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16 The Role of the Mesentery in Pancreatic Diseases 145
Table 16.1 Causes of
Panniculitis
Enzymatic
Pancreatic
Alpha-1 antitrypsin deficiency
Inflammatory
Erythema nodosum
Erythema nodosum migrans
Erythema induratum
Steroid use
Systemic lupus erythematosus
Dermatomyositis
Connective tissue disease
Rheumatoid Nodules
Sarcoidosis
Vasculitis
Lipodermatosclerosis
Superficial Migratory
Thrombophlebitis
Deposition
Gout
Calciphylaxis
Hyperoxaluria
Malignancy
Lymphoma
Leukemia
Cytophagic Histiocytic (occurs
with benign disease or
subcutaneous panniculitis-like
T-cell lymphoma)
Infection
Bacterial
Mycobacterial
Fungal
Parasitic
Arthropod
Trauma
Blunt Trauma
Iatrogenic
Post Radiation Exposure
Cold Exposure
Reused with permission from Requena L, Sanchez Y.
Panniculitis. Part II. Mostly lobular panniculitis. J Am Acad
Dermatol. 2001;45(3):325-364. Copyright © Elsevier
A series of two cases of patients presenting with pancreatic and a mesenteric
mass appearing to be pancreatic cancer was also published. These patients were
diagnosed with mesenteric panniculitis and both had resolution of their symptoms
with corticosteroid therapy.
A series of the imaging findings in 17 patients with mesenteric panniculitis
includes one patient with pancreatitis and pancreatic panniculitis.
146 C. Broy et al.
Heterotopic Pancreas
Heterotopic pancreas (HP) is defined as the presence of pancreatic tissue without
vascular or ductal connection to the orthotopic pancreas. It is a congenital anomaly
most commonly located in the stomach, duodenum and jejunum. HP may also be
present in the mesentery and mesenteric involvement was found in 3.8% in one
study of 184 consecutive histology-proven HP cases in China. It has been
hypothesized that HP occurs when deposits of pancreatic tissue are “dropped” into
the developing gastrointestinal system during fusion of the ventral and dorsal buds.
A study of the endoderm of chicken embryos, compared different concentrations of
cyclopamine, an inhibitor of the sonic hedgehog signaling pathway during development, that causes birth defects to controls. Stomach and mesenchyme were then
isolated at stage 15 and cell cultures were studied. 1.0 microMolar cyclopamine
exposure produced signs of pancreatic tissue growth whereas control and exposure
to 0.1 microMolar cyclopamine showed no growth of pancreatic tissue. This study
suggests that the sonic hedgehog gene has a role in the development of HP.
HP is usually an incidental finding during surgery or autopsy and the majority of
patients with HP are asymptomatic. However, since HP is composed of pancreatic
tissue, pancreatic diseases can affect areas of HP as well. A variety of complications
of HP have been described (See Table 16.2).
On imaging studies including computerized tomography (CT) and magnetic
resonance imaging (MRI), HP appears as small, homogenous, well enhancing
lesions with an appearance that is similar to pancreatic tissue. However, imaging
studies may not be able to differentiate mesenteric HP from metastatic tumors or
lymphoma. In one series of 17 patient with surgically confirmed HP, only one was
correctly diagnosed as HP before surgery. In one case report, an MRCP scan was
used to make the diagnosis of HP.
Histological examination of areas of HP reveals similar elements of the orthotopic pancreas, including pancreatic ducts, islet cells and acini. No treatment is
recommended for asymptomatic disease while surgical excision is performed for
HP-associated malignancy or other complications of HP.
There are a few case reports describing HP in the mesentery. Kok et al. reported
a 58-year-old woman who presented with clinical suspicion of acute pancreatitis.
