Is Pneumatosis Cystoides Intestinalis Gas-Distended and Ruptured Lymphatics? Reappraisal by Immunohistochemistry Xianyong Gui, MD; Yi Zhou, MD; Leslie Eidus, MD; Vincent Falck, MD; Zu-hua Gao, MD; Lihui Qin, MD  Context.—Pneumatosis cystoides intestinalis (PCI) is a condition with multiple gas-filled cysts within the bowel wall, associated with diverse background diseases. Its pathogenesis is still a mystery. Some previous observations scattered in the literature have suggested an association of the cystic spaces in PCI with the lymphatics. Objective.—To further investigate whether PCI results from the ballooning of gas-filled lymphatic channels. Design.—We did immunostaining of podoplanin, a mucoprotein preferentially expressed in lymphatic endo- thelial cells, in 13 cases (8 men, 5 women; age range, 18– 80 years) of PCI. Ten cases were diagnosed in resected segments of bowel and 3 in biopsies. Pneumatosis was seen in the right side of the colon (9 cases), transverse colon (1 case), sigmoid colon (1 case), and small bowel (2 cases). In addition, immunostaining for CD31, calretinin, WT1, CD68, smooth muscle actin, desmin, vimentin, and cytokeratins was also performed for comparison and correlation. Results.—A strong immunopositivity of podoplanin was seen in a condensed linear structure in the pericystic interstitium in 100% of the cases, but was not seen in the overlying giant and flat cells that were all CD68-positive histiocytes. Meanwhile, the podoplanin-expressing struc- ture was negative for calretinin and WT1, which ruled out the possible mesothelial origin. There were coexistent variable immunopositivity of smooth muscle actin, which suggests an admixture of myofibroblasts. These findings indicated that the PCI cases were gas-distended lymphatics with the lymphatic epithelium ruptured and embedded in the reactive histiocytes and giant cells. Conclusion.—Our findings support the lymphatic theory about the pathogenesis of PCI. (Arch Pathol Lab Med. 2014;138:1059–1066; doi: 10.5858/arpa.2013-0145-OA) P neumatosis cystoides intestinalis (PCI), also termed pneumatosis intestinalis, pneumatosis coli (when oc- curring in colon only), and several other uncommon names in the literature, is a rare condition characterized by multiple gas-filled cystic spaces within the bowel wall. It was first described by Du Vernoi 1 in 1783 and later documented in more detail by Bang 2 in 1876. Pneumatosis cystoides intestinalis is associated with a large variety of diseases and clinical conditions in which the loss of bowel mucosal integrity and/or luminal high pressure usually occur. Pneumatosis cystoides intestinalis per se is mostly asymp- tomatic. A spectrum of possible manifestations, usually related to the underlying pathologic conditions, includes vomiting, abdominal distention, abdominal pain, diarrhea, bloody stool, constipation, and tenesmus. These days, PCI is often identified incidentally on radiologic imaging or on pathologic examination. The etiology and pathogenesis of PCI have been a mystery. Several theories have been proposed based on different observations, including (1) luminal gas penetrat- ing the bowel mucosa into the bowel wall following mucosal injury, 3–5 (2) pulmonary gas released from the ruptured alveoli dissecting along vascular channels in mediastinum and tracking through the retroperitoneum into the mesenteric root, 6,7 (3) gas production of some bacteria that invades through the mucosal breaches into the intramural compartments and/or grows within the microscopic cysts, 8 and (4) gas production related to defects in food digestion causing excessive fermentation. 9 In addition, a suggestion that the cystic spaces in PCI are dilated lymphatic vessels has been lingering in literature. In the early days, this condition was also termed lymphop- neumatosis cystoides intestinalis or cystic lymphopneu- matosis based purely on assumption. In an experiment conducted half a century ago, Staudacher and Bencini 10 injected a dyed fluid into the lymphatics of hogs and demonstrated that the distended lymphatics formed cystic spaces. Some investigators also noticed a spatial relation- Accepted for publication September 30, 2013. From the Department of Pathology and Laboratory Medicine, University of Calgary, Calgary Laboratory Services, Calgary, Alberta, Canada (Drs Gui, Eidus, and Falck); the Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (Dr Zhou); the Department of Pathology, McGill University, Montreal, Montreal, Quebec, Canada (Dr Gao); and the Department of Pathology, Weill Cornell Medical College, Cornell University, New York, New York (Dr Qin). The authors have no relevant financial interest in the products or companies described in this article. Reprints: Xianyong Gui, MD, Department of Pathology, Foothills Medical Centre, Main Bldg, 11th Floor, Room 1137A, 1403 29 St NW, Calgary, AB, Canada T2N 2T9 (e-mail: xsean.gui@cls.ab.ca). Arch Pathol Lab Med—Vol 138, August 2014 Pneumatosis Intestinalis and Lymphatics—Gui et al 1059