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Autoimmune Pancreatitis

An IgG4 Systemic Sclerosing Disease

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Published: April 2013

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Dr. Lam-Himlin describes the histologic features and clinical presentation of autoimmune pancreatitis and explains the diagnostic criteria and use of IgG4 as a marker for the disease.

Presenter: Dora M. Lam-Himlin, MD

  • Senior Associate Consultant, Division of Anatomic Pathology
  • Assistant Professor of Laboratory Medicine and Pathology at Mayo Clinic in Arizona

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Thank you for the kind introduction. It is a privilege to speak to you about IgG4-related systemic sclerosing disease, an entity that encompasses multiple organ systems and for which our understanding continues to evolve. The intent of this lecture is to give a broad overview of the topic and discuss the histopathologic features and diagnosis. The content of this lecture is intended for pathologists who are new to IgG4-related systemic sclerosing disease, but also for those who are familiar with the entity, as I will be discussing some of the evolving concepts.

I have no conflicts of interest to disclose.

There are 4 primary objectives that viewers should achieve at the end of this presentation.

The first is the ability to outline the histopathologic features of autoimmune pancreatitis, or AIP.

The next objective is to recognize an emerging second type of autoimmune pancreatitis and discuss the histologic features for each type.

Next, viewers should recognize the systemic nature of IgG4 systemic sclerosing disease.

In doing so, by the end of this presentation, viewers will be able to list manifestations of IgG4-related systemic sclerosing disease in various organ systems.

This is the overview, or road map, for our discussion over the next 25 minutes.

I will start with a case presentation, followed by a discussion of the terminology of this disease entity in its historical context. Next, we will cover type 1 autoimmune pancreatitis and IgG4 systemic sclerosing disease. I will call attention to the clinical presentation, H-I-S-O-R-t diagnostic criteria, histologic features, IgG4 as a marker for the disease, involvement of organs outside the pancreas, and treatment options.

Finally, we will conclude with a brief discussion of type 2 autoimmune pancreatitis, describe the comparison to type 1, and comment on the future direction of this disease.

Let’s begin with our case presentation. This case involves a 77-year-old man who has had recent onset of diarrhea, weight loss, and jaundice. A computed tomography, or CT, scan showed a 3.3 by 4.0 centimeter mass in the head of the pancreas with multiple cysts measuring up to 0.9 centimeters.

An endoscopic ultrasonography-guided fine needle aspirate biopsy showed low-grade mucinous epithelium and the cyst fluid carcinoembryonic antigen, or CEA, measured 632 nanograms per millileter. Recall that pancreatic cyst fluid concentrations of greater than 200 nanograms per milliliter are suggestive, but not diagnostic, of a mucinous cyst. Given the suspicious laboratory and radiologic findings, in conjunction with patient preference, a pancreaticoduodenectomy, or Whipple resection, and cholecystectomy were performed.

Viewed here is a histologic section from the gallbladder. At low power, this gallbladder is markedly abnormal, with deep glands and a prominent eosinphilic stromal background which causes the mucosa to look markedly thickened.

Higher power examination shows benign surface epithelium, with similarly benign deep glands consistent with adenomyosis of the gallbladder. However, of particular interest is the stromal backdrop, which appears fibrotic and contains abundant inflammatory cells.

This high power view confirms the benign nature of the deep glands, which contain uniform epithelial cells with preserved nuclear to cytoplasmic ratios. Note how the stromal cells whorl in a concentric manner around these glands. In addition, note the chronic inflammatory backdrop admixed with the stromal cells.

Careful attention to the stromal and inflammatory background reveals an expansile storiform pattern of fibrosis with abundant plasma cells and lymphocytes.

In addition, further investigation shows multiple veins involved by lymphocytic venulitis or obliterative phlebitis. Pictured here is a paired artery and vein. At the top right, and clearly visualized, is a healthy and unaffected muscular artery. Its paired vein is at the lower left and is involved by an intense lymphocytic infiltrate that nearly obscures it from view.

Finally, an IgG4 immunohistochemical stain highlights greater than 40 IgG4-positive plasma cells within this single high powered field.