Imaging studies revealed a large lesion found to be HP in the small bowel
Table 16.2 Complications
of Heterotopic Pancreas
Cancer
Pancreatitis
Pseudocyst Formation
Abnormal Hormone Secretion
Bowel Obstruction
Intussusception
Common Bile Duct Obstruction
Gastrointestinal Bleeding
16 The Role of the Mesentery in Pancreatic Diseases 147
mesentery. Endoscopic ultrasound-guided fine needle aspiration of the lesion
showed benign cells and inflammati on characteristic of acute pancreatitis. Conservative treatment for one week helped to relieve the patient’s symptoms and
laboratory abnormalities. Exploratory laparoscopy was performed and excision of
the lesion revealed HP in the mesentery of the proximal jejunum. Histology confirmed the presence of pancreatic acini, ducts and islet cells.
Suggested Reading
Embryology
1. Hikspoors JPJM, Kruepunga N, et al. The development of the dorsal mesentery in human
embryos and fetuses. Semin Cell Dev Biol. 2018. https://www.sciencedirect.com/science/
article/pii/S1084952117305438.
Pancreatitis and Other Diseases
2. Blenkiron C, Askelund K, et al. MicroRNAs in mesenteric lymph and plasma during acute
pancreatitis. Ann Surg. 2014;260(2):341–7.
3. Chi XX, Zhang XM, et al. The normal transverse mesocolon and involvement of the
mesocolon in acute pancreatitis: an MRI study. PlosOne. 2014. https://doi.org/10.1371/
journal.pone.0093687.
4. Fanous MYZ, Phillips AJ, et al. Mesenteric lymph: the bridge to future management of
critical illness. JOP. 2007;8(4):374–99.
5. Caruso JM, Feketeova E, et al. Factors in intestinal lymph after shock increase neutrophil
adhesion molecule expression and pulmonary leukosequestration. J Trauma. 2003; 55:727–
33. Van MinnenLP, Besselink MG, et al. Colonic involvement in acute pancreatitis: a
retrospective study of 16 patients. Dig Surg 2004; 21: 33–38; discussion 39–40.
6. Mittal A, Phillips ARJ, et al. The proteome of mesenteric lymph during acute pancreatitis and
implications for treatment. JOP. 2009;10(2):130–42.
Panniculitis
7. Laureano A, Mestre T, Ricardo L, et al. Pancreatic panniculitis - a cutaneous manifestation of
acute pancreatitis. J Dermatol Case Rep. 2014;8(1):35– 7.
8. Acharya C, Navina S, et al. Role of pancreatic fat in the outcomes of pancreatitis.
Pancreatology. 2014;14(5):403–8.
9. Akram S, Pardi DS, Schaffner JA, Smyrk TC. Sclerosing mesenteritis: clinical features,
treatment, and outcome in ninety-two patients. Clin Gastroenterol Hepatol. 2007;5:589.
10. Requena L, Sanchez Y. Panniculitis: part II mostly lobular panniculitis. J Am Acad Dermatol.
2001;45(3):325–364.
11. García-Romero D, Vanaclocha F. Pancreatic panniculitis. Dermatol Clin. 2008;26:465–70.
148 C. Broy et al.
12. Camilleri MJ, Daniel Su WP. Disorders of subcutaneous tissue: panniculitis. In Freedberg IM,
Eisen AZ, Wolff K (eds) Fitzpatricḱs dermatology in general medicine, 6th edn, pp 1047–
1067. New York: Mc Graw Hill; 2003.
13. Price-Forbes AN, Filer A, et al. Progression of imaging in pancreatitis panniculitis
polyarthritis (PPP) syndrome. Scand J Rheumatol. 2006;35:72– 4.
14. Scudiere JR, Shi C, et al. Sclerosing mesenteritis involving the pancreas as mimicker of
pancreatic cancer. Am J Surg Pathol. 2010;34(4):447–53.
15. Phillips RH, Carr RA, Preston R, et al. Sclerosing mesenteritis involving the pancreas: two
cases of a rare cause of abdominal mass mimicking malignancy. Eur J Gastroenterol Hepatol.
1999;11:1323–9.
