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Mesenteric panniculitis: an update Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Nyu Medical Center on 02/03/15 For personal use only.
Expert Rev. Gastroenterol. Hepatol. 9(1), 67–78 (2015)
Mahmoud Rezk Abdelwahed Hussein*1 and Saad Rezk Abdelwahed2,3 1 Department of Pathology, Faculty of Medicine, Assuit University, Assuit, Egypt 2 Department of Radiology, Faculty of Medicine, AL-Azhar University, Assuit, Egypt 3 AL-Azhar University Hospitals, AL-Azhar University, Assuit, Egypt *Author for correspondence: Tel.: +20 935 3166 Fax: +20 883 73727 [email protected]
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In 1924, mesenteric panniculitis was first described in the medical literature by Jura et al. as ‘retractile mesenteritis.’ It represents a spectrum of disease processes characterized by degeneration, inflammation and scarring of the adipose tissue of the mesentery. The clinical presentations vary according to the stage of the disease and they include abdominal pain, weight loss, nausea and vomiting. Computed tomography findings are usually diagnostic. The gross findings include thickening of the mesentery, mass lesions and adhesion to the surrounding organs. Histologically, there is a chronic inflammatory process involving the adipose tissue with fat necrosis, inflammation and fibrosis. Herein, the authors address the clinicopathological features, course, treatment and pathogenetic mechanisms of mesenteric panniculitis. KEYWORDS: inflammation • mesenteric • mesentery • panniculitis • sigmoid • small bowel
The mesentery is a reflection of the peritoneum on the bowel surface that supports and attaches the intestine to the wall of the abdomen. It is a fold of tissue lined by two parallel layers within which lymph nodes, nerves, mesenteric blood vessels and lymphatics are entangled [1]. Mesenteric panniculitis was first identified by Jura back in 1924 [2]. It is a fibroinflammatory condition of uncertain etiology. Other synonyms for mesenteric panniculitis include Pfeiffer–Weber–Christian disease, xanthogranulomatous mesenteritis, mesenteric lipodystrophy, retractile mesenteritis, sclerosing mesenteritis, liposclerotic mesenteritis, lipomatosis and lipogranuloma of the mesentery [3–7]. It occurs usually in late adult life (23–87 years, with an average age of 60 years). Either sex may be affected, although there is a higher incidence in males [8]. It is characterized by nonspecific inflammation, necrosis and fibrosis of the adipose tissue. It usually involves the mesentery of the small bowel, appendix, mesoappendix and, less frequently, the sigmoid colon or other intraabdominal fatty tissue [9]. Several large series have been published about mesenteric panniculitis [5,8,10–12]. Durst et al. reviewed 62 cases of mesenteric panniculitis collected from the literature and six cases treated by the authors. They indicated that mesenteric panniculitis is a distinct clinical entity of unknown etiology, with a benign course and a favorable outcome. In their series, 10.1586/17474124.2014.939632
radical surgical treatment was suggested in patients with intestinal obstruction [11]. Emory et al. reviewed 84 cases of mesenteric lipodystrophy, mesenteric panniculitis and sclerosing mesenteritis. There was no sex or racial predominance. The average age was 60 years. Abdominal pain or masses were common presentations. A history of trauma or surgery was found in four of 84 patients. The most common site of involvement was the small bowel mesentery as a single mass (58 of 84), multiple masses (15 of 84) or diffuse mesenteric thickening (11 of 84) [8]. In another large case series, a history of abdominal surgery (cholecystectomy or appendicectomy) was noted in about 40% of the patients [5,12]. At the biochemical level, the fatty tissue obtained from patients with mesenteric panniculitis usually contains significant amounts of cholesteryl esters, in addition to 0.5–1.3% free cholesterol, 0.9–1.9% free fatty acids, 0.6–2.5% l-alkyl glyceryl ether diesters, squalene and alkl-enyl glyceryl ether diesters [13]. Clinical features of mesenteric panniculitis
Patients with mesenteric panniculitis may be asymptomatic or may present with abdominal discomfort, fever, nausea, vomiting, diarrhea and constipation [14,15]. Other presentations include fever of unknown origin [16,17], weight loss [18], shaking chills [19], features of Crohn’s
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Table 1. Clinical presentations of mesenteric panniculitis.
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Clinical presentations General symptoms • Weakness, fever of unknown origin and chills Gastrointestinal symptoms • Abdominal pain, bloating, anorexia, nausea, vomiting, early satiety, weight loss, intestinal obstruction and abdominal masses and palpitations near the abdominal area Differential diagnosis • Abdominal neoplasms (colorectal carcinoma, lymphoma, liposarcoma, lipoma, peritoneal carcinomatosis, carcinoid tumor, peritoneal mesothelioma desmoid tumor and gastrointestinal stromal tumor), retroperitoneal fibrosis and mesenteric inflammatory pseudotumor and mesenteric fibromatosis
Ref. [14–24]
Mesenteric panniculitis, IgG4-related disease [31]
disease [20], chylous ascites [21], Schonlein–Henoch disease [22] and multiple mesenteric lymphatic cysts [23]. The abdominal examination may reveal poorly defined abdominal mass or masses [24]. Goh et al. reported a case of mesenteric panniculitis in a 43-year-old male who presented with malaise, weight loss, microcytic anemia and a high erythrocyte sedimentation rate. There was initial and rapid resolution of the condition with high-dose oral prednisolone therapy. The patient presented with features of myeloma within 6 months (anemia, renal failure and hypercalcemia) and died later on from refractory pulmonary edema [25]. Schwery et al. reported a case of mesenteric panniculitis in a 70-year-old patient with a 6 6 12 cm mass involving the mesenteric root. The patient presented with abdominal pain and weight loss. On laparoscopic biopsy, there was infiltration of the mesentery by foamy lipid-laden macrophages, clusters of lymphocytes and fibrosis [26]. Mesenteric panniculitis associated with extensive fibrosis (retractile mesenteritis) may be associated with shortening of the mesentery and compression of the mesenteric vessels. Patients may present with manifestations of intestinal obstruction or vascular compression [26–28]. Bala et al. reported a case of sclerosing (idiopathic) mesenteritis in a 21-year-old man. The patient presented with abdominal pain and bowel obstruction. A partial ileal resection and a defunctioning ileostomy were performed. Subsequent therapy included steroids and azathioprine. The patient became disease-free after 5 months [29]. Carnicer Jauregui et al. reported the case of a 35-year-old female who presented with a paraneoplastic syndrome, abdominal pain, ascites, cachexia, anemia and high sedimentation of 1-year duration. The clinical impression was that of lymphoma. Radiological findings include loop distention (x-ray), ascites and mesenteric thickening (computed tomography findings). Laparotomy revealed retroperitoneal fibrosis and on histology, there was substantial collagen deposition and inflammatory infiltrate, together with giant cells of foreign body type [30]. 68
The clinical differential diagnosis of mesenteric panniculitis includes abdominal neoplasms (colorectal carcinoma, lymphoma, liposarcoma, lipoma, peritoneal carcinomatosis, carcinoid tumor, desmoid tumor and gastrointestinal stromal tumor), retroperitoneal fibrosis, mesenteric inflammatory pseudotumor and mesenteric fibromatosis [31]. A summary of the clinical presentations is shown in TABLE 1.
