Lymphangiomatous Lesions of the Gastrointestinal Tract. A Clinicopathologic Study and Comparison Between Adults and Children

AJCP / Original Article Lymphangiomatous Lesions of the Gastrointestinal Tract A Clinicopathologic Study and Comparison Between Adults and Children Margaret E. Lawless, MD, Kelly A. Lloyd, MD, Paul E. Swanson, MD, Melissa P. Upton, MD, and Matthew M. Yeh, MD, PhD From the Department of Pathology, University of Washington School of Medicine, Seattle. Key Words: Lymphangioma; Lymphangiectasia; Gastrointestinal tract; Adults; Children Am J Clin Pathol October 2015;144:563-569 ABSTRACT Objectives: Lymphangiomatous lesions involving the gastrointestinal (GI) tract remain incompletely characterized, and their clinical and histopathologic features have not been systematically evaluated. The distinction between a primary lymphatic malformation (lymphangioma) and a dilation of existing lymphatics (lymphangiectasia) is of clinical significance, since lymphangiectasia may occur in the setting of lymphatic obstruction due to an unsampled malignancy. We describe clinical and morphologic features of lymphangiomas of the GI tract in adult and pediatric populations and contrast them with lymphangiectasia. Methods: We performed a retrospective review of adult and pediatric lymphangiomas and lymphangiectasia involving the GI tract. Results: Thirty-six cases of lymphangioma and lymphangiectasia were retrieved, and clinical presentation and histologic features were compared. Lymphangiomas had distinct clinical presentations in adults and children, with adult lesions being more frequently asymptomatic and more frequently involving the superficial mucosal layers of the GI tract. Microscopically, lymphangiomas mostly consisted of confluent dilated spaces with a smooth muscle component. This appearance differed from lymphangiectasia, which lacked a complete distinct endothelial or smooth muscle lining and diffusely involved the mucosa and submucosa. Conclusions: Morphologic features of GI tract lymphangiomas can be reliably distinguished from lymphangiectasia by clinical and pathologic characteristics. Lymphangiomas are benign tumors formed by dilated lymphatic channels that occur most commonly in the head and neck or axillary region. 1-3 Gastrointestinal involvement, once thought to be rare, 4,5 is now more frequently recognized as increasing numbers of patients undergo endoscopic evaluations of the gastrointestinal tract. The prevailing histogenetic hypothesis is that lymphangiomas represent benign congenital malformations of lymphatic vasculature that form mass lesions that may enlarge and become obscured by inflammation or reactive changes. 6,7 By endoscopic examination, these lesions typically present as small incidental polyps; however, some of these tumors present as mass lesions capable of causing bowel obstruction, abdominal pain, and gastrointestinal bleeding. 8-12 Because of their intra-abdominal location, they may remain undetected until adulthood. In contrast, intestinal lymphangiectasia is defined as dilation of existing mucosal, submucosal, or subserosal lymphatics within the gastrointestinal tract. 13 In adults, it can be seen in association with Waldenström macroglobulinemia, sarcoidosis, mass-forming intestinal malignancy, and other inflammatory conditions, and it may result in protein-losing enteropathy or occult gastrointestinal bleeding. 14-16 However, lymphangiectasia is most frequently asymptomatic and has been reported as an incidental finding in 1.9% of adult patients undergoing endoscopy 17 and may be transient. 18 Morphologic criteria to distinguish lymphangiomas from intestinal lymphangiectasias have not been previously defined, and although clinical characteristics (such as concurrent medical conditions and endoscopic appearance) may point toward a particular diagnosis, the histologic features of lymphangiomas and intestinal lymphangiectasia in adult Am J Clin Pathol 2015;144:563-569 563

