Serum immunoglobulin G fraction 4 levels in pancreatic cancer: elevations not associated with autoimmune pancreatitis.
Abstract: Context.--Autoimmune pancreatitis is an uncommon, inflammatory disease of the pancreas that presents with clinical features, such as painless jaundice and a pancreatic mass, similar to those caused by pancreatic cancer. Patients with autoimmune pancreatitis frequently have elevated serum immunoglobulin G fraction 4 (IgG4) levels, and their pancreatic tissue may show IgG4-positive plasma cell infiltration. It is imperative to differentiate autoimmune pancreatitis from pancreatic cancer because autoimmune pancreatitis typically responds to corticosteroid treatment. A previous Japanese study reported that serum IgG4 greater than 135 mg/dL was 97% specific and 95% sensitive in predicting autoimmune pancreatitis.

Objective.--To prospectively measure serum IgG4 levels in pancreatic cancer patients to ascertain whether increased levels might be present in this North American population.

Design.--We collected blood samples and phenotypic information on 71 consecutive pancreatic cancer patients and 103 healthy controls who visited our clinics between October 2004 and April 2006. IgG4 levels were determined using a single radial immunodiffusion assay. A serum IgG4 level greater than 135 mg/dL was considered elevated.

Results.--Five cancer patients had IgG4 elevation, with a mean serum IgG4 level of 160.8 mg/dL. None of our cancer patients with plasma IgG4 elevation demonstrated evidence of autoimmune pancreatitis. One control subject demonstrated elevated serum IgG4 unrelated to identified etiology.

Conclusions.--As many as 7% of patients with pancreatic cancer have serum IgG4 levels above 135 mg/dL. In patients with pancreatic mass lesions and suspicion of cancer, an IgG4 level measuring between 135 and 200 mg/dL should be interpreted cautiously and not accepted as diagnostic of autoimmune pancreatitis without further evaluation.
Article Type: Report
Subject: Pancreatic cancer (Diagnosis)
Pancreatic cancer (Genetic aspects)
Immunoglobulin G (Research)
Immunoglobulin G (Physiological aspects)
Pancreatitis (Health aspects)
Authors: Raina, Amit
Krasinskas, Alyssa M.
Greer, Julia B.
Lamb, Janette
Fink, Erin
Moser, A. James
Zeh, Herbert J., III
Slivka, Adam
Whitcomb, David C.
Pub Date: 01/01/2008
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2008 College of American Pathologists ISSN: 1543-2165
Issue: Date: Jan, 2008 Source Volume: 132 Source Issue: 1
Topic: Event Code: 310 Science & research
Geographic: Geographic Scope: Japan Geographic Code: 9JAPA Japan; 4E Europe
Accession Number: 230246968
Full Text: Autoimmune pancreatitis (AIP) is a newly classified and rare form of inflammatory pancreatic disease. It often occurs in the presence of other autoimmune disease and is characterized by lymphoplasmacytic inflammatory infiltration of the pancreas and distinct radiographic findings. It has a varied clinical presentation that may include features similar to pancreatic cancer (PC), although AIP typically resolves following corticosteroid treatment. (1-3) Although some researchers argue that AIP falls under the rubric of chronic pancreatitis, others assert it is a focal, pancreatic manifestation of a systemic disorder called IgG4-related systemic disease that features elevated serum immunoglobulin G fraction 4 (IgG4) levels and infiltration with IgG4-positive plasma cells in affected organs. (4) Other terminology that has been used to describe AIP includes primary inflammatory pancreatitis, (5,6) sclerosing pancreatitis, (7) lymphoplasmacytic sclerosing pancreatitis, (8) and sclerosing pancreatocholangitis. (9) Knowledge gained from recent case studies has helped to characterize the pathological features and variants of AIP. (1,10)