The combination of histologic findings is diagnostic for lymphoplasmacytic sclerosing cholecystitis, a manifestation of IgG4 systemic sclerosing disease. This patient also demonstrated classic histologic features of autoimmune pancreatitis type 1, also known as lymphoplasmacytic sclerosing pancreatitis. However, by using the gallbladder as our case example, I hope to emphasize that these classic histologic features are highly characteristic regardless of the organ in which they are seen.

Because IgG4 systemic sclerosing disease is a relatively newly established entity, the literature contains references to a number of different terms that are synonymous with this disease in the pancreas, some of which you may have seen within your own practice. For example, some authors have referred to this entity as chronic sclerosing pancreatitis, nonalcoholic duct destructive pancreatitis, idiopathic chronic pancreatitis with periductal lymphoplasmacytic infiltration, lymphoplasmacytic sclerosing pancreatitis, idiopathic duct-centric chronic pancreatitis, and idiopathic tumefactive chronic pancreatitis. As you can see, these descriptive terms overlap significantly, and in retrospect, are essentially describing the same entity.

Over time, the terminology of autoimmune pancreatitis type 1 or lymphoplasmacytic sclerosing pancreatitis have become popularized and is the most commonly used nomenclature. With this in mind, let’s move on to discuss the clinical features and diagnosis for autoimmune pancreatitis type 1.

Patients often present with abdominal pain due to recurrent acute or chronic pancreatitis. In addition, jaundice may be a prominent clinical sign due to duct strictures from the sclerotic process. Imaging studies may indicate a pancreatic mass that can be confused with carcinoma or lymphoma. The clinical presentation is nonspecific, and the main diagnostic consideration is to exclude pancreatic malignancy, which can present in a similar fashion.

Investigators at the Mayo Clinic in Rochester published their experience with autoimmune pancreatitis in a seminal 2006 article that described specific criteria aiding in the diagnosis of this disease. These criteria are widely accepted and are known as the H-I-S-O-R-t criteria. This acronym can be broken down as

  • H for diagnostic Histology
  • I for characteristic Imaging on CT or pancreatography
  • S for elevated Serum IgG4 levels
  • O for Other Organ involvement
  • And Rt for Response to steroid Therapy.

It is not necessary to fulfill each and every one of the criteria listed here. Instead, these individual criteria are further grouped together to provide diagnostic groups A, B, and C, such that there are 3 opportunities to achieve a diagnosis.

Fulfillment of the criteria within any one group, either group A, group B, or group C, can yield a diagnosis of autoimmune pancreatitis type 1.

Group A can be satisfied by either the presence of a lymphoplasmacytic infiltrate with storiform fibrosis and obliterative phlebitis, or the presence of a lymphoplasmacytic infiltrate with storiform fibrosis showing abundant IgG4-positive plasma cells. This is defined as having 10 or more IgG4-positive plasma cells within a single high powered field. As you can see, diagnosis of autoimmune pancreatitis through Group A criteria encompasses purely histology, and represents only the H in H-I-S-O-R-t.

By comparison, a Group B diagnosis can be achieved through the use of imaging and serology, representing the I and the S in H-I-S-O-R-t. In order to fulfill the diagnosis in this setting, all 3 of the following much be achieved: 1. a CT scan or Magnetic Resonance Imaging study showing a diffusely enlarged pancreas with delayed and ‘rim’ enhancement;  2. a pancreatogram showing a diffusely irregular pancreatic duct;  and 3. elevated serum IgG4 levels, which is defined as greater than 140mg/dL. Interestingly, note that the Group B criteria do not require a tissue diagnosis. This can be of value when a biopsy is nondiagnostic, or is unavailable.

Finally, a third route to the diagnosis of autoimmune pancreatitis can be achieved by a combination of serology, other organ involvement, and response to therapy, utilizing the S, O, R and t of H-I-S-O-R-t. This group C can be fulfilled when all of the following are present:  1. unexplained pancreatic disease after negative workup for other known causes including cancer;  2. elevated serum IgG4 levels and/or other organ involvement confirmed by presence of abundant IgG4-positive cells; and 3. Resolution or marked improvement in pancreatic disease and/or extrapancreatic manifestations with steroid therapy.

As a reminder, the characteristic histology includes:  a dense lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis. These features, alone, are sufficient for a diagnosis, and immunohistochemical staining for IgG4 is not necessary in these cases.