IgG4-related disease is a fibroinflammatory condition characterized by a tendency to form tumor-like lesions at multiple sites, a characteristic histopathological appearance (tissue infiltration by many IgG4-positive plasma cells, fibrosis and obliterative phlebitis) and high serum IgG4 levels [32]. It was initially reported in the pancreas (autoimmune pancreatitis), but is now recognized in a number of conditions such as pancreatic cancer, atopic dermatitis, vasculitis and biliary tract disease. Of note, IgG4-related disease is also observed in about 5% of the normal population [33]. The histological diagnosis of IgG4-related disease requires the presence of two of the three major histological features. In most cases, these include a dense lymphoplasmacytic infiltrate and storiform-type fibrosis [32]. Although the constellation of the histological and immunohistochemical findings support the diagnosis of IgG4-related disease, correlation with the clinical and radiological findings is important for definitive opinion [32]. In sclerosing mesenteritis, some tumefactive lesions are characterized by the presence of a diffuse infiltration by IgG4-positive plasma cells. These lesions are considered to be a part of the spectrum of IgG4-related disease. Minato et al. reported a case of sclerosing mesenteritis in a 53-year-old man with an ileocecal ill-defined mass and manifestations of IgG4-related disease. Intraoperatively, there was an ileocecal ill-defined fibroinflammatory mass that involved the mesentery. Histologically, there was storiform fibrosis, obliterative phlebitis and infiltration of the adipose tissue by many IgG4-positive plasma cells. The ratio of IgG4-positive/IgG-positive cells was 64% and the ratio of forkhead box protein 3-positive/CD4-positive cells was elevated (13%). The authors indicated that at least some cases of sclerosing mesenteritis are manifestations of IgG4-related disease [34]. Similarly, Kim et al. reported a case of IgG4-related sclerosing mesenteritis in a 45-year-old woman who presented with weight loss and lower abdominal discomfort. The radiological findings included a mass lesion in the abdominal wall and the pelvis, a 5.9-cm-sized wall-enhancing mass with heterogeneous signal intensity from the right adnexa to the abdominal wall. Surgical resection, appendectomy and adhesiolysis were performed due to the presence of severe adhesions. On histology, the mass lesion consisted of inflammatory infiltrate with dense IgG4-positive plasma cells, a feature of IgG4-related sclerosing mesenteritis. Later on, the patient was diagnosed with Crohn’s disease on colonoscopy [35,36]. Expert Rev. Gastroenterol. Hepatol. 9(1), (2015)
Mesenteric panniculitis
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Mesenteric panniculitis, cancer & autoimmune diseases
Mesenteric panniculitis may be associated with several neoplasms. In most cases, these tumors are discovered before the diagnosis of mesenteric panniculitis. They include carcinomas (breast, colorectal, gynecological, renal and gastric cancers) and hematological malignancies (non-Hodgkin’s lymphomas and plasma cell tumors) [25,37–41]. The prevalence of tumors varies among different studies. Kipfer et al. found that 30% of patients with sclerosing mesenteritis had an underlying malignancy [10]. Wilkes et al. examined the prevalence of malignancy in 118 patients with computed tomography findings of mesenteric panniculitis. Malignant tumors were noted in 45 patients and included colorectal cancer (14 patients), lymphoma (13 patients) and cancers of the urogenital tract (7 patients). The lymph node size of >12 mm together with the absence of the fat ring sign were good predictors of the subsequent diagnosis of malignancy in patients with mesenteric panniculitis. In most cases, malignancy was diagnosed before mesenteric panniculitis [41]. Joerger et al. screened 120 patients who were treated for non-Hodgkin’s lymphoma for the presence of mesenteric changes. They were defined on computed tomography as nodular or diffuse infiltration of the abdominal mesentery with increased density of the mesenteric fat. The authors found 21 patients with radiological findings of mesenteric changes, such as mesenteric lymphadenopathy at the time of diagnosis of non-Hodgkin’s lymphoma. In about 50% of the patients, mesenteric changes could not be explained by direct infiltration of the mesentery by lymphoma or by lymphatic obstruction. Patients with mesenteric changes tended to have a better 4-year survival as compared to patients without such changes [42]. Bechade et al. reviewed the clinicopathological and radiological findings in seven patients with mesenteric panniculitis (four men and three women). Disease association included breast cancer (one patient), non-Hodgkin’s lymphoma (two patients) and cryoglobulinemic vasculitis (one patient). In three patients, isolated mesenteric panniculitis was the only abnormality. The authors indicated that mesenteric panniculitis is often associated with lymphoma [37]. Smith et al. examined cancer risk in patients with mesenteric panniculitis as revealed by abdominal computed tomography. The author identified 359 patients including 81 with a known malignancy at the time of the index abdominal CT scan. Nineteen of the remaining 278 patients had a new diagnosis of malignancy. Among the 240 patients without abnormality in their records, 11 developed cancer during the study period. Sixty-eight of the 248 patients without a known cancer had diseases associated with mesenteric abnormalities [43]. Mesenteric panniculitis may be associated with several autoimmune conditions such as sclerosing cholangitis, Riedel thyroiditis, mixed connective tissue disease [44], ankylosing spondylitis [36], Sjo¨gren’s syndrome [45], polychondritis [46] and Weber–Christian disease [47]. A summary of diseases associated with mesenteric panniculitis is presented in TABLE 2. informahealthcare.com
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Table 2. Mesenteric panniculitis and association with cancers and autoimmune disease. Associated conditions
Ref.
Previous abdominal surgeries or traumas – Prior abdominal trauma, retained suture materials and powdered surgical gloves – Abdominal hemorrhage – Abdominal surgeries (laparotomy, cholecystectomy and appendectomy)
[8,6,54]
Neoplasms – Colorectal, lung, gynecological, gastric, breast and renal carcinomas – Melanomas, thoracic mesothelioma and carcinoid tumors – Hematological malignancies (non-Hodgkin’s lymphomas, Hodgkin’s disease, chronic lymphocytic leukemia and plasma cell tumors) – Fibromatosis and orbital pseudotumor
[8,54,71,72]
Autoimmune diseases – Sjo¨gren’s syndrome, autoimmune hemolytic anemia, rheumatoid arthritis and lupus – Polychondritis and primary sclerosing cholangitis – Ridel’s thyroiditis and orbital pseudotumors Infectious diseases – Tuberculosis and schistosomiasis Gastrointestinal diseases – Cholelithiasis, cirrhosis, pancreatitis, jaundice conditions and bile blockage or leakage – Peptic ulcers, celiac disease and retroperitoneal fibrosis Vascular insufficiency – Mesenteric thrombosis, mesenteric arteriopathy and vasculitis – Coronary artery disease and abdominal aortic aneurysm Other factors – Tobacco consumption
[25,48,59]
[4,96]
[97]
[6,54,97]
[54]
Pathological features of mesenteric panniculitis
Grossly, there is thickening of the mesentery that can be divided into three types: diffuse thickening of the mesentery (type 1), single knotty thickenings at the root of the mesentery (type 2) and multiple knotty thickenings of the mesentery (type 3) [3,10,14] (FIGURE 1). In most cases, there is a mixed histology of three components: fat necrosis, chronic inflammation and fibrosis. The histological diagnosis is usually established by finding one of these components. According to the dominant pathological changes, histological examination reveals three sequential phases: mesenteric lipodystrophy type (fat necrosis), mesenteric panniculitis type (fat necrosis and dense inflammatory cell infiltrate) and sclerosing mesenteritis type (fibrosis) [31]. In all stages, the pathological changes involve the mesenteric and submucosal fat of the bowel, often with extension into the bowel muscle and submucosa. The mucosa remains intact [48]. 69
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malabsorption, weight loss, diarrhea, joint pain and arthritis. The disease can affect any part of the body, including the heart, lungs, brain, joints, skin and eyes. Whipple’s disease is significantly more common in men. It can usually be cured with long-term antibiotic therapy; untreated, the disease is ultimately fatal. Whipple’s disease has a wide range of endoscopic features such as brown discoloration of the mucosa, erythematous spots, subepithelial hemorrhages and megaduodenum. Features on magnification endoscopy include engorged and flattened villi, villi filled with white material, white ring-like structures inside of the villi and multiple yellow spots [51]. Histologically, small intestinal biopsies reveal foamy macrophages containing periodic-acid-Schiff-positive materials [52]. Scherrer et al. reported a case of Whipple’s disease with initial granulomatous and pseudotumorous infiltration of the mesenterium. The case was initially diagnosed as mesenteric panniculitis. After 18 months, the patient presented with malabsorption and the diagnosis of mesenteric panniculitis was invalidated by the histological findings of Whipple’s disease (a duodenal biopsy) [53]. Radiological findings in mesenteric panniculitis
Figure 1. Gross features of mesenteric panniculitis. The normal architecture of the mesentery is lost. It is markedly thickened with irregular nodular masses. The appendices epiploicae of the colon is markedly puckered.
