were false-positive for appendicitis, disclosed 19 in which the reported impression indicated findings of acute appendicitis or findings at least equivocal for acute appendicitis. Of these 19 patients, six subsequently underwent CT scans, each of which was negative for appendicitis, four underwent appendectomies producing TLE 3: Maximum Outer Diameter of ppendixes in Pediatric Patients With 6- to 8-mm Noncompressible ppendixes Finding No. of Patients specimens without appendicitis, and the remainder were managed with clinical observation and evaluation for alternative diagnoses. Maximum Outer Diameter (mm) of ppendix Range Mean (95% CI) Thickening of lamina propria No appendicitis ( ) ppendicitis ( ) No thickening of lamina propria No appendicitis ( ) ppendicitis ( ) Note ppendicitis was confirmed on histologic examination. Discussion Lymphoid hyperplasia of the appendix was first recognized as a clinical entity by surgeons and pathologists in the early 20th century [23, 24]. It was initially thought to play a role in the pathogenesis of acute appendicitis by causing appendiceal obstruction. However, this theory has largely been dismissed because Chang [25] examined over 3000 appendectomy specimens and found that only 15 of 1711 cases with acute appendicitis had concurrent lymphoid hyperplasia and, additionally, that 107 cases of lymphoid hyperplasia had no evidence of acute inflammation. ccordingly, it appears that lymphoid hyperplasia is, in fact, a physiologic response to inflammation rather than a primary cause of appendicitis. Lymphoid hyperplasia of the appendix is most commonly identified in pediatric patients, as was the case in our patient sample (87.1%), and is typically associated with inflammatory conditions such as viral gastroenteritis and mesenteric adenitis [1, 2]. recent review provides context for the sonographic features of lymphoid hyperplasia, or lymphoid nodular hyperplasia [26]. The process is defined histologically as a cluster of more than 10 lymphoid nodules that each contains lymphoid follicles with diameters 2 mm or larger. Given the size of these nodules relative to the normal appendix with its maximum outer diameter of less than 6 mm [3, 6 14], it seems probable that lymphoid hyperplasia could alter the compliance of the appendiceal wall, thus rendering it noncompressible during graded compression sonography, and expand the maximum outer diameter to 6 mm or more, providing bases for false-positive sonography findings. Compared with other imaging modalities, such as CT, a unique feature of sonography Fig year-old girl with lymphoid hyperplasia, appendicitis involving appendiceal tip, and sonography showing both echogenic periappendiceal fat and mural hyperemia. Maximum outer diameter of appendix measured 6.5 mm., Longitudinal sonographic image shows thickened hypoechoic lamina propria (long arrow) with effacement of concentric layered anatomy within appendiceal tip (short arrow)., Longitudinal color Doppler image shows echogenic periappendiceal fat (short arrow) and mural hyperemia (long arrow) within appendiceal tip. 192 JR:206, January 2016

5 Lymphoid Hyperplasia of the ppendix C Fig. 5 6-year-old girl with lymphoid hyperplasia, appendicitis of appendiceal tip on histologic examination, and sonography showing both hyperechoic periappendiceal fat and periappendiceal fluid., Longitudinal sonographic image shows thickened hypoechoic lamina propria (between long arrows), consistent with lymphoid hyperplasia. Note hyperechoic periappendiceal fat (F). Normal concentric layered anatomy, including echogenic submucosal echo (short arrow), is present in mid appendix but is effaced in enlarged appendiceal tip (T), which measured 6.5 mm. Calipers mark mid appendix., Transverse sonographic image near appendiceal tip shows adjacent hyperechoic periappendiceal fat (F). Effacement of normal concentric layered anatomy (long arrow) is seen adjacent to region with anatomic layers, including echogenic submucosa (short arrow). C, Transverse sonographic image just inferior to appendix shows periappendiceal free fluid (FF), external iliac artery () and vein (V). is its ability to identify specific layers of the bowel wall, such as the hypoechoic lamina propria and the echogenic submucosa. Lymphoid hyperplasia of the appendix results in discrete thickening of the lamina propria [15], which often effaces the submucosal layer. Of note is the fact that isolated thickening of the lamina propria is a finding histologically associated with lymphoid hyperplasia and not appendicitis. Our data indicate that thickening