Some clinicians may request IgG4 staining on biopsy material of the pancreas, ampulla, or duodenum, and professional courtesy may dictate that these are performed. However, the significance of elevated IgG4-positive plasma cells in the absence of characteristic histology is unclear. Staining for IgG4 in the absence of the characteristic histology is not recommended routinely.

There remains some discussion about the importance of IgG4 immunostains in the diagnosis of autoimmune pancreatitis, and various methods have emerged over time. The current accepted cutoff for elevated IgG4-positive plasma cells in small biopsy material remains 10 or more immunoreactive plasma cells in a single high powered field on biopsy material. Some authors have suggested that the cutoff in resection specimens should be higher. For example, a proposal exists that the cutoff in resection specimens should be greater than 50 IgG4-positive plasma cells in 1 high powered field, following a count and average of 3 fields.  In addition, some authors have suggested the use of an IgG4 to IgG ratio which is typically greater than 40% in cases of autoimmune pancreatitis. However, it is important to remember that a well sampled resection specimen is likely to show characteristic histologic features without the need for IgG4 plasma cells counts.

It is now widely accepted that autoimmune pancreatitis is only one manifestation of a systemic disease concept termed IgG4 systemic sclerosing disease which can affect virtually every organ system. These diseases share in common a fibroinflammatory process characterized by tumefactive lesions, a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis, and often, but not always, elevated serum IgG4 concentration. This slide, and the following 5 slides, detail some of the documented IgG4-related diseases found in other organ sites and may be useful as reference material. Although we will not spend much time discussing each of these entities, and I will move through these slides quickly, it is important to recognize the systemic nature of this disease process.

In the orbits and periorbital tissues, tumefactive and inflammatory lesions may be seen such as orbital pseudotumor, dacrocystitis, and orbital myositis. In the ears, nose, and sinuses allergic phenomena are common as well as eosinophilic angiocentric fibrosis.

The salivary glands can have submandibular and/or parotid enlargement. In the meninges, there is a predilection for the dura and a tendency to form mass lesions. Lymph node involvement can manifest as generalized lymphadenopathy or may be localized to areas near the affected primary organ.

Two organs that often have characteristic histology for IgG4-related disease include the thyroid, which can be involved by Riedel’s thyroiditis or the fibrosing variant of Hashimoto’s thyroiditis, and the lungs which may contain inflammatory pseudotumors, central airway disease, localized or diffuse interstitial pneumonia, or pleuritis.

Retroperitoneal lesions can be associated with the aorta, including lymphoplasmacytic aortitis of the thoracic or abdominal aorta as well as periaortitis and periartertitis. Consideration should be given for IgG4-related disease when an abdominal aneurysm shows a prominent inflammatory and fibrotic background. Retroperitoneal fibrosis has also been identified as an IgG4-related disease. Affected kidneys have a characteristic tubulointerstitial nephritis, but may also contain asymptomatic tumoral lesions which can be bilateral and multiple.

The pancreaticobiliary organs can present as type 1 autoimmune pancreatitis. Type 2 autoimmune pancreatitis, which we will discuss shortly, is not considered an IgG4-related disease at this time. The biliary tree may be affected by sclerosing cholangitis which shares histologic overlap with primary sclerosing cholangitis. In addition, the liver may contain inflammatory masses forming pseudotumors.

Finally, a number of other organs also manifest lesions of IgG4-related disease, as listed here. The gallbladder may show lymphoplasmacytic sclerosing cholecystitis, as we saw in the case presentation. The breast and prostate may contain tumefactive fibroinflammatory lesions. Some cases of pericarditis, and most cases of sclerosing mesenteritis and sclerosing mediastinitis are now recognized as IgG4-related diseases. Less commonly, IgG4 related disease may affect the skin and peripheral nerve. As you can see, nearly every organ system has a documented manifestation of IgG4-related disease.

Treatment for documented IgG4-related disease is relatively straightforward. Glucocorticoids are the first-line therapy and clinical response is often dramatic with rapid shrinkage of any tumefactive lesions. Cases of autoimmune pancreatitis will also show resolution of the obstructive jaundice. In some cases that lack definitive histologic features on small biopsy, a trial of steroids may be of value. As you may recall, response to steroid therapy fulfills a portion of the Group C criteria for diagnosis.

