Form Of Autoimmune Pancreatitis Research Articles

S4 Autoimmune Pancreatitis Secondary to Immune Checkpoint Inhibitor Therapy (Type 3 AIP): Insights into a New Disease from Clinical Review and Serial Pancreatic Imaging

Introduction: Autoimmune pancreatitis (AIP), types 1 and 2, are well described. While type 1 AIP is a pancreatic manifestation of immunoglobulin G4-related disease (IgG4-RD) and type 2 AIP is a duct-centric pancreatic injury sometimes associated with inflammatory bowel disease. A third form of AIP (type 3) is caused by increased immune activity by immune checkpoint inhibitor therapy (ICI-℞) for advanced malignancies. We describe the clinico-radiological spectrum and short-term natural history of type 3 AIP. Methods: We performed a detailed clinical record review of the 248/11,165 (2.2%) adult patients receiving ICI-℞ who developed type 3 AIP (>3-fold serum lipase elevation + pain, absent other etiologies). A radiologist reviewed 379 abdominal computerized tomography scans (CT) and measured pancreas volume in a subset of CTs done before, during and after pancreatitis. Results: At onset, type 3 AIP was painful in 96 (38%) and asymptomatic in 154 (62%); none had jaundice or local/systemic complications. CT showed normal pancreas (43%), peri-pancreatic edema (27%), loss of feathery pattern (21%) or diffuse/focal pancreatic enlargement (10%). A minority achieved complete and persistent biochemical resolution, more often when ICI-℞ was held (32/89) vs no intervention (13/84, P = 0.003) or vs steroid treatment alone (2/23, P = 0.01). Early or late relapses occurred equally frequently regardless of intervention. Compared to pancreas volume before ICI-℞, >20% volume loss occurred in 55% 1 year post-pancreatitis, more so with dual ICI-Rx, regardless of pain or steroid therapy at presentation. 18% had new diabetes within 2 years of pancreatitis. No patient developed calcifications or duct dilation. Conclusion: Type 3 AIP is a novel drug-induced chronic inflammatory disease of the pancreas. Predominantly asymptomatic and mild in severity, it causes rapid pancreatic atrophy and functional endocrine failure despite steroid therapy or ICI-℞ withdrawal. Table 1. - Clinical profile of all type 3 and subjects in imaging cohorts Type 3 AIP* (n=248) Imaging cohort (n=93) Symptomatic (n=94) Asymptomatic (n=154) ≥3x lipase elevation cohort (n=48) 2x lipase elevation cohort (n=24) Normal lipase cohort (n=21) Median Age in years (IQR) 61 (50-68) 62 (54-69) 58 (49-67) 63 (54-69) 59 (55-67) Male N (%) 37 (39%) 72 (47%) 17 (35%) 18 (75%) 13 (62%) Cancer type (%) Genitourinary 27 (29%) 63 (41%) 20 (42%) 14 (58%) 10 (48%) Melanoma 26 (28%) 28 (18%) 16 (33%) 3 (13%) 5 (24%) Other 41 (44%) 63 (41%) 12 (25%) 7 (29%) 6 (29%) ICI Agent (%) CTLA-4 8 (9%) 10 (6%) 5 (10%) 2 (8%) 4 (19%) PD-1 62 (66%) 95 (62%) 28 (58%) 14 (58%) 10 (48%) Combined 24 (26%) 49 (32%) 15 (31%) 8 (33%) 7 (33%) ICI doses prior to elevated lipase (IQR) 4 (2-6) 3 (2-8) 5.5 (3-10) 4.5 (3-13) 3 (2-5, to normal lipase) Median days from ICI to pancreatitis (IQR) 114 (69-264) 113 (52-230) 124 (83-261) 175 (63-348) 95 (47-167, to normal lipase) ICI discontinued (%) 67 (71%) 74 (48%) 28 (58%) 14 (58%) 11 (52%) Risk factors (%) Alcohol consumption 40 (43%) 69 (45%) 22 (46%) 13 (54%) 12 (57%) Smoking history 52 (55%) 77 (50%) 24 (50%) 17 (71%) 7 (33%) Diabetes prior to pancreatitis 16 (17%) 44 (29%) 15 (31%) 6 (25%) 4 (19%) Drug allergy 56 (60%) 81 (53%) 22 (46%) 10 (42%) 10 (48%) Prior history of pancreatitis 5 (5%) 6 (4%) 2 (4%) 1 (4%) 0 *Autoimmune pancreatitis, IQR= interquartile range, ICI= immune checkpoint inhibitor, CTLA-4 (cytotoxic T lymphocyte-associated protein 4), PD-1 (programmed cell death receptor-1) and PD-L1 (programmed cell death ligand-1) Figure 1.: a: Serial pancreatic volume in normal lipase, 2x and 3x groups (median, cm3), b: Serial Pancreatic Volume: Single Agent vs Combination in 3x group (median, cm3), c: Percentage of patients with >20% pancreas volume loss in each group.