Lawless et al / Lymphangiomatous Lesions of the GI Tract Table 1 Pediatric Lymphangiomas: Clinical and Histologic Characteristics Age Sex Primary Site Clinical Presentation Size, cm Confluent vs 4 mo M Jejunum Incidental lesion in small bowel resection for necrotizing enterocolitis 0.6 8 mo M Mesentery Vomiting, bowel obstruction 3 Confluent 1.5 y F Jejunum Small bowel obstruction 12.4 Confluent 3 y F Jejunum Chronic abdominal pain 7.5 Confluent 4 y M Mesentery Acute abdominal pain 3.5 Confluent 4 y F Mesentery Acute abdominal pain 1.2 Confluent 5 y M Jejunum Palpable abdominal mass 2.7 Confluent 5 y F Mesentery Acute abdominal pain 12.4 Confluent 5 y F Retroperitoneal Acute abdominal pain 7 Confluent 6 y M Retroperitoneal Acute abdominal pain 6.2 Confluent 7 y M Mesentery Acute abdominal pain 11 Confluent 12 y F Mesentery Palpable abdominal mass 1.2 % of positive findings, present;, absent. Table 2 Adult Lymphangiomas: Clinical and Histologic Characteristics Age, y Sex Primary Site Clinical Presentation Endoscopic Appearance 38 M GE junction Longstanding history of GE reflux, melena Irregular z-line, mucosal erythema 41 F Jejunum Abdominal pain and bloating 1 year Submucosal mass 54 M Proximal stomach Incidental lesion in resection for esophageal adenocarcinoma NA 54 F Jejunum Melena Polyp 55 F Ileocecal valve Positive fecal occult blood test Polyp 61 F Jejunum Incidental subserosal small bowel nodule discovered during NA exploratory laparotomy 63 F Sigmoid colon Screening colonoscopy Polyp 71 M Duodenum Abdominal pain Polypoid pink-tan mass 78 M Ileocecal valve Screening colonoscopy Polyp 79 F Duodenum Small bowel obstruction/ileus Submucosal mass % of positive findings GE, gastroesophageal; NA, not available;, present;, absent. and pediatric populations have yet to be contrasted in detail. Furthermore, most of the studies to date describing the clinicopathologic features of intra-abdominal lymphangiomas have been limited to cases requiring surgical resection and thus have not included smaller incidental or endoscopically detected lesions. The aim of this study is to define the clinical and morphologic characteristics of gastrointestinal tract lymphangiomas within adult and pediatric cohorts based on a more broadly inclusive set of surgically and endoscopically evaluated lesions and contrast those morphologic features with intestinal lymphangiectasia. the abdomen and included portions of the gastrointestinal tract. Clinical data (age, sex, significant medical history, presenting symptoms), endoscopic findings, and histologic features were compiled and reviewed. The diagnoses of lymphangioma and lymphangiectasia were rendered using previously described morphologic descriptions 1,2 and were correlated with clinical history and relevant follow-up. This study was performed in compliance with relevant and institutional guidelines. Results Materials and Methods We conducted a retrospective review at the University of Washington Medical Center and Seattle Children s Hospital to identify cases of lymphangioma or lymphangiectasias diagnosed between 1982 and 2012 that involved Demographics and Clinical Characteristics The demographic and clinical attributes of all cases are summarized in Table 1, Table 2, and Table 3. A total of 36 specimens were identified, including 12 pediatric lymphangiomas (all resections), 10 adult lymphangiomas (four 564 Am J Clin Pathol 2015;144:563-569

AJCP / Original Article Submucosal Mucosal Complete Endothelial Lining Smooth Muscle Component Lymphoid Tissue Foam Cells 50 8 100 100 67 25 67 Intraluminal Proteinaceous Fluid Size, cm Confluent vs Submucosal Mucosal Complete Endothelial Lining Smooth Muscle Component Lymphoid Tissue Foam Cells 0.3 2.5 Confluent 0.5 Confluent 1.1 Confluent 0.7 Confluent 0.5 Confluent 0.6 Confluent 0.4 Confluent 0.2 Confluent 1.2 Confluent 90 50 100 100 10 0 100 Intraluminal Proteinaceous Fluid resections and six biopsy specimens), and 14 adult lymphangiectasias (all biopsy specimens). Sex distribution was equal in the pediatric lymphangioma group (male/female, 6:6), whereas females predominated in the adult lymphangioma and lymphangiectasia groups (male/female, 4:6 and 4:10, respectively). The median patient ages for pediatric lymphangiomas, adult lymphangiomas, and adult lymphangiectasia were 4.5 (range, 0.3-12) years, 58 (range, 38-79) years, and 58 (range, 40-89) years, respectively. Pediatric lymphangiomas were most commonly discovered in previously healthy children, with the exception of one patient who underwent a small bowel resection for necrotizing enterocolitis. The most common presentation was acute abdominal pain (n = 6). Less commonly, children had bowel obstruction (n = 2) or a palpable abdominal mass