In mesenteric lipodystrophy, there is fat necrosis, lipid-filled macrophages within the fat-filled septa of the mesenteric adipose tissue with absent or minimal inflammation (FIGURE 2). During this phase, the disease is usually asymptomatic. In mesenteric panniculitis, there is fat necrosis and mixed inflammatory cell infiltrate (lymphocytes, plasma cells, neutrophils, histiocytes and giant cells) (FIGURE 3). The patients present with abdominal pain, fatigue, fever, nausea and vomiting. In sclerosing mesenteritis, there is necrosis, fibrosis and scarring of the mesentery (FIGURE 4). There is retraction of the mesentery with the formation of abdominal masses and symptoms of intestinal obstruction. The histological differential diagnosis of mesenteric panniculitis includes lymphoma, liposarcoma, lipoma, retroperitoneal fibrosis, desmoid tumor, mesenteric inflammatory pseudotumor, gastrointestinal stromal tumor, Whipple’s disease and mesenteric fibromatosis [9,31,49]. Sometimes, it may be difficult to separate mesenteric panniculitis from gastrointestinal stromal tumors and mesenteric fibromatosis. Immunostains (CD117, b-catenin, CD34, smooth muscle actin, desmin, keratin and S-100 protein) are helpful in this regard [50]. Whipple’s disease is a rare, systemic infectious condition caused by Tropheryma whipplei. The patients commonly present with features of 70
Mesenteric panniculitis is often an incidental diagnosis, while sclerosing mesenteritis shows 0.6% prevalence in patients undergoing abdominal computed tomography [54]. Abdominal computed tomography is the best modality for the diagnosis of these conditions and the findings include increased thickness of the involved mesentery [55], increased fat density due to infiltration by inflammatory cells, fibrosis and enlarged lymph nodes [56,57], fat halo sign (fat ring sign) with a halo of fat surrounding the mesenteric vessels [58], pseudocapsule of a peripheral band limiting the inflammatory mesenteric mass from the surrounding normal folds, dilated or engorged mesenteric vessels [56,58], well-defined or poorly defined mesenteric mass (usually small bowel mesentery) with displacement of the bowel loops, strand-like densities around the mesenteric vessels, well-defined soft tissue nodules usually less than 5 mm and variable degrees of bowel obstruction. Some computed tomography findings are shown in FIGURE 5. Sonography may show a well-defined hyperechoic abdominal mass with small, central hypoechoic areas. However, the fatty content of the mass usually reduces ultrasonographic transmission, preventing the acquisition of full information. Color Doppler ultrasonography usually provides little data, except some isolated color spots within the mass in some cases [59]. Of note, plain radiography is usually negative in mesenteric panniculitis. Treatment of mesenteric panniculitis
The rarity of mesenteric panniculitis makes it hard to assess the response of the disease to the therapeutic strategies. Accordingly, treatment options are empiric. They are derived on the basis of individual cases, without the use of a measure to determine the severity of symptoms. Drugs used in the treatment of mesenteric panniculitis include corticosteroids [7,60], colchicine [61], azathioprine [29,62], thalidomide [60], Expert Rev. Gastroenterol. Hepatol. 9(1), (2015)
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Mesenteric panniculitis
cyclophosphamide [29,49,63,64], tamoxifen [65] and progesterone [66,67]. Surgical resection or debulking is indicated in cases with extensive fibrosis and bowel obstruction [49,64,68]. A summary of the treatment options is provided in TABLE 2. Akram et al. reviewed ninety-two cases with mesenteric panniculitis. Common presenting symptoms included abdominal pain, diarrhea and weight loss. Treatment strategies included drug therapy, surgical excision alone and surgery followed by medical therapy. Ten percent of patients responded to surgery alone, 20% responded to additional medical treatment after surgery and 38% responded to medical therapy alone. A combination of tamoxifen and prednisone was used in 20 patients with improvement in 60% of patients. Non-tamoxifen-based regimens were used in 12 patients with improvement in 8% of patients. Eighteen deaths were noted during the study period [5].
Course of mesenteric panniculitis
Mesenteric panniculitis is essentially a fibroinflammatory process. It can regress spontaneously, run a stationary course or progress to varying degrees of fibrosis [69]. The disease is generally benign but occasionally it may have an extremely erratic course with rare complications, including bowel obstruction or vascular compression. Dieguez Aliaga et al. reported the case of a 64-year-old male patient with mesenteric panniculitis who presented with abdominal pain and leukocytosis. Spontaneous resolution of the condition occurred within 2 months [69]. Robbrecht et al. reported three patients with mesenteric panniculitis but with different clinical outcomes. One case was that of a 44-year-old woman with mesenteric panniculitis presenting with recurrent abdominal pain. The patient had a stable condition while maintaining a conservative approach. The other case was that of a 43-year-old woman with mesenteric panniculitis complicated by autoimmune hemolytic anemia. Full resolution occurred following steroid therapy. The third patient was a 73-year-old man with mesenteric panniculitis and autoimmune hemolytic informahealthcare.com
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Figure 2. Histological features of mesenteric panniculitis (predominantly fat necrosis). In mesenteric lipodystrophy, there is fat necrosis (steatonecrosis), lipid-filled macrophages within the fat-filled septa of the mesenteric adipose tissue with minimal inflammation (lymphocytes).
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Figure 3. Histological features of mesenteric panniculitis (predominantly inflammatory component). There is fat necrosis, lipid laden-macrophages and mixed inflammatory cell infiltrate (lymphocytes, plasma cells, neutrophils and histiocytes).
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IL-8 and eotaxin [73–77]. The proinflammatory cytokines are produced mainly by adipose tissue homed macrophages rather than by the adipocytes [78–80]. Leptin is a 16-kDa nonglycosylated protein, which belongs to the type I cytokine superfamily. It has both proinflammatory as well as anti-inflammatory properties depending on the experimental set-up [81,82]. Adiponectin is expressed in the differentiated adipocytes and it circulates at high levels in the bloodstream. It has anti-inflammatory properties based on its antagonism against TNF-a. These molecules suppress each other’s production and antagonize each other’s action in their target tissues [83]. Resistin is a peptide hormone and its effects are similar to that of TNF-a [84,85]. Adipocytokines & inflammatory bowel disease
Figure 4. Histological features of mesenteric panniculitis (fibrosis/retractile mesenteritis). There is a reactive fibroinflammatory process with proliferation of the cellular connective tissue and bars of mononuclear inflammatory cell infiltrate (lymphohistiocytic cells). Residual tiny islands of mature adipocytes are noted.
anemia, both may represent consequences of an angioimmunoblastic T-cell lymphoma [70]. Etiological factors & mesenteric panniculitis
Although several factors have been associated with mesenteric panniculitis, the exact etiology remains unknown. Conditions associated with the development of mesenteric panniculitis include blunt abdominal trauma, prior abdominal surgery, neoplasms, autoimmune processes, infections (such as tuberculosis) and vascular disorders [4,9,37,49,68,69,71,72]. A summary of the conditions is presented in TABLE 3. Adipocytokines
In humans, the white adipose tissue is partitioned into two large depots (mesenteric and subcutaneous) and many small visceral depots. Adipocytes are currently recognized as endocrine cells that secrete a variety of bioactive signaling proteins ‘adipocytokines.’ These molecules regulate various physiological processes such as energy homeostasis and endothelial, immunological, hematological, angiogenetic and vascular functions [3]. The adipocytokines include proinflammatory mediators and anti-inflammatory molecules and are involved in the inflammatory pathways. The anti-inflammatory molecules include adiponectin, IL-10, IL-1 receptor antagonist, TGF-b, NGF, and metallothionein-1 and -2 and tissue inhibitor of matrix metalloproteinase. Proinflammatory molecules include TNF-a, IL-1, IL-6, IL-18, leptin, plasminogen activator inhibitor-1, resistin, matrix metalloproteinases, monocyte chemoattractant protein-1, 72
Adipocytokines, potent modulators of inflammation [74,86], are involved in some inflammatory conditions by inducing a state of ‘low-grade chronic inflammation’ [3,82]. For instance, in Crohn’s disease there is dysregulation of adipocytokine secretion [74,86] including upregulation of mRNA expression for NGF and its receptor tyrosine kinase A with increased NGF immunoreactivity in the intestinal cells [74,86]. There is alteration of the adipocytokines (leptin, adiponectin and resistin) in the mesenteric adipose tissue of the operated patients with Crohn’s disease [87]. Schaffler et al. proposed that the microenvironment created by adipose tissue secretion of macrophage colony-stimulating factor supports the process of differentiation, transdifferentiation and maturation of preadipocytic and nonpreadipocytic macrophage precursor cells. The creeping fat in Crohn’s disease is infiltrated by macrophages and this cellular compartment of macrophages has a pathophysiological relevance to the development of this condition [80]. Similarly, Paul et al. examined adipose tissue specimens of creeping fat contiguous to the involved intestine of 10 patients with Crohn’s disease. The fat tissue specimens were incubated ex vivo for 24 h and the release of several adipocytokines (adiponectin, resistin, leptin, IL-6, macrophage colony-stimulating factor, monocyte chemotactic protein-1 and migration inhibitory factor) was measured using ELISA. The expression of AdipoR1 and AdipoR2 receptors was examined by PCR. The authors found upregulated secretion of several adipocytokines (adiponectin and macrophage colonystimulating factor as well as leptin and migration inhibitory factor) in Crohn’s disease compared with the control group (adipose tissue from colon cancer and diverticulitis). The authors indicated that there is a specific secretion pattern of proinflammatory and anti-inflammatory adipocytokines in Expert Rev. Gastroenterol. Hepatol. 9(1), (2015)
Mesenteric panniculitis
Crohn’s disease [88]. Taken together, these studies support the pathogenetic roles of the adipocytokines in the development of Crohn’s disease.