Heterotopic Pancreas
16. Tang XB, Liao MY, Wang WL, Bai YZ. Mesenteric heterotopic pancreas in a pediatric
patient: A case report and review of literature. World J Clin Cases. 2018;6(14):847–53.
17. Wong J, Robinson C, et al. Recurrent ectopic pancreatitis of the jejunum and mesentery over a
30-year period. Hepatobiliary Pancreat Dis Int. 2011;10(2):218–20.
18. Canbaz H, Colak T, et al. An unusual cause of acute abdomen: mesenteric heterotopic
pancreatitis causing confusion in clinical diagnosis. Turk J Gastroenterol. 2009;20(2):142–5.
19. Hsia CY, Wu CW, et al. Heterotopic pancreas: a difficult diagnosis. J Clin Gastroenterol.
1999;28:144–7.
20. Silva AC, Charles JC, et al. MR Cholangiopancreatography in the detection of symptomatic
ectopic pancreatitis in the small-bowel mesentery. Am J Roentgenol. 2006;187:W195–7.
21. Kim SK, Melton DA. Pancreas development is promoted by cyclopamine, a hedgehog
signaling inhibitor. Proc Natl Acad Sci. 1998;95:13036–41.
22. de Kok BM, de Korte FI, et al. Acute clinical manifestation of mesenteric heterotopic
pancreatitis: a pre-and postoperative confirmed case. Case Reports in Gastrointestinal
Medicine; 2018.
IgG4-Related Diseases and the Mesentery
Ahmed Khattab, David H. Kruchko, and Eli D. Ehrenpreis
Introduction
IgG4 is one of four subcomponents of IgG, or immunoglobulin G. IgG is the most
common immunoglobulin in the circulation, representing almost 75% of circulating
immunoglobulins in human blood. IgG is produced in plasma cells. The role of IgG
is to bind to foreign invaders such as bacteria, fungi, and viruses to prevent these
organisms from producing disease states. Of the four subgroups of IgG, IgG4
represents the lowest concentration in human serum. Tissue level of IgG4 is directly
related to the presence of acute inflammation. There is evidence to suggest that
IgG4 has a regulatory rather than a direct inflammatory effect, and with this model,
IgG4 has the physiologic function of protecting other molecules of the IgG subclasses. IgG4 produces a pathologic state when deviation from its physiologic
action occurs. In this setting, rearrangement of the antibody structure of IgG4
occurs across a labile disulfide bond (Fig. 17.1). The figure demonstrates
downward-facing red arrows that indicate the disulfide bonds. This is referred to as
the hinge region of the molecule. Occasionally, these labile disulfide bonds enable
inappropriate transformation of the IgG4 molecule, resulting in pathogenic IgG4
autoantibodies that inappropriately attack self-antigens.
17
A. Khattab
Department of Internal Medicine, Division of Gastroenterology, Advocate Lutheran General
Hospital, Park Ridge, IL 60068, USA
D. H. Kruchko
Department of Internal Medicine, Advocate Lutheran General Hospital, Chicago, IL 60068,
USA
E. D. Ehrenpreis (&)
Department of Medicine, Advocate Lutheran General Hospital, 1775 Dempster St,
6 South, Park Ridge, IL 60068, USA
e-mail: e2bioconsultants@gmail.com
© Springer Nature Switzerland AG 2021
E. D. Ehrenpreis et al. (eds.), The Mesenteric Organ in Health and Disease,
https://doi.org/10.1007/978-3-030-71963-0_17
149
150 A. Khattab et al.
Fig. 17.1 Characteristic feature of Fab (Antigen-binding Fragment) arm exchange across the
disulfide bond of IgG4. The hinge region, (downward-facing red arrowhead), contains the disulfide
bond. These disulfide bonds are labile and thereby permit inappropriate splitting and exchange of
the Fab structure found in IgG4. This is what allows IgG4 molecules to transform from regulatory
to pathogenic antibodies. Reused from Kawa S. Immunoglobulin G4-related Disease: An
Overview. JMA J. 2019;2(1):11–27. Attribution 4.0 International (CC BY 4.0)
These disease states are referred to as IgG4-Related Disease, or IgG4-RD.