and/or increasing abdominal girth (n = 2). Adult lymphangiomas were most commonly discovered incidentally during procedures performed for other indications, including colonoscopy for gross or occult gastrointestinal bleeding (n = 3) and screening colonoscopy (n = 2). A minority of adult patients experienced symptoms that could be attributed to their lymphangiomas (n = 2); one patient had a 1-year history of abdominal pain and bloating, and one experienced acute abdominal pain due to small bowel obstruction by the lymphangioma. Adult patients with lymphangiectasia had a variety of symptoms prior to endoscopic investigation. Seven patients had separate lesions in the proximity of the sampled mucosa that could plausibly result in secondary lymphangiectasia due to lymphatic obstruction; malignancy was identified in two of these cases. One patient carried a diagnosis of Waldenström disease and had experienced large-volume diarrhea. This patient had a serum albumin level of 1.6 g/dl (reference, 3.5-4.9 g/dl), and white villi were observed throughout the ileum on lower endoscopy. Lymphangiectasia was identified on screening colonoscopy in two patients who were otherwise healthy and had no significant findings on subsequent colonoscopy. Am J Clin Pathol 2015;144:563-569 565

Lawless et al / Lymphangiomatous Lesions of the GI Tract Table 3 Lymphangiectasia: Clinical and Histologic Characteristics Age, y Sex Primary Site Clinical Presentation Endoscopic Appearance 40 F Terminal ileum Large-volume diarrhea White villi 45 M Rectum Bright red blood per rectum Diminutive polyp 52 F Ileocecal valve Screening colonoscopy Polyp 52 F Rectum Screening colonoscopy Polyp 54 F Duodenum Constipation Luminal narrowing 55 F Duodenum Postprandial vomiting Flattened folds 58 F Duodenum Diarrhea White plaque 58 M Jejunum Dyspepsia White plaque 60 F Jejunum Anemia White plaque with prominent folds 65 M Duodenum Anemia Dilated lacteals 71 F Duodenum Anemia Two diminutive polyps 73 M Duodenum Nausea and vomiting Abrupt narrowing 74 F Jejunum Nausea and vomiting Polyp 89 F Jejunum Anemia Yellowish nodules (<4 mm) % of positive findings, present;, absent. The mean size of pediatric lymphangiomas was 5.7 (median, 4.85; range, 0.6-12.4) cm, and primary sites were mesentery (n = 6), small bowel (n = 4), or retroperitoneum (n = 2). The mean size of adult lymphangiomas was 0.8 (median, 0.55; range, 0.2-2.5) cm, and primary sites were small bowel (n = 7), stomach (n = 2), and sigmoid colon (n = 1), typically appearing as polypoid mucosal or submucosal lesions on endoscopy. Pediatric lymphangiomas were significantly larger than their adult counterparts (P =.003). Lymphangiectasia was identified in the small bowel (n = 12) and rectosigmoid colon (n = 2) and most often appeared as whitish plaques on endoscopy, although there were five instances when the endoscopic appearance was polypoid. Microscopic Features A number of microscopic features were evaluated and are highlighted in Tables 1, 2, and 3. The distribution of lymphatic channels within the mucosal and/or submucosal compartments was recorded. The lymphatic spaces were further characterized as either diffuse, widely spaced proliferations or confluent, discrete masses. Half of pediatric lymphangiomas occupied the submucosa, and only one involved the mucosa. Adult lymphangiomas did not have a characteristic pattern of distribution. of both mucosa and submucosa was seen almost uniformly in all cases of lymphangiectasia, with one exception of a polypoid lesion at the anal verge that was confined to the mucosa. All adult and pediatric lymphangiomas contained anastomosing dilated spaces with complete endothelial lining and at least partial investment by smooth muscle. In contrast, cases of lymphangiectasias generally lacked a complete endothelial lining or smooth muscle component, and lymphatic spaces were more widely spaced throughout the mucosa and submucosa. When Image 1 Pediatric lymphangioma: large submucosal space lined by flat endothelial lining and smooth muscle with associated lymphoid tissue, intraluminal proteinaceous fluid, and foam cells (H&E, 10). visualized, the endothelium was relatively thin and attenuated compared with that of lymphangiomas. Prominent lymphoid tissue Image 1 was associated with the lymphatic spaces in all cases of pediatric lymphangioma but was absent in all cases of lymphangiectasia and all but two of the adult lymphangiomas. Intraluminal proteinaceous fluid was seen in all cases of adult lymphangioma Image 2 and most cases of lymphangiectasia Image 3 and pediatric lymphangioma. Foam cells were present within lymphatic channels only in pediatric lymphangiomas (Image 1). Generally, foam cells were few in number and observed at the periphery of intact lymphatic spaces, accompanied by 566 Am J Clin Pathol 2015;144:563-569