Autiue pacreatitis a surgica istae.

Autiue pacreatitis is a specific type f chric pacreatitis Its ciica aifestati iics pacreatic cacer A utidiscipiary apprach is ecessary t estabish the crrect diagsis Autiue pacreatitis ca be diagsed the basis f syptatgy iagig ethds edscpy sergy ad histpathgica exaiati There are tw differet frs f autiue pacreatitis type 1 ad type 2 Type 1 is yphpasacytic scersig pacreatitis ad type 2 is idipathic cetrducta scersig pacreatitis The disease st fte taes a chric fr with acute exacerbatis I this paper we preset tw case reprts f patiets perated fr suspected aigacy f the pacreas wh were subsequety diagsed with autiue pacreatitis based histpathgica exaiati The ai f this cuicati is t pit ut the diagstic pitfas f this disease Surgica treatet is t csidered as a stadard therapeutic ethd accrdig t the curret guideies.

Adolescent Type 2 Autoimmune Pancreatitis

There are two forms of autoimmune pancreatitis (AIP). Type 1 is associated with immunoglobulin G4 (IgG4)-related systemic fibro- inflammatory disease, whereas type 2 AIP is localized to the pancreas and not associated with IgG4. The number of children presenting with type 2 AIP has recently increased. Here, we report a case of type 2 AIP in a 16-year-old adolescent who presented with clinical acute pancreatitis and associated pancreatic masses. He was diagnosed with type 2 AIP based on pancreatic biopsy results showing granulocytic epithelial lesions and supportive radiological imaging and steroid responsiveness.

A case report of IgG4-related disease: an insidious path to the diagnosis through kidney, heart and brain

BackgroundIgG4-related disease, described around the years 2000 as a form of autoimmune pancreatitis, is now increasingly accepted as a systemic syndrome. The diagnosis is based on both comprehensive and organ-specific criteria. For the kidney, Mayo clinic classification and the guidelines of the Japanese Nephrology Society are used. Ultimately, together with parameters that characterize every organ or apparatus involved, the key element is the confirmation of growing levels of IgG4 in blood or in tissues.Case presentationWe describe a male patient with chronic renal failure associated to hypertension without proteinuria. IgG4-related disease was diagnosed through renal biopsy. After an initial positive response to steroids, he presented tinnitus, and histological assessment showed cerebral and subsequently cardiac damage, both IgG4-related. This case appears unique for the type of histologically documented cardiac and neurological parenchymal involvement, and at the same time, exemplifies the subtle and pernicious course of the disease. Frequently, blurred and non-specific signs prevail. Here, kidney damage was associated with minimal urinary findings, slowly progressive renal dysfunction and other factors that can be equivocated in the differential diagnosis. Neurological involvement was represented by tinnitus alone, while cardiac alterations were completely asymptomatic.ConclusionsThis report is representative of the neurological and cardiac changes described in the literature for IgG4-related disease, which may be correlated or not with the renal form and highlights the need, in some cases, of targeted therapeutic approaches. In addition to glucocorticoids, as in this case, rituximab may be necessary.