IgG4-RD are characterized by excessive inflammatory response leading to fibrosis.
For this reason, IgG4-RD are referred to as a fibroinflammatory conditions. Most
organs are potential targets of IgG4-RD, including the mesentery, and gastrointestinal (GI) tract organs, including the biliary tree and the pancreas.
Pathogenesis
Pathogenetic development of IgG4-RD can ultimately be summarized as lymphoplasmacytic infiltration of IgG4+ plasma cells. The term lymphoplasmacytic indicates a concentration of lymphoid cells and plasma cells. Interestingly,
IgG4-containing plasma cells may be confined to affected tissues and frequently
are not circulating in the blood; therefore, IgG4 levels may not be elevated when
measured in the peripheral blood. When local inflammation is p resent, lymphoid
cells are generally recruited along with the plasma cells. Specifically, regulatory T
(Treg) cells are most commonly associated with IgG4-RD as well as other
autoimmune diseases. Treg cells are responsible for secreting specific cytokines in
17 IgG4-Related Diseases and the Mesentery 151
normal immune physiology. In IgG4-RD, dysregulation of Treg cells occurs with
associated inappropriate cytokines secretion, (see Fig. 11.4 in Chap. 11 Immunologic Function of the Mesentery). The most notable cytokines secreted by Treg cells
are IL-4, IL-5, IL-10, IL-13, and TGF-beta. These cytokines play an important role
in the production and recruitment of eosinophils. This ultimately leads to eosinophilic deposition in target tissues and organs. Peripheral eosinophilia and elevated
serum IgE levels also occur. IL-10 was found to have the most intimate relationship
with IgG4 production and this ultimately leads to local fibrosis via TGF-beta
expression. Local fibrosis can best be explained by the fact that TGF-beta is primarily responsible for cell growth, proliferation, and apoptosis (cell death).
Therefore, if any of these three roles of TGF-beta are dysregulated, inappropriate
cell growth and proliferation and inadequate cell death follow.
Storiform fibrosis is a key histologic feature of IgG4-RD and is defined as
“swirling fibrotic tissue encasing cellular infiltrate in collagen fibrils.” When seen
on tissue biopsy, storiform fibrosis is highly suggestive, although not pathognomonic, of IgG4-RD. Storiform fibrosis is commonl y seen in Type I Autoimmune
Pancreatitis, an IgG4-RD affecting the pancreas.
Autoimmune pancreatitis (AIP) is the most well studied IgG4-RD of the GI tract.
AIP can present as an acute pancreatitis, but more often, it manifests as a more
insidious onset. It is estimated that AIP accounts for approximately 5% of all cases
of chronic pancreatitis. IgG4-related sclerosing cholangitis, has attracted recent
investigation, as have studies of the pathogenesis of retroperitoneal fibrosis and
other mesenteric manifestations of IgG4-RD. Human leukocyte antigen (HLA) genes have been implicated in the development of IgG4-RD. Specifically, HLA
subtypes DQB1_0401 and DRB1_0405 were found to be highly expressed in
patients with AIP as compared to healthy patients. Furthermore, AIP patients also
have higher levels of DQB1_0401 and DRB1_0405 expres sion compared to other
patients with chronic pancreatitis.
Non-HLA genes that are associated with AIP consist of single nucleotide polymorphisms (SNPs). SNPs have been increasingly found to have clinical significance
as it relates to the development, response to treatment, and prognosis of a variety of
diseases. The SNPs associated with AIP are CTLA-4_49A, Cytotoxic
T-Lymphocyte Antigen-4, and TNF-alpha promoter_863, a Tumor Necrosis
Factor-alpha promoter gene. Studies performed in Chinese and Japanese patients
have found these SNPS to be more highly expressed in AIP patients than in patients
without known disease. In terms of clinical significance, CTLA-4_49A was a marker
for a higher likelihood of relapse after seemingly adequate initial treatment of AIP.