Before we complete our discussion of autoimmune pancreatitis type 1, and since our case example was that of a gallbladder, I would like to show you an example of a pancreatic needle core biopsy to review the characteristic histologic features one more time. This photomicrograph shows a pancreas needle core at low power with significant abnormality characterized as loss of the normal pancreatic acinar parenchyma.  At this magnification, one can appreciate the parenchyma has been replaced by a somewhat concentric fibrosis around the residual lobules that show intact ducts.

Higher magnification allows us to appreciate the fibroinflammatory nature of this process that contains abundant lymphocytes and plasma cells. Although the acinar parenchyma has been replaced by the lymphoplasmacytic infiltrate, note the intact duct at the bottom of the photo.

The lymphocytic venulitis is prominent in this example. At the right, an intact muscular artery is present. To the left, the paired vein shows marked lymphocytic infiltration with near destruction.

Another example of a smaller paired artery and vein showing lymphocytic venulitis. Often, it is easier to search for the muscular arteries and upon finding them, look for their paired veins. As you can see in this example, the lymphocytic phlebitis can be camouflaged by the background lymphoplasmacytic infiltrate.

A third example of venulitis within this needle core is seen here. Note again how the paired artery appears relatively healthy by comparison.

A fourth dramatic example within this same core shows lymphocytic venulitis with wall damage that contrasts nicely to its healthy paired artery. This needle core showed highly characteristic and dramatic examples of autoimmune pancreatitis type 1. However, not every needle core will have the good fortune of containing vascular structures. Some may have none at all.

In the absence of lymphocytic venulitis, an IgG4 immunohistochemical stain that highlights 10 or more IgG4-positive plasma cells in a single high powered field can fulfill the remaining Group A histologic criteria. This single high powered field contains abundant IgG4-positive plasma cells and exceeds the diagnostic cutoff.

Before we complete this session, I will include a very brief overview of an emerging entity termed autoimmune pancreatitis type 2. This is considered a distinct entity from autoimmune pancreatitis type 1, and, despite the similar nomenclature, it is not currently considered part of the IgG4-related diseases. The histology between type 1 and type 2 autoimmune pancreatitis shows some overlap, with the presence of a dense periductal inflammatory infiltrate common to both entities. However, type 2 autoimmune pancreatitis lacks the storiform fibrosis and the obliterative phlebitis that is so characteristic of type 1 autoimmune pancreatitis. In addition, type 2 autoimmune pancreatitis characteristically contains neutrophilic abscesses within the ducts which have been termed granulocytic epithelial lesions.

This slide highlights some of the histologic differences between type 1 and type 2 autoimmune pancreatitis. It is not necessary to comment on each of these features, and this chart is included for your reference, only. However, I bring your attention to the last row of this chart, and would like to emphasize that IgG4-positive plasma cells are typically not seen in type 2 autoimmune pancreatitis.

Similarly, this chart comparing the clinical features of type 1 and type 2 autoimmune pancreatitis is for reference purposes. At this time, I would like to direct your attention only to the rows indicating systemic diseases and serum IgG4 levels. While these features are commonly seen in type 1 autoimmune pancreatitis, they are not seen in type 2. These data are relatively new and further investigation as to the significance of this second histologic subtype of autoimmune pancreatitis remains to be investigated.

As we conclude our session, I would like to emphasize some of the major take-home messages we have covered today. Recall, type 1 autoimmune pancreatitis is among the IgG4-related systemic sclerosing diseases and has highly characteristic histology. We have also discussed that IgG4-positive plasma cells in the absence of characteristic histology is not diagnostic for autoimmune pancreatitis. In addition, we have introduced type 2 autoimmune pancreatitis as an evolving concept that has histologic and clinical features distinct from those seen in type 1. I hope you find these take home messages helpful in daily practice.

Finally, as a reminder, review these session objectives to ensure that this topic has been thoroughly reviewed.

For those interested in learning more about this entity, selected references are included. Thank you for taking the time to join me today in our discussion of autoimmune pancreatitis and IgG4-related systemic sclerosing diseases. It has been my pleasure and privilege.


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