Untypical autoimmune pancreatitis and pancreatic cancer: differential diagnosis experiences extracted from misdiagnose of two cases

BackgroundDifferentiation between pancreatic cancer (PC) and focal form of autoimmune pancreatitis (AIP) is very challenging, with similar clinical presentations, laboratory results and morphologic imagings of US, CT, EUS, MRI, ERCP, PET-CT. Even serum IgG4 and biopsy sometimes cannot give clear-cut differential accurate diagnostis. Considering the totally different management strategy of the two diseases, accurate diagnostic value is urgently needed to remind the clinicians of the rare diagnosis of untypical AIP among frequent PC-suspected patients.ResultsWe present 2 laparotomy cases of AIP that had a high similar characteristic to PC and retrospectively extracted the warning signs that may help select untypical AIP in PC-suspected patients.ConclusionsWe find that mild fluctuating jaundice with abdominal pain, young age, tumor marker of TPS, TPA and diverse results between variable radiological tests can help to differentiate AIP mass from PC, through retrospectively analyzing work-up process of AIP in two patients who underwent laparotomy for suspected PC.

IgG4-Related Disease: A Reminder for Practicing Pathologists

IgG4-related disease (IgG4-RD) is a systemic autoimmune fibroinflammatory disease that produces sclerotic, tumefactive masses containing dense lymphoplasmacytic infiltrates rich in immunoglobulin (Ig) G4+ plasma cells. Initially characterized as a form of autoimmune pancreatitis, the distinctive histopathology of IgG4-RD has now been described in almost every organ system. However, because the clinical manifestations of IgG4-RD are diverse and nonspecific, the disease may go unsuspected until a biopsy or resection specimen is obtained to diagnose a presumed malignancy. Pathologists thus play a key role in the diagnosis of IgG4-RD, and familiarity with its histopathologic features is essential to preventing the irreversible comorbidities associated with this treatable disease. This brief review outlines the epidemiology, clinical manifestations, and histopathology of IgG4-RD, with the aim of furthering pathologists' awareness of and ability to diagnose this disorder.

Histostructure of pancreas in patients with autoimmune pancreatitis type I and II: connection with the level of IgG4-positive plasma cells

Differential diagnosis of autoimmune pancreatitis apart from everything else is based on specifics of immunoglobulin G4 involvement into the pathogenesis.
 Aim is to analyze two forms of autoimmune pancreatitis and their relation to the level of IgG4-positive plasma cells.
 Methods and results. The present study was conducted on 54 patients with chronic pancreatitis, from which 15 cases with autoimmune pancreatitis were selected by using morphological and immunohistochemical methods.
 Conclusion. It has been established that for autoimmune pancreatitis type I dense lymphocytic periductal infiltrate, multilevel fibrosis, obliterating venulitis and high IgG4-positive plasma cells in the pancreas (>30 per high power field) were typical. In the cases of autoimmune pancreatitis type II, besides the specific histopathological signs of AIP, significantly epithelial damage of pancreatic ducts by leukocytes, low levels of IgG4-PPC in the pancreas and focal lesions on stages I–III of disease (80%) were observed.

IgG4-Related Nasal Pseudotumor.

IgG4-related disease is recognized as one form of autoimmune pancreatitis. During the last ten years, it has also been described in several other organs. We present two patients with lesions showing a histological picture of fibrosis and lymphoplasmacytic infiltrations with abundant IgG4 positive plasma cells at hitherto unreported symmetrical nasal locations. The symmetrical complex consisted of one central lesion in the anterior nasal septum and the two others in each of the lateral nasal walls. The lesions extended from the anterior part of the inferior concha into the vestibulum and caused severe nasal obstruction.