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Mesenteric panniculitis may represent a low-grade inflammatory disease
The adipose tissue has a high cellular plasticity. Charriere et al. used profiling analysis to define the common features shared by preadipocyte, adipocyte and macrophage populations. They reported that stromavascular cells from adipose tissue or 3T3-L1 preadipocytes can transdifferentiate into macrophages and acquire phagocytic activity. They indicated that preadipocyte and macrophage phenotypes are very similar and that preadipocytes have the potential to be converted into macrophages [89]. In mesenteric panniculitis, the pathological components include fat necrosis, chronic inflammation and fibrosis. The authors propose that the pathogenetic events in mesenteric panniculitis have some relevance to the plasticity of the adipose tissue. They also bear some similarity to the pathogenetic events in the creeping fat (Crohn’s disease), that is, mesenteric panniculitis represents a state of a low-grade inflammation mediated by the release of adipocytokines. The authors propose that under normal conditions, there is a delicate balance between the proinflammatory and anti-inflammatory adipocytokines produced by the mesenteric fat. In mesenteric panniculitis, the preadipocytes have more potential to convert over time into macrophages. The latter release increased amounts of proinflammatory adipocytokines (such as macrophage colony-stimulating factor, leptin and migration inhibitory factor) that initiate and maintain the inflammatory changes. This inflammatory stage is followed by the release of fibrogenic factors (such as transforming growth factor) with activation of the fibroblasts and collagen deposition [90], resulting in mesenteric fibrosis (fibrotic stage). Expert commentary
Mesenteric panniculitis is characterized by mesenteric inflammation without any involvement of the adjacent gut, lymph nodes or blood vessels. It mostly affects the mesentery of the small bowel and is characterized by lymphoplasmacytic infiltrate, fat necrosis, foamy macrophages and fibrosis [3,91]. The development of mesenteric panniculitis involves three stages. During the first stage, there is degeneration and necrosis of the adipose tissue (mesenteric lipodystrophy), which is usually asymptomatic. During the subsequent stage, there is inflammation of the adipose tissue (mesenteric panniculitis). The presenting symptoms include poorly defined abdominal mass(s), abdominal pain, nausea, malaise, low-grade fever and weight loss. Fibrosis (retractile mesenteritis) represents the third stage and the patients usually present with features of intestinal obstruction. Malignancies associated with mesenteric panniculitis are lymphomas and colorectal, gynecological, gastric and renal cancers. Biopsy is not always required in mesenteric panniculitis. For most cases, the computed tomography findings are very typical and depend on the stage of the disease (fat necrosis, inflammation and fibrosis). The treatment of mesenteric panniculitis includes drug therapy informahealthcare.com
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Figure 5. Computed tomography findings in mesenteric panniculitis. (A) A 47-year-old male patient who presented with repeated abdominal colic and frequent attacks of vomiting. Axial CT scan after intravenous contrast revealed prominent mesentery, associated with multiple enhancing nodules. (B) Another computed tomography section shows fibrous strands within the mesentery, associated with nodules formation. Laparoscopy guided biopsy revealed features consistent with mesenteric panniculitis.
(steroids, colchicine, immunosuppressive agents or orally administered progesterone) and surgery [92,93]. Five-year view
Adipose tissue, the body’s largest endocrine and paracrine organ, is increasingly appreciated not only as a major source but also a target for inflammatory signals. Adipocytokines are secretory products of preadipocytes and mature adipocytes [74]. Adipocytokines regulate a broad spectrum of biological processes, with inflammation being a key example. Alterations in these molecules are observed in several inflammatory conditions such as inflammatory bowel disease (Crohn’s disease) [80,87], arthritis, rheumatic diseases and acute pancreatitis [3,82,94,95]. The authors propose that mesenteric panniculitis may represent 73
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Table 3. Treatment strategies in mesenteric panniculitis. The authors emphasize that all of the recommended treatments are empiric and derived on the basis of individual cases, without the use of a measure to determine the severity of symptoms. Treatment modality
Comment
Case studies
Corticosteroids
Steroids can be used as initial therapy directed at the inflammatory component. However, their longterm use is associated with some complications (e.g., peripheral neuropathy and hyperglycemia) which limit their utility [7,60]
– Issa et al. reported a case of mesenteric panniculitis in a 68-year-old female who was started on prednisone daily with gradual improvement in symptoms within 8 weeks. However, she could not tolerate the steroids much longer and was switched to colchicine [7] – Goh et al. reported a case of mesenteric panniculitis in a 43-year-old male who presented with malaise, weight loss, microcytic anemia and a high erythrocyte sedimentation rate. There was initial and rapid resolution of the condition with high-dose oral prednisolone therapy [25]
Colchicine [61]
Colchicine is a medication that is used in the treatment of gout. Colchicine inhibits microtubule polymerization by binding to tubulin, one of the main constituents of microtubules [61,98]
– Fasoulas et al. described a case of mesenteric panniculitis in which steroid dependence was successfully managed with colchicine [98]
Azathioprine
Azathioprine belongs to the chemical class of purine analogues and has been widely used as an immunosuppressant for more than 50 years in organ transplantation and autoimmune diseases [29,62]
– Bala et al. reported a case of sclerosing mesenteritis in a 21-year-old man. The patient presented with abdominal pain and bowel obstruction. A partial ileal resection and defunctioning ileostomy were performed. Subsequent therapy included steroids and azathioprine. The patient became disease free after 5 months [29]
Thalidomide
Thalidomide is a sedative and an antiemetic agent. It has anti-inflammatory, immunomodulatory and antiangiogenic effects [60]
– Ginsburg et al. indicated that thalidomide is safe and well tolerated in the treatment of symptomatic mesenteric panniculitis [60]
Cyclophosphamide
Cyclophosphamide is a nitrogen mustard alkylating agent that is used to treat cancers and autoimmune disorders [29,49,63,64,99]
– Colomer Rubio et al. reported a case of mesenteric panniculitis involving the colon, right ureter and iliac vein. Immunosuppressive treatment with monthly intravenous pulse cyclophosphamide and oral corticosteroids resulted in the disappearance of the abdominal mass without relapse during 10 months of monitoring [64]
Tamoxifen
Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, 4-hydroxytamoxifen [65]. Its side effects include hot flashes; vaginal dryness, discharge or irritation; and reduced interest in sex [100]
– A 61-year-old female presented with abdominal and pelvic pain and multiple large irresectable mesenteric masses. Histological examination established the diagnosis of mesenteric lipodystrophy. Tamoxifen 20 mg orally once daily was tried to reduce the size of the mesenteric masses, but without any response after 6 months of therapy. Tamoxifen was discontinued and 2 years after the initial surgery, the patient remained well [65]
Progesterone
Progesterone downregulates proliferation and metabolism of fibroblasts and fibrogenesis [66,67]
– Mazure et al. reported a case of a 42-year-old man with retractile mesenteritis refractory to surgical intervention who had a good response to oral progesterone (10 mg/ day for 6 months) with complete disappearance of tumor mass and clinical symptoms [66]
Pentoxyfylline
Pentoxyfylline is an antifibrotic agent used in case of sclerosing mesenteritis [101] Dapsone [18,101]
– Kapsoritakis et al. reported a case of retractile mesenteritis in a 62-year-old man with initial treatment with steroids. He was subsequently treated with oral pentoxifylline (800 mg/day) with clinical improvement [101]
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Table 3. Treatment strategies in mesenteric panniculitis. The authors emphasize that all of the recommended treatments are empiric and derived on the basis of individual cases, without the use of a measure to determine the severity of symptoms (cont.). Treatment modality
Comment
Case studies
Surgical resection or debulking
In patients with bowel obstruction, surgical resection may be indicated [9]
– Popkharitov et al. presented a case of mesenteric panniculitis in a 63-year-old man who presented with a palpable mass in the left abdomen and features of intestinal obstruction. Laparotomy was performed and revealed markedly thickened mesentery. The sigmoid colon and its mesocolon were resected and the postoperative course was uneventful [9] – Kikiros et al. reported two patients with mesenteric panniculitis. The first developed obstruction of the sigmoid colon and was treated by decompressing proximal sigmoid end colostomy. The second case presented with an incomplete small bowel obstruction. The patient responded to steroid therapy [102]
a low-grade inflammatory disease, resulting from imbalance between the proinflammatory and anti-inflammatory adipocytokines released by macrophages (transdifferentiated preadipocytes). Fat cell necrosis and lipid-laden macrophages (foam cells) are characteristic in mesenteric panniculitis and may represent a primary event. Studies that examine the expression of the adipocytokines in mesenteric panniculitis (short-term cultures of surgical specimens of adipose tissue) would improve our understanding of the pathogenesis of this condition. Moreover, it is possible that promotion of anti-inflammatory and
suppression of proinflammatory adipocytokine-mediated signals may represent a possible therapeutic avenue. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues • Mesenteric panniculitis is a fibroinflammatory condition of unknown etiology. • The patients usually have recurrent complaints of the same rapidly reversible and variable clinical presentations. • Computed tomography is optimal for accurate, noninvasive diagnosis of mesenteric panniculitis and follow-up of sclerosing mesenteritis and of any complications. The presence of some radiological findings such as lymph node size of more than 12 mm and the absence of the fat ring sign should raise the concern of subsequent malignancy in patients with mesenteric panniculitis. • Some authors consider mesenteric panniculitis as a single disease entity with two pathological subgroups: mesenteric panniculitis (common subgroup), where inflammation and fat necrosis predominate, and retractile mesenteritis (rare subgroup), where fibrosis and retraction predominate. • In mesenteric panniculitis, the fibroinflammatory condition may infiltrate other organs such as the urinary bladder and the pancreas presenting as palpable mass, raising the concern for malignancy.