The common clinical presentation of AIP includes abdominal discomfort, painless obstructive jaundice, mild attacks of pancreatitis, recent onset of diabetes mellitus, and weight loss and other nonspecific symptoms. This disease predominantly affects men older than 50 years, although women and younger individuals have been observed to be afflicted. (1,2,11) The pancreatic gland may demonstrate focal or diffuse swelling, and the ducts frequently display diffuse or segmental narrowing or ectatic irregularities--features that might be confused with PC on abdominal imaging. (12-14) Two retrospective studies among North American populations concluded that between 2.2% and 2.4% of people who undergo pancreaticoduodenectomy for a pancreatic mass believed to be PC were actually observed to have pathology that is consistent with AIP. (15,16)

In 2001, Hamano et al (17) reported that an elevated IgG4 level was a predictable marker of AIP. IgG4 typically composes close to 4% of the total circulating immunoglobulin G in adults. (18) Elevated IgG4 levels have been reported in pemphigus vulgaris and pemphigus foliaceous, (19) atopic dermatitis, (20) and some parasitic infections (21-24) but rarely have been observed to occur in the context of other diseases. Using an upper normal limit for serum IgG4 of 135 mg/dL, Hamano et al (17) reported a diagnostic 95% sensitivity and 97% specificity for AIP and, thus, the ability to exclude a diagnosis of PC. In their study, the serum IgG4 levels of patients with pancreatic adenocarcinoma, chronic pancreatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and Sjogren syndrome were found to be similar to those of healthy subjects. Based upon these findings, Hamano et al suggested that elevated IgG4 levels could be used to accurately diagnose AIP and also to differentiate AIP from PC.

Although an elevated IgG4 level appeared to be useful in confirming the diagnosis of AIP in selected patients in Japan, it is not clear that this same measurement is effective in screening unselected populations for AIP or that elevated IgG4 levels are useful in excluding PC in subjects with radiographic evidence of a pancreatic mass. A number of investigators have recently reported on patients with histologically proven pancreatic adenocarcinoma who were observed to have elevated serum IgG4 levels. (25-27) Nonetheless, a significantly elevated serum IgG4 level is increasingly used clinically to establish AIP and to exclude PC in patients with clinical symptoms and a radiographic evaluation consistent with either entity. The current study was designed to prospectively measure serum IgG4 levels in patients being treated for PC and to determine whether our patient population corroborated the previous finding in a Japanese patient group that IgG4 levels elevated above 135 mg/dL are generally indicative of AIP

PATIENTS AND METHODS

Subjects

Between October 2004 and April 2006, 71 consecutive patients who had been diagnosed with pancreatic cancer and 103 healthy control subjects were recruited into our internal review board (IRB)-approved study. Ethics committee approval for this study was provided by the University of Pittsburgh IRB, IRB No. 0308010, in October 2003. Control subjects were spouses or friends of patients in our digestive disease clinics who were accompanying a patient on his or her visit and who were willing to complete a comprehensive questionnaire. Patients and control subjects were informed of their rights and of the study protocol; they provided informed consent as per protocol. Thereafter, cases and their evaluating physicians completed a standardized questionnaire that included demographic, epidemiologic, medical, and family history, as well as treatment information. Controls completed a questionnaire that was identical except that it lacked diagnosis- and treatment-related information. Blood samples were collected, and questionnaire information was recorded in a confidential database. Whenever available, tissue obtained from surgical case resection was also examined.

Diagnosis of pancreatic adenocarcinoma was based on histocytologic information in 70 patients (98.5%) and on radiologic criteria in 1 (1.5%). Follow-up information was available for all patients as secondary confirmation of PC.

Laboratory Test

Serum samples were stored at -80[degrees]C and were thawed only once immediately prior to testing. Single radial immunodiffusion assay (Binding Site, Birmingham, United Kingdom) was used to measure serum IgG4 concentrations in subjects, as has been validated in a previous study. (17) IgG4 levels greater than 135 mg/dL were classified as being elevated based upon the criteria of Hamanoetal. (17) IgG4 levels for 3 subjects were calculated in multiple assays with internally consistent results that confirmed the reproducibility of the assay. The histology of all available specimens was reviewed by a pathologist. Immunohistochemistry for IgG4-positive plasma cells was performed on formalin-fixed, paraffin-embedded tissue sections. The monoclonal anti-human IgG4 antibody (Zymed, San Francisco, Calif) was applied to 4[micro]m-thick sections using a standard technique. The number of IgG4-positive plasma cells in a high-power field (HPF) was quantified and recorded.