of the lamina propria is indeed associated with significantly increased sonographic false-positive diagnoses of appendicitis in patients with 6- to 8-mm appendiceal maximum outer diameters; the false-positive rate for pediatric patients was 81.5% when lymphoid hyperplasia was present and 50.9% when it was absent, confirming the original hypothesis. lthough adults showed similar findings, the adult group was small and their findings were not statistically significant. ecause the mean maximum outer diameter was not greater among patients with a thickened lamina propria than it was among those without, we speculate that reduced compliance conferred by lymphoid hyperplasia may be the dominant factor leading to false-positive diagnoses. Concomitant appendicitis was present only infrequently among patients with lymphoid hyperplasia, affecting 16.1% of patients in our entire sample and 18.5% of pediatric patients in particular. These patients were not distinguishable from those without appendicitis on the basis of their maximum outer diameters. Fortunately, these individuals were distinguishable at a highly significant level on the basis of their having at least two additional sonographic findings from the group of periappendiceal fluid, hyperechoic periappendiceal fat, and mural hyperemia. ccordingly, a practical approach to the appendiceal sonogram showing lymphoid hyperplasia would be to first note whether the individual is a pediatric patient, as is usually the case. If so, the risk of appendicitis is low, and a specific search for periappendiceal fluid, hyperechoic periappendiceal fat, and mural hyperemia is in order; the presence of at least two of these findings is associated with a high likelihood of appendicitis. Radiologists unfamiliar with lymphoid hyperplasia may misinterpret its appearance as appendicitis. Of 26 patients in our sample who had lymphoid hyperplasia rather than appendicitis on retrospective review of their sonograms, the original sonography reports for 19 specified appendicitis or findings at least equivocal for appendicitis, and 10 of these patients subsequently underwent appendectomy with negative findings or additional imaging with CT. We speculate that knowledge of lymphoid hyperplasia and its sonographic appearance may have reduced these misdiagnoses. number of limitations deserve mention with respect to this study. We considered appendixes positive for appendicitis when they were noncompressible and met or exceeded the conventional published maximum outer diameter criterion of 6 mm [3, 6 14]. Other authors, however, have proposed that additional criteria be required, such as periappendiceal inflammatory infiltration [27], periappendiceal fat infiltration [28], or mural hyperemia [29], or that a larger threshold maximum outer diameter of 7 mm be used [14]. Had we used different diagnostic criteria, our results might have been different; however, the 6-mm threshold is in wide use and has been termed the traditionally accepted criterion for the diagnosis of appendicitis [14]. The lamina propria was considered thickened when it met or exceeded 1.0 mm on short-axis views; had a different criterion been used, our results might have been different. t our institution, the need for imaging for specific patients and decisions regarding surgical intervention are determined by clinical colleagues in the Departments of Surgery and Emergency Medicine; decisions made at other institutions might differ. The focus of our study was on lymphoid hyperplasia and its contribution to incorrect positive diagnoses; we are not aware of ways in which lymphoid hyperplasia might similarly JR:206, January

6 Xu et al. contribute to false-negative diagnoses and, thus, did not address this issue. In summary, lymphoid hyperplasia involving the appendix has a characteristic sonographic appearance, producing thickening of the hypoechoic lamina propria. It is a relatively common finding, seen in roughly one quarter of our patients with noncompressible 6- to 8-mm appendixes, of whom 87.1% were pediatric patients. It is associated with statistically significantly increased false-positive diagnoses of appendicitis on graded-compression sonography. In the absence of two or more additional signs of appendicitis on sonography (i.e., periappendiceal fluid, hyperechoic periappendiceal fat, or mural hyperemia), patients with appendiceal lymphoid hyperplasia and 6- to 8-mm maximum outer diameters have a low likelihood of appendicitis and, therefore, should be managed conservatively. 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