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Expert Rev. Gastroenterol. Hepatol. 9(1), 67–78 (2015)
Mahmoud Rezk Abdelwahed Hussein*1 and Saad Rezk Abdelwahed2,3 1 Department of Pathology, Faculty of Medicine, Assuit University, Assuit, Egypt 2 Department of Radiology, Faculty of Medicine, AL-Azhar University, Assuit, Egypt 3 AL-Azhar University Hospitals, AL-Azhar University, Assuit, Egypt *Author for correspondence: Tel.: +20 935 3166 Fax: +20 883 73727 [email protected]
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In 1924, mesenteric panniculitis was first described in the medical literature by Jura et al. as ‘retractile mesenteritis.’ It represents a spectrum of disease processes characterized by degeneration, inflammation and scarring of the adipose tissue of the mesentery. The clinical presentations vary according to the stage of the disease and they include abdominal pain, weight loss, nausea and vomiting. Computed tomography findings are usually diagnostic. The gross findings include thickening of the mesentery, mass lesions and adhesion to the surrounding organs. Histologically, there is a chronic inflammatory process involving the adipose tissue with fat necrosis, inflammation and fibrosis. Herein, the authors address the clinicopathological features, course, treatment and pathogenetic mechanisms of mesenteric panniculitis. KEYWORDS: inflammation • mesenteric • mesentery • panniculitis • sigmoid • small bowel
The mesentery is a reflection of the peritoneum on the bowel surface that supports and attaches the intestine to the wall of the abdomen. It is a fold of tissue lined by two parallel layers within which lymph nodes, nerves, mesenteric blood vessels and lymphatics are entangled [1]. Mesenteric panniculitis was first identified by Jura back in 1924 [2]. It is a fibroinflammatory condition of uncertain etiology. Other synonyms for mesenteric panniculitis include Pfeiffer–Weber–Christian disease, xanthogranulomatous mesenteritis, mesenteric lipodystrophy, retractile mesenteritis, sclerosing mesenteritis, liposclerotic mesenteritis, lipomatosis and lipogranuloma of the mesentery [3–7]. It occurs usually in late adult life (23–87 years, with an average age of 60 years). Either sex may be affected, although there is a higher incidence in males [8]. It is characterized by nonspecific inflammation, necrosis and fibrosis of the adipose tissue. It usually involves the mesentery of the small bowel, appendix, mesoappendix and, less frequently, the sigmoid colon or other intraabdominal fatty tissue [9]. Several large series have been published about mesenteric panniculitis [5,8,10–12]. Durst et al. reviewed 62 cases of mesenteric panniculitis collected from the literature and six cases treated by the authors. They indicated that mesenteric panniculitis is a distinct clinical entity of unknown etiology, with a benign course and a favorable outcome. In their series, 10.1586/17474124.2014.939632
radical surgical treatment was suggested in patients with intestinal obstruction [11]. Emory et al. reviewed 84 cases of mesenteric lipodystrophy, mesenteric panniculitis and sclerosing mesenteritis. There was no sex or racial predominance. The average age was 60 years. Abdominal pain or masses were common presentations. A history of trauma or surgery was found in four of 84 patients. The most common site of involvement was the small bowel mesentery as a single mass (58 of 84), multiple masses (15 of 84) or diffuse mesenteric thickening (11 of 84) [8]. In another large case series, a history of abdominal surgery (cholecystectomy or appendicectomy) was noted in about 40% of the patients [5,12]. At the biochemical level, the fatty tissue obtained from patients with mesenteric panniculitis usually contains significant amounts of cholesteryl esters, in addition to 0.5–1.3% free cholesterol, 0.9–1.9% free fatty acids, 0.6–2.5% l-alkyl glyceryl ether diesters, squalene and alkl-enyl glyceryl ether diesters [13]. Clinical features of mesenteric panniculitis
Patients with mesenteric panniculitis may be asymptomatic or may present with abdominal discomfort, fever, nausea, vomiting, diarrhea and constipation [14,15]. Other presentations include fever of unknown origin [16,17], weight loss [18], shaking chills [19], features of Crohn’s
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Table 1. Clinical presentations of mesenteric panniculitis.
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Clinical presentations General symptoms • Weakness, fever of unknown origin and chills Gastrointestinal symptoms • Abdominal pain, bloating, anorexia, nausea, vomiting, early satiety, weight loss, intestinal obstruction and abdominal masses and palpitations near the abdominal area Differential diagnosis • Abdominal neoplasms (colorectal carcinoma, lymphoma, liposarcoma, lipoma, peritoneal carcinomatosis, carcinoid tumor, peritoneal mesothelioma desmoid tumor and gastrointestinal stromal tumor), retroperitoneal fibrosis and mesenteric inflammatory pseudotumor and mesenteric fibromatosis
Ref. [14–24]
Mesenteric panniculitis, IgG4-related disease [31]
disease [20], chylous ascites [21], Schonlein–Henoch disease [22] and multiple mesenteric lymphatic cysts [23]. The abdominal examination may reveal poorly defined abdominal mass or masses [24]. Goh et al. reported a case of mesenteric panniculitis in a 43-year-old male who presented with malaise, weight loss, microcytic anemia and a high erythrocyte sedimentation rate. There was initial and rapid resolution of the condition with high-dose oral prednisolone therapy. The patient presented with features of myeloma within 6 months (anemia, renal failure and hypercalcemia) and died later on from refractory pulmonary edema [25]. Schwery et al. reported a case of mesenteric panniculitis in a 70-year-old patient with a 6 6 12 cm mass involving the mesenteric root. The patient presented with abdominal pain and weight loss. On laparoscopic biopsy, there was infiltration of the mesentery by foamy lipid-laden macrophages, clusters of lymphocytes and fibrosis [26]. Mesenteric panniculitis associated with extensive fibrosis (retractile mesenteritis) may be associated with shortening of the mesentery and compression of the mesenteric vessels. Patients may present with manifestations of intestinal obstruction or vascular compression [26–28]. Bala et al. reported a case of sclerosing (idiopathic) mesenteritis in a 21-year-old man. The patient presented with abdominal pain and bowel obstruction. A partial ileal resection and a defunctioning ileostomy were performed. Subsequent therapy included steroids and azathioprine. The patient became disease-free after 5 months [29]. Carnicer Jauregui et al. reported the case of a 35-year-old female who presented with a paraneoplastic syndrome, abdominal pain, ascites, cachexia, anemia and high sedimentation of 1-year duration. The clinical impression was that of lymphoma. Radiological findings include loop distention (x-ray), ascites and mesenteric thickening (computed tomography findings). Laparotomy revealed retroperitoneal fibrosis and on histology, there was substantial collagen deposition and inflammatory infiltrate, together with giant cells of foreign body type [30]. 68
The clinical differential diagnosis of mesenteric panniculitis includes abdominal neoplasms (colorectal carcinoma, lymphoma, liposarcoma, lipoma, peritoneal carcinomatosis, carcinoid tumor, desmoid tumor and gastrointestinal stromal tumor), retroperitoneal fibrosis, mesenteric inflammatory pseudotumor and mesenteric fibromatosis [31]. A summary of the clinical presentations is shown in TABLE 1.