Autoimmune pancreatitis: a guide for the histopathologist

Autoimmune pancreatitis (AIP) is a distinct form of pancreatitis with a characteristic histological appearance. Clinically and radiologically, many of these patients show enlargement of pancreas and pancreatic duct/bile duct strictures, thus mimicking pancreatic carcinoma. There are 2 forms of the disease: (1) type 1 AIP characterized by storiform type fibrosis, obliterative phlebitis, and elevated numbers of immunoglobulin G4 (IgG4) positive plasma cells, typically >50 per high-power field, and, (2) type 2 AIP characterized by granulocytic epithelial lesions and only occasional IgG4-bearing plasma cells, typically <10 per high-power field. The type 1 variant of AIP is the pancreatic manifestation of IgG4-related disease, thus both pancreatic and extrapancreatic recurrences are common. The type 2 variant is unrelated to IgG4-related disease, and disease recurrence is uncommon. Both forms of the disease show a swift response to immunosuppressive therapy. This review highlights the clinical and pathological differences between the 2 forms of AIP. We also review guidelines that assist in distinguishing AIP from its closest mimic, pancreatic adenocarcinoma.

Serum IgG4 in autoimmune pancreatitis: A marker of disease severity and recurrence?

Autoimmune pancreatitis (AIP) is a well-defined clinical entity athologically different from all the other forms of chronic panreatitis. Since its first description, the concept of the disease has reatly changed over time. On the basis of pathological findings, the disease has been ecently classified in type 1 AIP (also called Lympho-Plasmacytic clerosing Pancreatitis – LPSP), and type 2 AIP (also called Idiopathic uct-centric Chronic Pancreatitis – IDCP), as reported by Matsubyashi et al. [1]. These two forms of AIP seem to have different linical profiles, since type 1 AIP is characterized by other organ nvolvement (biliary tract, salivary glands, gastrointestinal tract, idney, retroperitoneum) and frequent relapses after steroid treatent, whereas type 2 AIP seems to be associated with ulcerative olitis and does not relapse. However, both forms show a good esponse to steroids. Morphologically, the disease has been classified in focal AIP, nvolving only a part of the pancreatic gland at imaging techniques, ith or without the presence of a low-density mass, mimicking ancreatic adenocarcinoma, and in diffuse AIP, involving all the lands [2]. This classification is clinically relevant, since the diagostic algorithm is different, as recently reported [3]. Indeed, in he presence of focal AIP, particularly in the presence of a lowensity mass, a diagnosis of pancreatic adenocarcinoma must be xcluded before steroid treatment, whereas in the diffuse form, the ifferential diagnosis is with acute pancreatitis and a diagnosis of holangiocarcinoma needs to be excluded only in the presence of a ingle stenosis of the common biliary tract. In 2001, Hamano et al. [4] reported for the first time high levls of serum IgG4 (sIgG4) in patients suffering from AIP, called in his paper sclerosing pancreatitis, but not in normal subjects and in atients suffering from “ordinary” chronic pancreatitis, or in other utoimmune diseases (primary biliary cirrhosis, primary sclerosng cholangitis, or Sjogren’s syndrome) or in pancreatic cancer. he authors therefore suggested the use of sIgG4 in the diagnosis f AIP, since sensitivity and specificity were very high (respecively 95% and 97%). This paper had a tremendous impact in the

ミクリッツ病とキュットナー腫瘍（慢性硬化性唾液腺炎）の新しい疾患概念

The newly established concepts of Mikulicz's disease and Kuttner's tumor (chronic sialadenitis) are discussed. Mikulicz's disease has been included within the diagnosis of primary Sjogren's syndrome, but it represents a unique condition involving persistent enlargement of the lacrimal and salivary glands. Recently, elevated IgG4 concentration in serum and prominent infiltration by plasmacytes expressing IgG4 in the salivary glands was demonstrated in Mikulicz's disease. Mikulicz's disease differs from Sjogren's syndrome, and may be a systemic IgG4-related plasmacytic disease. Kuttner's tumor is a chronic sclerosing sialadenitis that presents with asymmetrical firm swelling of the submandibular glands. The histological characteristics of Kuttner's tumor are severe fibrosis, atrophic acinus, and mononuclear cell infiltration. Immunohistochemical evaluation demonstrated that the proportion of IgG4-positive plasmacytes was elevated in Kuttner's tumor similar to that in Mikulicz's disease. Therefore, it is possible that both Mikulicz's disease and Kuttner's tumor may involve a similar pathogenesis of IgG4-related disease as a form of autoimmune pancreatitis.