RESULTS

Of our 71 PC patients, 26 (36.7%) were women and 45 (63.3%) were men. Of our 103 control subjects, 63 (61.2%) were women and 40 (38.8%) were men. The mean age (range) of the patients was 65.2 (41-92) years and of the controls was 53.2 (24-83) years (data not shown). The average measurable serum IgG4 concentration for our PC patient population was 44.8 mg/dL (not shown). Five study subjects (7%) had a serum IgG4 level below the level of detection, while an additional 5 (7%) subjects displayed IgG4 levels above the threshold of 135 mg/dL. Table 1 summarizes the clinical features of patients with pancreatic adenocarcinoma who demonstrated increased IgG4 levels. The average, measurable serum IgG4 concentration of controls was 42.6 mg/dL, with 4 control participants having serum IgG4 concentrations below the level of detection. One control subject, a 56-year-old woman with a medical history of hypertension, demonstrated an elevated serum IgG4 level of 159 mg/dL, which, on reevaluation, was measured as 164 mg/dL.

Figure 1 compares serum IgG4 levels in PC cases and control subjects. Although the average overall IgG4 level was similar in the 2 groups, the Fisher exact test demonstrated that the elevation was significant in PC cases when compared with controls (2-sided P = .04) (data not shown).

The majority of patients with PC and elevated IgG4 levels received histocytopathologic confirmation of pancreatic adenocarcinoma. Table 2 describes clinical features of PC cases. Three of these patients (60%) demonstrated evidence of locally advanced or distant metastasis. Of the 5 patients with PC and IgG4 elevation, histology was not available for 1 patient (patient 1), although the patient had gross vascular invasion and positive regional lymph nodes. Of the remaining 4 patients, 1 patient (patient 5) was diagnosed on duodenal biopsy (adenocarcinoma infiltrating into duodenum), and 1 (patient 3) was diagnosed on cytology. The remaining 2 patients (patients 2 and 4) underwent surgery following preoperative chemoradiation therapy. Histologic sections from each of the 2 resulting pancreatic resections were remarkable for peritumoral pancreatic fibrosis.

[FIGURE 1 OMITTED]

One patient (patient 2) had no significant chronic inflammation within the pancreas but did have a prominent lymphoplasmacytic infiltrate beneath the bile duct epithelium (Figure 2, A and B), while the other patient (patient 4) had evidence of pancreatic atrophy and scattered chronic inflammatory cells throughout the fibrotic, atrophic pancreas. Neither patient displayed histologic evidence of AIP. The IgG4 immunohistochemical stains in these specimens revealed rare, scattered foci of IgG4-positive cells within the pancreas; fewer than 5 HPF contained up to 15 IgG4-positive cells (Figure 2, C). Additionally, the lymphoplasmacytic infiltrate within the common bile duct of patient 2 contained up to 50 IgG4-positive plasma cells per HPF (Figure 2, B). One lymph node was present on the slide from patient 4, and this lymph node contained up to 40 IgG4-positive cells in 1 HPF. Histologic sections from the duodenal biopsy (patient 5) demonstrated a mild increase in lamina propria lymphoplasmacytic inflammation in the peritumoral duodenal mucosa. The IgG4 immunohistochemical stain in this patient displayed up to 50 IgG4-positive cells within the lamina propria of the duodenum (Figure 2, D).