IgG4-related disease is a fibroinflammatory condition characterized by a tendency to form tumor-like lesions at multiple sites, a characteristic histopathological appearance (tissue infiltration by many IgG4-positive plasma cells, fibrosis and obliterative phlebitis) and high serum IgG4 levels [32]. It was initially reported in the pancreas (autoimmune pancreatitis), but is now recognized in a number of conditions such as pancreatic cancer, atopic dermatitis, vasculitis and biliary tract disease. Of note, IgG4-related disease is also observed in about 5% of the normal population [33]. The histological diagnosis of IgG4-related disease requires the presence of two of the three major histological features. In most cases, these include a dense lymphoplasmacytic infiltrate and storiform-type fibrosis [32]. Although the constellation of the histological and immunohistochemical findings support the diagnosis of IgG4-related disease, correlation with the clinical and radiological findings is important for definitive opinion [32]. In sclerosing mesenteritis, some tumefactive lesions are characterized by the presence of a diffuse infiltration by IgG4-positive plasma cells. These lesions are considered to be a part of the spectrum of IgG4-related disease. Minato et al. reported a case of sclerosing mesenteritis in a 53-year-old man with an ileocecal ill-defined mass and manifestations of IgG4-related disease. Intraoperatively, there was an ileocecal ill-defined fibroinflammatory mass that involved the mesentery. Histologically, there was storiform fibrosis, obliterative phlebitis and infiltration of the adipose tissue by many IgG4-positive plasma cells. The ratio of IgG4-positive/IgG-positive cells was 64% and the ratio of forkhead box protein 3-positive/CD4-positive cells was elevated (13%). The authors indicated that at least some cases of sclerosing mesenteritis are manifestations of IgG4-related disease [34]. Similarly, Kim et al. reported a case of IgG4-related sclerosing mesenteritis in a 45-year-old woman who presented with weight loss and lower abdominal discomfort. The radiological findings included a mass lesion in the abdominal wall and the pelvis, a 5.9-cm-sized wall-enhancing mass with heterogeneous signal intensity from the right adnexa to the abdominal wall. Surgical resection, appendectomy and adhesiolysis were performed due to the presence of severe adhesions. On histology, the mass lesion consisted of inflammatory infiltrate with dense IgG4-positive plasma cells, a feature of IgG4-related sclerosing mesenteritis. Later on, the patient was diagnosed with Crohn’s disease on colonoscopy [35,36]. Expert Rev. Gastroenterol. Hepatol. 9(1), (2015)
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Mesenteric panniculitis, cancer & autoimmune diseases
Mesenteric panniculitis may be associated with several neoplasms. In most cases, these tumors are discovered before the diagnosis of mesenteric panniculitis. They include carcinomas (breast, colorectal, gynecological, renal and gastric cancers) and hematological malignancies (non-Hodgkin’s lymphomas and plasma cell tumors) [25,37–41]. The prevalence of tumors varies among different studies. Kipfer et al. found that 30% of patients with sclerosing mesenteritis had an underlying malignancy [10]. Wilkes et al. examined the prevalence of malignancy in 118 patients with computed tomography findings of mesenteric panniculitis. Malignant tumors were noted in 45 patients and included colorectal cancer (14 patients), lymphoma (13 patients) and cancers of the urogenital tract (7 patients). The lymph node size of >12 mm together with the absence of the fat ring sign were good predictors of the subsequent diagnosis of malignancy in patients with mesenteric panniculitis. In most cases, malignancy was diagnosed before mesenteric panniculitis [41]. Joerger et al. screened 120 patients who were treated for non-Hodgkin’s lymphoma for the presence of mesenteric changes. They were defined on computed tomography as nodular or diffuse infiltration of the abdominal mesentery with increased density of the mesenteric fat. The authors found 21 patients with radiological findings of mesenteric changes, such as mesenteric lymphadenopathy at the time of diagnosis of non-Hodgkin’s lymphoma. In about 50% of the patients, mesenteric changes could not be explained by direct infiltration of the mesentery by lymphoma or by lymphatic obstruction. Patients with mesenteric changes tended to have a better 4-year survival as compared to patients without such changes [42]. Bechade et al. reviewed the clinicopathological and radiological findings in seven patients with mesenteric panniculitis (four men and three women). Disease association included breast cancer (one patient), non-Hodgkin’s lymphoma (two patients) and cryoglobulinemic vasculitis (one patient). In three patients, isolated mesenteric panniculitis was the only abnormality. The authors indicated that mesenteric panniculitis is often associated with lymphoma [37]. Smith et al. examined cancer risk in patients with mesenteric panniculitis as revealed by abdominal computed tomography. The author identified 359 patients including 81 with a known malignancy at the time of the index abdominal CT scan. Nineteen of the remaining 278 patients had a new diagnosis of malignancy. Among the 240 patients without abnormality in their records, 11 developed cancer during the study period. Sixty-eight of the 248 patients without a known cancer had diseases associated with mesenteric abnormalities [43]. Mesenteric panniculitis may be associated with several autoimmune conditions such as sclerosing cholangitis, Riedel thyroiditis, mixed connective tissue disease [44], ankylosing spondylitis [36], Sjo¨gren’s syndrome [45], polychondritis [46] and Weber–Christian disease [47]. A summary of diseases associated with mesenteric panniculitis is presented in TABLE 2. informahealthcare.com
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Table 2. Mesenteric panniculitis and association with cancers and autoimmune disease. Associated conditions
Ref.
Previous abdominal surgeries or traumas – Prior abdominal trauma, retained suture materials and powdered surgical gloves – Abdominal hemorrhage – Abdominal surgeries (laparotomy, cholecystectomy and appendectomy)
[8,6,54]
Neoplasms – Colorectal, lung, gynecological, gastric, breast and renal carcinomas – Melanomas, thoracic mesothelioma and carcinoid tumors – Hematological malignancies (non-Hodgkin’s lymphomas, Hodgkin’s disease, chronic lymphocytic leukemia and plasma cell tumors) – Fibromatosis and orbital pseudotumor
[8,54,71,72]
Autoimmune diseases – Sjo¨gren’s syndrome, autoimmune hemolytic anemia, rheumatoid arthritis and lupus – Polychondritis and primary sclerosing cholangitis – Ridel’s thyroiditis and orbital pseudotumors Infectious diseases – Tuberculosis and schistosomiasis Gastrointestinal diseases – Cholelithiasis, cirrhosis, pancreatitis, jaundice conditions and bile blockage or leakage – Peptic ulcers, celiac disease and retroperitoneal fibrosis Vascular insufficiency – Mesenteric thrombosis, mesenteric arteriopathy and vasculitis – Coronary artery disease and abdominal aortic aneurysm Other factors – Tobacco consumption
[25,48,59]
[4,96]
[97]
[6,54,97]
[54]
Pathological features of mesenteric panniculitis
Grossly, there is thickening of the mesentery that can be divided into three types: diffuse thickening of the mesentery (type 1), single knotty thickenings at the root of the mesentery (type 2) and multiple knotty thickenings of the mesentery (type 3) [3,10,14] (FIGURE 1). In most cases, there is a mixed histology of three components: fat necrosis, chronic inflammation and fibrosis. The histological diagnosis is usually established by finding one of these components. According to the dominant pathological changes, histological examination reveals three sequential phases: mesenteric lipodystrophy type (fat necrosis), mesenteric panniculitis type (fat necrosis and dense inflammatory cell infiltrate) and sclerosing mesenteritis type (fibrosis) [31]. In all stages, the pathological changes involve the mesenteric and submucosal fat of the bowel, often with extension into the bowel muscle and submucosa. The mucosa remains intact [48]. 69
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malabsorption, weight loss, diarrhea, joint pain and arthritis. The disease can affect any part of the body, including the heart, lungs, brain, joints, skin and eyes. Whipple’s disease is significantly more common in men. It can usually be cured with long-term antibiotic therapy; untreated, the disease is ultimately fatal. Whipple’s disease has a wide range of endoscopic features such as brown discoloration of the mucosa, erythematous spots, subepithelial hemorrhages and megaduodenum. Features on magnification endoscopy include engorged and flattened villi, villi filled with white material, white ring-like structures inside of the villi and multiple yellow spots [51]. Histologically, small intestinal biopsies reveal foamy macrophages containing periodic-acid-Schiff-positive materials [52]. Scherrer et al. reported a case of Whipple’s disease with initial granulomatous and pseudotumorous infiltration of the mesenterium. The case was initially diagnosed as mesenteric panniculitis. After 18 months, the patient presented with malabsorption and the diagnosis of mesenteric panniculitis was invalidated by the histological findings of Whipple’s disease (a duodenal biopsy) [53]. Radiological findings in mesenteric panniculitis
Figure 1. Gross features of mesenteric panniculitis. The normal architecture of the mesentery is lost. It is markedly thickened with irregular nodular masses. The appendices epiploicae of the colon is markedly puckered.