AJCP / Original Article vs Confluent Submucosal Mucosal Complete Endothelial Lining Smooth Muscle Lymphoid Tissue Foam Cells Intraluminal Proteinaceous Fluid 93 100 7 7 7 0 64 Image 2 Adult lymphangioma: mucosal and submucosal collection of endothelial and smooth musclelined spaces containing intraluminal proteinaceous fluid (H&E, 4). Image 3 Lymphangiectasia: scattered dilated mucosal and submucosal spaces containing intraluminal proteinaceous fluid (H&E, 10). intraluminal proteinaceous fluid. Neutrophilic inflammation was not observed in any of the cases within the series. tract, the clinical presentations of gastrointestinal lesions are myriad, ranging from asymptomatic adenoma-like polypoid lesions to large obstructing masses.4-10,19-22 Accurate preoperative diagnosis of intra-abdominal lymphangioma is uncommon, particularly in adult patients,6,10,12 and the characteristics of smaller asymptomatic lesions in adults have not been well described in the literature. The diagnosis of lymphangioma is further complicated by histologic overlap with lymphangiectasia of the gastrointestinal mucosa. The latter is of particular clinical relevance to endoscopic mucosal biopsy interpretation when it is not immediately clear if the sampled tissue represents the primary lesion Discussion Lymphangiomas typically occur in the head and neck or axillary areas during childhood and are thought to represent congenital malformations of lymphatic spaces that form early in life.1-3 They may acquire secondary changes from inflammation, fibrosis, or obstruction of lymphatic spaces.6 Although they less commonly involve the gastrointestinal Am J Clin Pathol 2015;144:563-569 567

Lawless et al / Lymphangiomatous Lesions of the GI Tract Image 4 Small bowel follow-through study with 5-cm lobular jejunal lymphangioma (arrows). Imaging courtesy of Joel E. Lichtenstein, MD, Department of Radiology, University of Washington. Image 5 Gross representation of focal 5-cm lymphangioma in the jejunum. (lymphangioma) or obstructive lymphangiectasia in the vicinity of an unsampled malignant neoplasm. The most reliable histologic features distinguishing lymphangioma from lymphangiectasia in this series were the presence of smooth muscle surrounding the lymphatic spaces and complete circumferential lining of spaces by endothelial-type cells. Most cases of lymphangiectasia lacked a complete endothelial lining and/or investing smooth muscle component. One of the classic histologic elements of lymphangioma (which reliably distinguishes it from other cystic neoplasms in the abdomen, including hemangioma and mesothelial cysts) is dense lymphoid aggregates. 1 While most of the pediatric lymphangiomas exhibited this pattern, it was present in only a minority of adult lymphangiomas. These findings suggest that these lesions are associated with a more exuberant immune reaction in the pediatric population, although the contribution of lesion size, mass effect, and continuity with the surrounding lymphatics should be considered. It is interesting that foam cells were unique to the pediatric population in this study (although others have described foam cells in adult lymphangiomas as well). 6 The clinical presentation of pediatric lymphangiomas differed from that of adult lymphangiomas with respect to size and distribution; pediatric lymphangiomas were significantly larger, more commonly involved mesentery, and most frequently presented with acute abdomen and bowel obstruction. Adult lymphangiomas were, for the most part, incidental mucosal polyps, although a case presenting as a mass lesion was included in this series Image 4 and Image 5. We recognize that there is an element of sampling bias, since children are not subjected to endoscopic cancer screening (minimizing opportunities for detection of incidental mucosal involvement), and clinical protocols for workup of gastrointestinal symptoms differ between children and adults. Nevertheless, the tendency for mesenteric lymphangiomas to be larger and present in childhood and smaller mucosal lymphangiomas to present in adulthood has been described previously. 