Seven of our PC patients who also underwent surgery but who did not have serologic elevation of IgG4 were reviewed for comparison. On routine histology, the peritumoral pancreatic tissue of these PC cases demonstrated fibrosis and scattered chronic inflammation in 4 patients; evidence of chronic pancreatitis with fibrosis, increased chronic inflammation and atrophy in 2 patients; and moderate peritumoral chronic inflammation in 1 patient. Three of these patients had received preoperative chemoradiation therapy, and none of the 7 PC patients with nonelevated IgG4 was observed to have any histologic evidence of AIP. IgG4 immunohistochemistry was performed on all 7 and revealed rare, scattered foci of IgG4-positive cells within the pancreas; fewer than 5 HPF contained up to 15 IgG4-positive cells (similar to that seen in Figure 2, B); in 1 case, a lymph node was present that contained up to 30 IgG4-positive cells in 2 HPF.

COMMENT

Autoimmune pancreatitis is a rare pancreatic disease that may be associated with a variety of autoimmune conditions, including Sjogren syndrome, sclerosing cholangitis, systemic lupus erythematosus, Hashimoto thyroiditis, and inflammatory bowel disease. (3,28-30) The disease can present in a heterogeneous or indolent manner with mild or subclinical attacks of pancreatitis; it sometimes presents as diffuse pancreatic enlargement or a focal pancreatic mass. The clinical signs and symptoms of AIP, such as abdominal discomfort and painless jaundice, are disease manifestations frequently observed in pancreatic adenocarcinoma. Additionally, the demographics for AIP and PC are identical, in that both occur predominantly in older individuals and are more common in men than women. Before AIP was widely recognized and defined by clinical criteria, some studies estimated that a small but significant percentage of patients who underwent surgery for PC were found to actually have AIP. (15,16) However, AIP is a benign condition that usually responds well to corticosteroid therapy and does not require surgical resection. Prompt and accurate diagnosis is therefore necessary to properly treat patients and to distinguish those with malignancy from those with AIP.

[FIGURE 2 OMITTED]

The majority of research on AIP, to date, has been conducted in Japan and Europe. * From these studies, patients with AIP have been observed to demonstrate characteristically increased levels of various autoantibodies as well as elevations of serum IgG4. However, no single autoantibody is predictive of AIP. In such fashion, measuring serum IgG4 has been proposed as a diagnostic, preoperative method to confirm AIP and exclude PC in patients with pancreatic mass lesions. (12,17,31) This proposal has been supported by some Japanese studies reporting a reproducible high sensitivity and specificity of IgG4 in diagnosing AIP. (12,31) However, the utility of serum IgG4 testing to differentiate AIP from pancreatic adenocarcinoma has recently become controversial following case reports of elevated IgG4 levels in PC patients. (25-27)

The present study was designed to confirm the predictability of IgG4 levels in PC patients in a North American population and to reassert the clinical feasibility of using IgG4 elevations in distinguishing PC from AIP, especially in patients who present with similar clinical symptoms and radiographically defined pancreatic mass lesions. We ascertained PC cases from a prospective study in which individuals provided detailed demographic and epidemiologic evaluation and were undergoing a prospective evaluation. The recruitment was conducted in a tertiary referral center where all subjects with PC received a thorough diagnostic evaluation.

In the present study, we examined IgG4 levels among 71 consecutive patients with PC. Five patients (7%) were found to have elevated IgG4 levels. The mean serum IgG4 level among these 5 patients was 160.8 mg/dL, with a range from 144.1 to 194.0 mg/dL. None of these patients displayed any evidence of having a condition known to be associated with a serum IgG4 elevation. (19,21-24) Immunohistochemically, there was no significant infiltration by IgG4-positive plasma cells within the peritumoral pancreatic tissue. However, 3 of the 5 IgG4-elevated cancer cases stained for IgG4 did show significant numbers of IgG4-positive plasma cells outside of the pancreatic parenchyma. Most importantly, these patients did not have any histological evidence of AIP. Additionally, 1 control subject without evidence of pancreatitis or autoimmune disease was found to have a serum IgG4 level above 135 mg/dL. On further examination, the control participant did not have a history of allergies, skin disorders, or parasitic infections--the illnesses that, outside of AIP, have been associated with increased serum IgG4 levels. Thus, idiopathic serum IgG4 increases may also exist.