In mesenteric lipodystrophy, there is fat necrosis, lipid-filled macrophages within the fat-filled septa of the mesenteric adipose tissue with absent or minimal inflammation (FIGURE 2). During this phase, the disease is usually asymptomatic. In mesenteric panniculitis, there is fat necrosis and mixed inflammatory cell infiltrate (lymphocytes, plasma cells, neutrophils, histiocytes and giant cells) (FIGURE 3). The patients present with abdominal pain, fatigue, fever, nausea and vomiting. In sclerosing mesenteritis, there is necrosis, fibrosis and scarring of the mesentery (FIGURE 4). There is retraction of the mesentery with the formation of abdominal masses and symptoms of intestinal obstruction. The histological differential diagnosis of mesenteric panniculitis includes lymphoma, liposarcoma, lipoma, retroperitoneal fibrosis, desmoid tumor, mesenteric inflammatory pseudotumor, gastrointestinal stromal tumor, Whipple’s disease and mesenteric fibromatosis [9,31,49]. Sometimes, it may be difficult to separate mesenteric panniculitis from gastrointestinal stromal tumors and mesenteric fibromatosis. Immunostains (CD117, b-catenin, CD34, smooth muscle actin, desmin, keratin and S-100 protein) are helpful in this regard [50]. Whipple’s disease is a rare, systemic infectious condition caused by Tropheryma whipplei. The patients commonly present with features of 70
Mesenteric panniculitis is often an incidental diagnosis, while sclerosing mesenteritis shows 0.6% prevalence in patients undergoing abdominal computed tomography [54]. Abdominal computed tomography is the best modality for the diagnosis of these conditions and the findings include increased thickness of the involved mesentery [55], increased fat density due to infiltration by inflammatory cells, fibrosis and enlarged lymph nodes [56,57], fat halo sign (fat ring sign) with a halo of fat surrounding the mesenteric vessels [58], pseudocapsule of a peripheral band limiting the inflammatory mesenteric mass from the surrounding normal folds, dilated or engorged mesenteric vessels [56,58], well-defined or poorly defined mesenteric mass (usually small bowel mesentery) with displacement of the bowel loops, strand-like densities around the mesenteric vessels, well-defined soft tissue nodules usually less than 5 mm and variable degrees of bowel obstruction. Some computed tomography findings are shown in FIGURE 5. Sonography may show a well-defined hyperechoic abdominal mass with small, central hypoechoic areas. However, the fatty content of the mass usually reduces ultrasonographic transmission, preventing the acquisition of full information. Color Doppler ultrasonography usually provides little data, except some isolated color spots within the mass in some cases [59]. Of note, plain radiography is usually negative in mesenteric panniculitis. Treatment of mesenteric panniculitis
The rarity of mesenteric panniculitis makes it hard to assess the response of the disease to the therapeutic strategies. Accordingly, treatment options are empiric. They are derived on the basis of individual cases, without the use of a measure to determine the severity of symptoms. Drugs used in the treatment of mesenteric panniculitis include corticosteroids [7,60], colchicine [61], azathioprine [29,62], thalidomide [60], Expert Rev. Gastroenterol. Hepatol. 9(1), (2015)
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Mesenteric panniculitis
cyclophosphamide [29,49,63,64], tamoxifen [65] and progesterone [66,67]. Surgical resection or debulking is indicated in cases with extensive fibrosis and bowel obstruction [49,64,68]. A summary of the treatment options is provided in TABLE 2. Akram et al. reviewed ninety-two cases with mesenteric panniculitis. Common presenting symptoms included abdominal pain, diarrhea and weight loss. Treatment strategies included drug therapy, surgical excision alone and surgery followed by medical therapy. Ten percent of patients responded to surgery alone, 20% responded to additional medical treatment after surgery and 38% responded to medical therapy alone. A combination of tamoxifen and prednisone was used in 20 patients with improvement in 60% of patients. Non-tamoxifen-based regimens were used in 12 patients with improvement in 8% of patients. Eighteen deaths were noted during the study period [5].
Course of mesenteric panniculitis
Mesenteric panniculitis is essentially a fibroinflammatory process. It can regress spontaneously, run a stationary course or progress to varying degrees of fibrosis [69]. The disease is generally benign but occasionally it may have an extremely erratic course with rare complications, including bowel obstruction or vascular compression. Dieguez Aliaga et al. reported the case of a 64-year-old male patient with mesenteric panniculitis who presented with abdominal pain and leukocytosis. Spontaneous resolution of the condition occurred within 2 months [69]. Robbrecht et al. reported three patients with mesenteric panniculitis but with different clinical outcomes. One case was that of a 44-year-old woman with mesenteric panniculitis presenting with recurrent abdominal pain. The patient had a stable condition while maintaining a conservative approach. The other case was that of a 43-year-old woman with mesenteric panniculitis complicated by autoimmune hemolytic anemia. Full resolution occurred following steroid therapy. The third patient was a 73-year-old man with mesenteric panniculitis and autoimmune hemolytic informahealthcare.com
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Figure 2. Histological features of mesenteric panniculitis (predominantly fat necrosis). In mesenteric lipodystrophy, there is fat necrosis (steatonecrosis), lipid-filled macrophages within the fat-filled septa of the mesenteric adipose tissue with minimal inflammation (lymphocytes).
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Figure 3. Histological features of mesenteric panniculitis (predominantly inflammatory component). There is fat necrosis, lipid laden-macrophages and mixed inflammatory cell infiltrate (lymphocytes, plasma cells, neutrophils and histiocytes).
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IL-8 and eotaxin [73–77]. The proinflammatory cytokines are produced mainly by adipose tissue homed macrophages rather than by the adipocytes [78–80]. Leptin is a 16-kDa nonglycosylated protein, which belongs to the type I cytokine superfamily. It has both proinflammatory as well as anti-inflammatory properties depending on the experimental set-up [81,82]. Adiponectin is expressed in the differentiated adipocytes and it circulates at high levels in the bloodstream. It has anti-inflammatory properties based on its antagonism against TNF-a. These molecules suppress each other’s production and antagonize each other’s action in their target tissues [83]. Resistin is a peptide hormone and its effects are similar to that of TNF-a [84,85]. Adipocytokines & inflammatory bowel disease
Figure 4. Histological features of mesenteric panniculitis (fibrosis/retractile mesenteritis). There is a reactive fibroinflammatory process with proliferation of the cellular connective tissue and bars of mononuclear inflammatory cell infiltrate (lymphohistiocytic cells). Residual tiny islands of mature adipocytes are noted.
anemia, both may represent consequences of an angioimmunoblastic T-cell lymphoma [70]. Etiological factors & mesenteric panniculitis
Although several factors have been associated with mesenteric panniculitis, the exact etiology remains unknown. Conditions associated with the development of mesenteric panniculitis include blunt abdominal trauma, prior abdominal surgery, neoplasms, autoimmune processes, infections (such as tuberculosis) and vascular disorders [4,9,37,49,68,69,71,72]. A summary of the conditions is presented in TABLE 3. Adipocytokines
In humans, the white adipose tissue is partitioned into two large depots (mesenteric and subcutaneous) and many small visceral depots. Adipocytes are currently recognized as endocrine cells that secrete a variety of bioactive signaling proteins ‘adipocytokines.’ These molecules regulate various physiological processes such as energy homeostasis and endothelial, immunological, hematological, angiogenetic and vascular functions [3]. The adipocytokines include proinflammatory mediators and anti-inflammatory molecules and are involved in the inflammatory pathways. The anti-inflammatory molecules include adiponectin, IL-10, IL-1 receptor antagonist, TGF-b, NGF, and metallothionein-1 and -2 and tissue inhibitor of matrix metalloproteinase. Proinflammatory molecules include TNF-a, IL-1, IL-6, IL-18, leptin, plasminogen activator inhibitor-1, resistin, matrix metalloproteinases, monocyte chemoattractant protein-1, 72
Adipocytokines, potent modulators of inflammation [74,86], are involved in some inflammatory conditions by inducing a state of ‘low-grade chronic inflammation’ [3,82]. For instance, in Crohn’s disease there is dysregulation of adipocytokine secretion [74,86] including upregulation of mRNA expression for NGF and its receptor tyrosine kinase A with increased NGF immunoreactivity in the intestinal cells [74,86]. There is alteration of the adipocytokines (leptin, adiponectin and resistin) in the mesenteric adipose tissue of the operated patients with Crohn’s disease [87]. Schaffler et al. proposed that the microenvironment created by adipose tissue secretion of macrophage colony-stimulating factor supports the process of differentiation, transdifferentiation and maturation of preadipocytic and nonpreadipocytic macrophage precursor cells. The creeping fat in Crohn’s disease is infiltrated by macrophages and this cellular compartment of macrophages has a pathophysiological relevance to the development of this condition [80]. Similarly, Paul et al. examined adipose tissue specimens of creeping fat contiguous to the involved intestine of 10 patients with Crohn’s disease. The fat tissue specimens were incubated ex vivo for 24 h and the release of several adipocytokines (adiponectin, resistin, leptin, IL-6, macrophage colony-stimulating factor, monocyte chemotactic protein-1 and migration inhibitory factor) was measured using ELISA. The expression of AdipoR1 and AdipoR2 receptors was examined by PCR. The authors found upregulated secretion of several adipocytokines (adiponectin and macrophage colonystimulating factor as well as leptin and migration inhibitory factor) in Crohn’s disease compared with the control group (adipose tissue from colon cancer and diverticulitis). The authors indicated that there is a specific secretion pattern of proinflammatory and anti-inflammatory adipocytokines in Expert Rev. Gastroenterol. Hepatol. 9(1), (2015)
Mesenteric panniculitis
Crohn’s disease [88]. Taken together, these studies support the pathogenetic roles of the adipocytokines in the development of Crohn’s disease.