Clinical Manifestations
IgG4-RD has been identified in virtually all organ systems. In most cases (60–90%)
it affects more than one system simultaneously by causing subacute painless
enlargement of the affected organs. As expected, clinical manifestations vary
152 A. Khattab et al.
depending on the organ system involved and commonly include complications
secondary to compression of nearby structures. Thus, IgG4-RD should be considered in patients presenting with unexplained enlargement of one or more organs.
At the time of diagnosis, the patients are usually well and have no systemic
symptoms, especially fever. However, significant weight loss in the months preceding diagnosis is not uncommon. Due to an increased awareness of the IgG4-RD,
these more commonly being diagnosed as an incidental finding seen on imaging or
histopathology in otherwise asymptomatic patients.
IgG4-RD include type 1 autoimmune pancreatitis (AIP)*, sclerosing cholangitis*,
sclerosing mesenteritis*, Mikulicz disease, sclerosing sialadenitis, Inflammatory
orbital pseudotumor, chronic sclerosing dacryoadenitis, idiopathic retroperitoneal
fibrosis*, Chronic sclerosing aortitis and periaortitis*, and Riedel’s thyroiditis.
Because diseases with an (*) are closely related to the mesentery, they will be
discussed in more detail.
Type 1 Autoimmune Pancreatitis (AIP)
Type 1 AIP was the first identified form of IgG4-RD and is considered to be the
prototypical form. It accounts for approximately 5% of patients with chronic
pancreatitis. Almost all patients are older than 45 at the time of diagnosis. Type 1
AIP often presents with a pancreatic mass or painless jaundice and can therefore be
mistaken for pancreatic cancer. It has been estimated that 3–9% of patients who
undergo pancreatic resection are discovered to have had Type 1 AIP. Patients with
Type 1 AIP develop diabetes mellitus due to destruction of endocrine portions of
the pancreas. It is commonly associated with other IgG4-related conditions. Radiologic features of AIP include a “sausage-shaped” pancreas with a surrounding halo
of edema around the organ. It is very difficult to distinguish AIP from pancreatic
adenocarcinoma on imaging. Some authors have suggested that diffusion-weighted
magnetic resonance (MR) imaging findings maybe more useful than CT in making
such a distinction.
IgG4-Related Sclerosing Cholangitis (SC)
IgG4-related SC is the second most common manifestation of IgG4-RD. Although
IgG4-related SC affects 60–80% of patients with type 1 AIP, it can occasionally
occur as an isolated manifestation. Because it leads to focal or diffuse bile duct wall
thickening IgG4-related SC tends to present as obstructive jaundice. The most
commonly affected segment is the intra-pancreatic portion of the common bile duct.
IgG4-related SC and primary sclerosing cholangitis have similar magnetic resonance cholangiopancreatographic (MRCP) and endoscopic retrograde cholangiopancreatographic (ERCP) findings. Primary sclerosing cholangitis is usually a
17 IgG4-Related Diseases and the Mesentery 153
disease of young and middle age males while IgG4-related SC typically affects
middle aged and elderly me. IgG4-related SC exhibits a good response to glucocorticoid therapy.
Sclerosing mesenteritis (SM), mesenteric lipodystrophy and mesenteric panniculitis are terms that have been used interchange ably in the literature (Table 17.1).
There have been some case reports relating SM to IgG4-RD. However, to this date,
there is not enough evidence to determine this association (see Chap. 20 Mesenteric
Panniculitis).
SM likely represents a specific form of mesenteric panniculitis that is predominated by fibrosis. As in other IgG4-RD, SM may present with weight loss fever and
malaise. In these cases, an abdominal mass can be palpated on examination, and
occurs in one-third to one-half of patients. Abdominal tenderness, distension, signs
of peritoneal irritation and ascites are less common. Some patients present with
bowel obstruction, obstructive uropathy or renal failure, chylous ascites, and vascular occlusion. Laboratory findings include elevated erythrocyte sedimentation rate
and C-reactive protein. The natural history o f SM associated with IgG4-RD has not
been fully established in the literature.