Recently, some researchers have recounted cases of PC with elevated serum IgG4 levels. Kamisawa et al (26) described a case of histologically proven pancreatic adenocarcinoma with elevated IgG4 levels (IgG4 = 433 mg/dL). On immunohistochemical staining, they found abundant IgG4-positive plasma cells (>20/HPF) infiltrating the cancerous pancreatic region, but only a few (<3/HPF) IgG4-positive cells infiltrating cancer-free areas. They observed that the patient's regional lymph nodes were enlarged up to a diameter of 1.5 cm with abundant IgG4-positive cell infiltration and that there was evidence of IgG4-positive plasma cell infiltration of the duodenum. They concluded, nonetheless, that the patient most likely had PC and IgG4-related system disorder as separate processes. Inoue et al (25) described a patient who met diagnostic criteria for AIP and also had features of PC. Based on these case reports and our results, it seems that there is a subpopulation of patients with PC who may have a serum IgG4 level greater than 135 mg/dL, as well as IgG4-laden plasma cell infiltration in the pancreas adjacent to the cancer and in the peripancreatic tissue. Future studies should be conducted to address whether AIP and pancreatic adenocarcinoma actually occur as independent processes as suggested by Kamisawa et al, whether the possibility exists that untreated AIP can somehow incite the development of cancer, or whether PC can initiate an immune response with subsequent plasma cell infiltration in pancreatic and peripancreatic tissue that is considered to be characteristic of AIP.

Because AIP is a newly characterized entity, discrepancies in interpretation of disease manifestations may exist. For example, although they have recently been revised, (40) radiographic criteria in Japan were stringent in the past, when the Japan Pancreas Society in 2002 mandated the presence of characteristic pancreatic enlargement with a diffusely irregular, narrow pancreatic duct for diagnosis of AIP. (41) The Mayo Clinic, however, noted that on computed tomographic scans of 22 of their documented AIP patients, only 6 patients (27%) had diffuse enlargement, while the remaining 16 displayed either focal enlargement, a distinct mass, focal acute pancreatitis, or a normal-appearing pancreas. (41) The recent HISORt criteria from the Mayo Clinic, in fact, consist of 5 categories: histology, imaging studies, serology, other organ involvement, and response to steroid therapy. (42) Another newly designed system of categorizing AIP, the Kim criteria, is similar to HISORt but lacks a category for other organ involvement. (43)

The possibility of ethnic variation in immune-related genetic polymorphisms or mutations influencing IgG4 levels also exists. However, while the majority of published reports have documented increased IgG4 levels only in AIP or primary sclerosing cholangitis, (31,44,45) as previously noted, at least 2 patients with PC in Japanese patient populations have demonstrated high serum IgG4 levels. (25,26) Recent research from North America has discussed the importance, as well as the challenging nature, of differentiating AIP from PC in avoiding unnecessary surgery for a benign condition. (46)

The strengths of our study include our history of expertise in evaluating pancreatic disease and pancreatic cancer patients, the thoroughness in collecting epidemiologic information and evaluating blood samples, and our ability to histologically examine pancreatic tumor and peritumoral tissue. Our PC cases who demonstrated elevated IgG4 levels were not a homogenous group, but rather were in different stages of disease progression and resectability, as is reflective of the PC population in general. However, not all of the PC patients at our center agreed to enter our study for a variety of reasons, including being newly diagnosed with cancer or being at an advanced stage of disease and in poor health. Whether these PC patients might have had elevated levels of serum IgG4 is unknown, and whether these levels would strengthen or attenuate our findings cannot be discerned. Nonetheless, we believe that our 71 participating PC cases were representative of the regional PC population as well as of such patients in North America.

In summary, our study demonstrates that as many as 7% of patients with PC have serum IgG4 levels above 135 mg/dL. This quantity influences the performance characteristics of serum IgG4 levels vis-a-vis false positives for diagnosing AIP, and must be incorporated into clinical algorithms used in the evaluation and management of patients with suspected PC or AIP. In patients with established PC and elevated IgG4 levels, we found no histological evidence of underlying AIP but did observe IgG4-rich inflammatory infiltrates in surrounding nonpancreatic tissue. Therefore, in patients with pancreatic mass lesions, a serum IgG4 level in the 135 to 200 mg/dL range should not be regarded as an unequivocal diagnostic criterion for AIP and should not preclude a thorough evaluation for pancreatic adenocarcinoma.