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Mesenteric panniculitis may represent a low-grade inflammatory disease
The adipose tissue has a high cellular plasticity. Charriere et al. used profiling analysis to define the common features shared by preadipocyte, adipocyte and macrophage populations. They reported that stromavascular cells from adipose tissue or 3T3-L1 preadipocytes can transdifferentiate into macrophages and acquire phagocytic activity. They indicated that preadipocyte and macrophage phenotypes are very similar and that preadipocytes have the potential to be converted into macrophages [89]. In mesenteric panniculitis, the pathological components include fat necrosis, chronic inflammation and fibrosis. The authors propose that the pathogenetic events in mesenteric panniculitis have some relevance to the plasticity of the adipose tissue. They also bear some similarity to the pathogenetic events in the creeping fat (Crohn’s disease), that is, mesenteric panniculitis represents a state of a low-grade inflammation mediated by the release of adipocytokines. The authors propose that under normal conditions, there is a delicate balance between the proinflammatory and anti-inflammatory adipocytokines produced by the mesenteric fat. In mesenteric panniculitis, the preadipocytes have more potential to convert over time into macrophages. The latter release increased amounts of proinflammatory adipocytokines (such as macrophage colony-stimulating factor, leptin and migration inhibitory factor) that initiate and maintain the inflammatory changes. This inflammatory stage is followed by the release of fibrogenic factors (such as transforming growth factor) with activation of the fibroblasts and collagen deposition [90], resulting in mesenteric fibrosis (fibrotic stage). Expert commentary
Mesenteric panniculitis is characterized by mesenteric inflammation without any involvement of the adjacent gut, lymph nodes or blood vessels. It mostly affects the mesentery of the small bowel and is characterized by lymphoplasmacytic infiltrate, fat necrosis, foamy macrophages and fibrosis [3,91]. The development of mesenteric panniculitis involves three stages. During the first stage, there is degeneration and necrosis of the adipose tissue (mesenteric lipodystrophy), which is usually asymptomatic. During the subsequent stage, there is inflammation of the adipose tissue (mesenteric panniculitis). The presenting symptoms include poorly defined abdominal mass(s), abdominal pain, nausea, malaise, low-grade fever and weight loss. Fibrosis (retractile mesenteritis) represents the third stage and the patients usually present with features of intestinal obstruction. Malignancies associated with mesenteric panniculitis are lymphomas and colorectal, gynecological, gastric and renal cancers. Biopsy is not always required in mesenteric panniculitis. For most cases, the computed tomography findings are very typical and depend on the stage of the disease (fat necrosis, inflammation and fibrosis). The treatment of mesenteric panniculitis includes drug therapy informahealthcare.com
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Figure 5. Computed tomography findings in mesenteric panniculitis. (A) A 47-year-old male patient who presented with repeated abdominal colic and frequent attacks of vomiting. Axial CT scan after intravenous contrast revealed prominent mesentery, associated with multiple enhancing nodules. (B) Another computed tomography section shows fibrous strands within the mesentery, associated with nodules formation. Laparoscopy guided biopsy revealed features consistent with mesenteric panniculitis.
(steroids, colchicine, immunosuppressive agents or orally administered progesterone) and surgery [92,93]. Five-year view
Adipose tissue, the body’s largest endocrine and paracrine organ, is increasingly appreciated not only as a major source but also a target for inflammatory signals. Adipocytokines are secretory products of preadipocytes and mature adipocytes [74]. Adipocytokines regulate a broad spectrum of biological processes, with inflammation being a key example. Alterations in these molecules are observed in several inflammatory conditions such as inflammatory bowel disease (Crohn’s disease) [80,87], arthritis, rheumatic diseases and acute pancreatitis [3,82,94,95]. The authors propose that mesenteric panniculitis may represent 73
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Table 3. Treatment strategies in mesenteric panniculitis. The authors emphasize that all of the recommended treatments are empiric and derived on the basis of individual cases, without the use of a measure to determine the severity of symptoms. Treatment modality
Comment
Case studies
Corticosteroids
Steroids can be used as initial therapy directed at the inflammatory component. However, their longterm use is associated with some complications (e.g., peripheral neuropathy and hyperglycemia) which limit their utility [7,60]
– Issa et al. reported a case of mesenteric panniculitis in a 68-year-old female who was started on prednisone daily with gradual improvement in symptoms within 8 weeks. However, she could not tolerate the steroids much longer and was switched to colchicine [7] – Goh et al. reported a case of mesenteric panniculitis in a 43-year-old male who presented with malaise, weight loss, microcytic anemia and a high erythrocyte sedimentation rate. There was initial and rapid resolution of the condition with high-dose oral prednisolone therapy [25]
Colchicine [61]
Colchicine is a medication that is used in the treatment of gout. Colchicine inhibits microtubule polymerization by binding to tubulin, one of the main constituents of microtubules [61,98]
– Fasoulas et al. described a case of mesenteric panniculitis in which steroid dependence was successfully managed with colchicine [98]
Azathioprine
Azathioprine belongs to the chemical class of purine analogues and has been widely used as an immunosuppressant for more than 50 years in organ transplantation and autoimmune diseases [29,62]
– Bala et al. reported a case of sclerosing mesenteritis in a 21-year-old man. The patient presented with abdominal pain and bowel obstruction. A partial ileal resection and defunctioning ileostomy were performed. Subsequent therapy included steroids and azathioprine. The patient became disease free after 5 months [29]
Thalidomide
Thalidomide is a sedative and an antiemetic agent. It has anti-inflammatory, immunomodulatory and antiangiogenic effects [60]
– Ginsburg et al. indicated that thalidomide is safe and well tolerated in the treatment of symptomatic mesenteric panniculitis [60]
Cyclophosphamide
Cyclophosphamide is a nitrogen mustard alkylating agent that is used to treat cancers and autoimmune disorders [29,49,63,64,99]
– Colomer Rubio et al. reported a case of mesenteric panniculitis involving the colon, right ureter and iliac vein. Immunosuppressive treatment with monthly intravenous pulse cyclophosphamide and oral corticosteroids resulted in the disappearance of the abdominal mass without relapse during 10 months of monitoring [64]
Tamoxifen
Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, 4-hydroxytamoxifen [65]. Its side effects include hot flashes; vaginal dryness, discharge or irritation; and reduced interest in sex [100]
– A 61-year-old female presented with abdominal and pelvic pain and multiple large irresectable mesenteric masses. Histological examination established the diagnosis of mesenteric lipodystrophy. Tamoxifen 20 mg orally once daily was tried to reduce the size of the mesenteric masses, but without any response after 6 months of therapy. Tamoxifen was discontinued and 2 years after the initial surgery, the patient remained well [65]
Progesterone
Progesterone downregulates proliferation and metabolism of fibroblasts and fibrogenesis [66,67]
– Mazure et al. reported a case of a 42-year-old man with retractile mesenteritis refractory to surgical intervention who had a good response to oral progesterone (10 mg/ day for 6 months) with complete disappearance of tumor mass and clinical symptoms [66]
Pentoxyfylline
Pentoxyfylline is an antifibrotic agent used in case of sclerosing mesenteritis [101] Dapsone [18,101]
– Kapsoritakis et al. reported a case of retractile mesenteritis in a 62-year-old man with initial treatment with steroids. He was subsequently treated with oral pentoxifylline (800 mg/day) with clinical improvement [101]
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Table 3. Treatment strategies in mesenteric panniculitis. The authors emphasize that all of the recommended treatments are empiric and derived on the basis of individual cases, without the use of a measure to determine the severity of symptoms (cont.). Treatment modality
Comment
Case studies
Surgical resection or debulking
In patients with bowel obstruction, surgical resection may be indicated [9]
– Popkharitov et al. presented a case of mesenteric panniculitis in a 63-year-old man who presented with a palpable mass in the left abdomen and features of intestinal obstruction. Laparotomy was performed and revealed markedly thickened mesentery. The sigmoid colon and its mesocolon were resected and the postoperative course was uneventful [9] – Kikiros et al. reported two patients with mesenteric panniculitis. The first developed obstruction of the sigmoid colon and was treated by decompressing proximal sigmoid end colostomy. The second case presented with an incomplete small bowel obstruction. The patient responded to steroid therapy [102]
a low-grade inflammatory disease, resulting from imbalance between the proinflammatory and anti-inflammatory adipocytokines released by macrophages (transdifferentiated preadipocytes). Fat cell necrosis and lipid-laden macrophages (foam cells) are characteristic in mesenteric panniculitis and may represent a primary event. Studies that examine the expression of the adipocytokines in mesenteric panniculitis (short-term cultures of surgical specimens of adipose tissue) would improve our understanding of the pathogenesis of this condition. Moreover, it is possible that promotion of anti-inflammatory and
suppression of proinflammatory adipocytokine-mediated signals may represent a possible therapeutic avenue. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues • Mesenteric panniculitis is a fibroinflammatory condition of unknown etiology. • The patients usually have recurrent complaints of the same rapidly reversible and variable clinical presentations. • Computed tomography is optimal for accurate, noninvasive diagnosis of mesenteric panniculitis and follow-up of sclerosing mesenteritis and of any complications. The presence of some radiological findings such as lymph node size of more than 12 mm and the absence of the fat ring sign should raise the concern of subsequent malignancy in patients with mesenteric panniculitis. • Some authors consider mesenteric panniculitis as a single disease entity with two pathological subgroups: mesenteric panniculitis (common subgroup), where inflammation and fat necrosis predominate, and retractile mesenteritis (rare subgroup), where fibrosis and retraction predominate. • In mesenteric panniculitis, the fibroinflammatory condition may infiltrate other organs such as the urinary bladder and the pancreas presenting as palpable mass, raising the concern for malignancy.
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