Table 17.1 Summary of terminology used to describe sclerosing mesenteritis among different
disciplines
Discipline Mesenteric
lipodystrophy
Pathology Predominant fat
necrosis
Radiology Not frequently
used
Clinical All 4 terms have
been used
interchangeably
throughout the
literature
From Danford CJ, Lin SC, Wolf JL. Sclerosing Mesenteritis. Am J Gastroenterol. 2019 Jun;114
(6):867–873. Copyright © Wolters Kluwer.
Mesenteric
panniculitis
Predominant chronic
inflammation
Meets at least 3 of 5
criteria (i) Fatty
mesenteric mass;
(ii) Hyperattenuated
mesenteric fat;
(iii) Mesenteric
small (<10 mm)
lymph nodes;
(iv) Fat halo sign;
(v) Pseudocapsule
Retractile
mesenteritis
Predominant
fibrosis
Both terms used
interchangeably
and are not clearly
defined. Often
describe more
aggressive disease
with signs of
obstruction or
encasement of
bowel or vessels
Sclerosing
mesenteritis
Umbrella term for
any benign
fibroinflammatory
disease of the
mesentery with any
degree of fat
necrosis, chronic
inflammation and
fibrosis
154 A. Khattab et al.
Retroperitoneal Fibrosis, Chronic Sclerosing Aortitis and Periaortitis
Retroperitoneal fibrosis (RF), chronic sclerosing aortitis and periaortitis are other
forms of IgG4D. It has been suggested that previously described “idiopathic” RF is
actually an IgG4-mediated disease. RF typically affects the infrarenal portion of the
abdominal aorta with the simultaneous involvement of the iliac arteries. Progressive
fibro-inflammatory changes in the distal aorta lead to obstructive uropathy. On
imaging, IgG4-related RF is seen as a soft-tissue mass encasing the abdominal aorta
and its branches. Hydronephrosis and hydroureter are not uncommon. As with AIP,
RP is responsive to glucocorticoid therapy. IgG4-related periaortitis, may lead to
aneurysmal formation and possible rupture.
Diagnosis of IgG4-RD
The diagnostic process of IgG4-RD begins by clinical recognition of the symptoms
and physical exam findings suggestive of the disease. Alternatively, these conditions
are suggested by incidental findings found on imaging studies. Biopsy findings are
the cornerstone of diagnosing IgG4-RD. These findings include lymphoplasmacytic
tissue infiltration of IgG4-positive plasma cells and lymphocytes in association with
storiform fibrosis. These findings are often accompanied by obliterative phlebitis and
tissue eosinophilia. IgG4 lymphoplasmacytic infiltrates are not specifictoIgG4-RD.
They can be found in malignancies and autoimmune disorders. It is important to rule
out those disorders first as they are much more common than IgG4-RD. After the
diagnosis of IgG4-RD has been established, the extent of the disease should be
determined. Imaging of the chest, abdomen and pelvis via CT or MRI is highly
effective in achieving that purpose. Characteristic findings include diffuse and focal
organ infiltration and encasement by inflammatory and fibrotic tissue.
Treatment
The location, severity and duration of patient symptomology and clinical findings
determine the treatment regimen for IgG4-RD. Gastrointes tinal disease (e.g.
mesentery, biliary tree, and pancreatic) often presents acutely and requires urgent
treatment. Treatment principles focus on reducing inflammation and host immune
response. The initial treatment focuses on glucocorticoid therapy, often administered at high doses followed by a slow taper. However, some patients may not be
able to tolerate corticosteroids or may have ongoing symptoms and disease activity
despite corticosteroids. In these patients, other immunosuppressive agents are
administered and these treatments may be used in combination with glucocorticoids. Rituximab monotherapy is has shown to eliminate relapses within a