We thank Susan J. Urda for assistance with the pancreatic cancer registry, Emil Bauer for data entry and database management, and Jeremy J. Martinson, DPhil, for assistance in preparation of Figure 1. Support for this work was provided by the National Institute of Diabetes and Digestive and Kidney Diseases DK061451 (Dr Whitcomb), The Gott Family Foundation (Dr Whitcomb), the National Institutes of Health Digestive Disease Training Program T32DK063922 (Dr Greer), and the University of Pittsburgh Medical Center cancer registry.

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* References 2, 4, 10-12, 17, 25, 26, 31-39.

Amit Raina, MD; Alyssa M. Krasinskas, MD; Julia B. Greer, MD, MPH; Janette Lamb, PhD; Erin Fink, MS; A. James Moser, MD; Herbert J. Zeh III, MD; Adam Slivka, MD, PhD; David C. Whitcomb, MD, PhD

Accepted for publication August 10, 2007.

From the Departments of Medicine (Drs Raina, Greer, Lamb, Slivka, and Whitcomb and Ms Fink), Pathology (Dr Krasinskas), and Surgical Oncology (Drs Moser and Zeh), University of Pittsburgh Medical Center; Cell Biology & Physiology and Human Genetics, University of Pittsburgh (Dr Whitcomb); University of Pittsburgh Cancer Institute (Drs Zeh and Whitcomb); and University of Pittsburgh Medical Center Liver Pancreas Institute (Drs Moser, Zeh, Slivka, and Whitcomb), Pittsburgh, Pa.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Julia B. Greer, MD, MPH, GI Administration, Mezzanine Level 2, C Wing, UPMC Presbyterian Hospital, 200 Lothrop Street, Pittsburgh, PA 15213 (e-mail: jbg6@pitt.edu).
Table 1. Features of Patients With Pancreatic
Adenocarcinoma and Elevated Serum Immunoglobulin
G Fraction 4 (IgG4)

             Age at
Patient    Diagnosis,              Serum IgG4,
No.          y/Sex        Race        mg/dL

1             59/M       White        144.1
2             50/M       White        148.5
3             65/M       Asian        166.9
4             61/M       White        194.0
5             72/M       White        150.8

Table 2.   Clinical Features of the 5 Patients With Pancreatic
Adenocarcinoma *

Patient
No.       Diagnostic Confirmation      Metastasis

1         Pancreaticoduodenectomy      None

2         Pancreaticoduodenectomy      Liver, abdom-
                                       inal, supra-
                                       clavicular

3         Cytology (FNA of pancreas)   Bone, liver

4         Distal pancreatectomy        None

5         EUS-guided duodenal biopsy   None

                                                       Positive
Patient                                                Regional
No.       Surgical/Radiologic           Survival, mo      LN
          Findings

1         Locally infiltrating               9            2/8
          disease with vascular
          invasion

2         No local infiltration.             22          0/15
          Lesion abutting transverse
          colon

3         Multiple hepatic lesions,          6            NA
          bony metastasis, locally
          invasive pancreatic tumor

4         Mass near the neck;           Living at 14      0/2
          fibrosis around hepatic ar-     mo post-
          tery; numerous small venous    diagnosis
          collaterals at the
          hepatoduodenal ligament;
          the superior mesen-teric
          and portal veins coarsened
          beneath the pancreas were
          narrowed; no gross evidence
          of metastatic disease

5         Irregular mass invading the   Living at 6       NA
          duodenum, celiac trunk, and     mo post-
          portal vein                    diagnosis

* LN indicates lymph nodes; FNA, fine-needle aspiration; NA,
not applicable; and EUS, endoscopic ultrasound.
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