12 Selected studies suggest that intraabdominal lymphangiomas predominate in males in pediatric patients, 5,8,23 while others note a female predominance in adult cohorts, 10 raising questions of true sex distribution in these lesions and whether lymphangiomas, like other cystic lesions such as hemangiomas and hepatic cysts, may exhibit growth in response to circulating estrogens. Although we did also observe a slight female predominance in the adult lymphangioma group, there was no significant relationship between tumor size and sex in either the pediatric or adult lymphangioma groups (P =.26 and.15, respectively). Recently, Handra-Luca and Montgomery 24 described an entity, hemangiolymphangioma, as a proliferation of varied vessel types (lymphatics, capillaries, veins); almost all were located in both the submucosa and the mucosa, whereas in our study, half of pediatric lymphangiomas occupied the submucosa and only one involved the mucosa. Adult lymphangiomas did not have a characteristic pattern of distribution. In our series, intraluminal proteinaceous fluid was seen in all cases of adult lymphangioma and most cases of lymphangiectasia and pediatric lymphangioma, which was not described by Handra-Luca and Montgomery. 24 Most of our lymphangioma 568 Am J Clin Pathol 2015;144:563-569

AJCP / Original Article cases also consisted of confluent dilated spaces with a surrounding smooth muscle component and prominent lymphoid tissue, especially in the pediatric cases, but these were also not described by Handra-Luca and Montgomery. 24 Hemorrhage and thrombosis were noted in their article but not observed in our study. Based on these different findings, the lymphangiomas in our series do not appear similar to the hemangiolymphangiomas described by Handra-Luca and Montgomery, 24 suggesting they represent two different lesions. In conclusion, this series better characterizes lymphangiomas involving the gastrointestinal tract as discrete masses with anastomosing and distinct lymphatic spaces. In pediatric patients, lymphangiomas are mesentery based, are large, and present with obstruction, whereas in adult patients, they range from incidental polyps to mass lesions within the bowel. Histologically, pediatric and adult lymphangiomas are similar, consisting of dilated cystic spaces with associated smooth muscle and endothelial lining, although the presence of abundant lymphoid tissue and foam cells appears to distinguish pediatric from adult forms. Intestinal lymphangiectasia consists of more widely spaced mucosal and submucosal cystic spaces that lack both a smooth muscle and (to varying extents) a prominent endothelial lining. The distinction of lymphangiectasia from lymphangioma may be of significant clinical implication, since lymphangiectasia may indicate the presence of an unsampled mass lesion or concurrent medical condition that requires medical attention. Future studies, including immunohistochemistry, to further define the histologic differences between adult/pediatric lymphangiomas and intestinal lymphangiectasia are warranted. Corresponding author: Matthew M. Yeh, MD, PhD, Dept. of Pathology, University of Washington School of Medicine, 1959 NE Pacific St, NE140D, Box 356100, Seattle, WA 98195; myeh@uw.edu. Acknowledgment: We thank Raj P. Kapur, MD, PhD, Seattle Children s Hospital and Department of Pathology, University of Washington, for his contribution of cases and critical comments in this manuscript. References 1. Weiss SW, Goldblum JR, Enzinger FM. Enzinger and Weiss s Soft Tissue Tumors. 5th ed. Philadelphia, PA: Mosby Elsevier; 2008. 2. Fenoglio-Preiser CM, Pascal RR, Perzin K. Tumors of the Intestines. Washington, DC: Armed Forces Institute of Pathology under the auspices of Universities Associated for Research and Education in Pathology; 1990. 3. Alqahtani A, Nguyen LT, Flageole H, et al. 25 years experience with lymphangiomas in children. J Pediatr Surg. 1999;34:1164-1168. 4. Girdwood TG, Philp LD. Lymphatic cysts of the colon. Gut. 1971;12:933-935. 5. Steyaert H, Guitard J, Moscovici J, et al. 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