Getting the right diagnosis

On the road to diagnosing IgG4-RD, a biopsy is one of the tools doctors use to help make an accurate diagnosis. Biopsies clarify the diagnosis by identifying key inflammatory and fibrotic patterns and excluding alternative causes.

Biopsy in IgG4‑RD: What tissue samples reveal

In IgG4-related disease (IgG4‑RD), biopsies provide helpful information that isn’t always clear from blood tests or imaging alone. When doctors combine biopsy findings with scans and blood work, it strengthens diagnostic confidence and supports careful, well-informed treatment decisions.

In this lesson, we’ll walk through why tissue samples matter, what pathologists actually look for under the microscope, and how biopsy findings fit into the bigger diagnostic picture.

We’ll also watch a pathology conversation between clinicians who have spent years puzzling through these cases side-by-side at the microscope.

Why do I need a biopsy?

A biopsy is a small sample of tissue taken from an affected organ so it can be examined under a microscope.

Why is it done? A biopsy allows histologic (microscopic) evaluation of cells, inflammation, fibrosis, and immune markers within tissue.

A biopsy lets doctors see the structure, examine the layers, and understand what the tissue is actually made of—cell by cell. That direct look often reveals details that no scan or blood test can show. Most biopsies fall into two broad method types:

• Needle biopsies

These procedures are performed by passing a needle through anesthetized skin to the area of concern, removing a small piece of tissue. Common needle biopsy approaches include fine ‑ needle aspiration and core needle biopsy.

• Surgical (open) biopsies

These remove a larger piece of tissue (or sometimes the whole abnormal area) using a procedure in an operating room or procedure suite.

During the procedure, the area is made comfortable with local a nesthesia (numbing medicine) and sometimes sedation or general anesthesia, depending on the site and the type of biopsy.

After the sample is collected, it is sent to a lab where a path ologist examines it, staining the slides of cells for different markers to differentiate normal cells from abnormal ones. The goal is to identify the underlying disease process by correlating what is seen under the microscope with information from the patient’s medical history, blood test results, and imaging studies.

Common biopsies for IgG4‑RD

Here are the biopsy approaches you’ll most commonly see in IgG4-RD care:

Core needle biopsy (imag ‑guided core biopsy)
This is one of the most common approaches for IgG4 ‑ RD when there is a mass or enlarged organ that can be safely reached with imaging guidance (CT or ultrasound). It is used for sites such as retroperitoneal masses, kidney, lung lesions, and other deep tissue targets.

Endoscopic ultrasound‑guided biopsy of the pancreas or bile duct region (EUS‑FNB/FNA)
When IgG4‑RD involves the pancreas or biliary tree (for example, type 1 autoimmune pancreatitis), gastroenterology teams often use endoscopic ultrasound to obtain tissue. Newer fine‑needle biopsy (FNB) techniques are often favored over fine‑needle aspirate (FNA) when the goal is to preserve tissue architecture for IgG4‑RD histology.

Salivary gland biopsy (major or minor) and lacrimal gland/orbital biopsy
Because salivary glands and lacrimal/orbital tissues are common IgG4-RD sites, biopsy from these areas may be used when they are involved.

Lymph node biopsy (selected cases, not always definitive alone)
Lymph nodes can be involved, but multiple expert sources emphasize that lymph node (and bone marrow) samples are less specific than other biopsy sites for confirming IgG4‑RD diagnoses. Lymph node or bone marrow biopsies are often part of the diagnostic journey, however, because these procedures are needed to exclude certain mimickers of IgG4-RD (e.g., lymphoma, sarcoidosis). When IgG4-RD is the leading diagnostic candidate, though, it is probably more useful to target another organ.

Kidney biopsy (percutaneous renal biopsy)
If IgG4‑RD is suspected in the kidneys (for example, tubulointerstitial nephritis), a kidney biopsy can be critical because it directly informs diagnosis and management. A kidney biopsy is performed under the guidance of CT or ultrasound.

Skin biopsy (when there are skin lesions)
If IgG4‑RD affects the skin, a punch or excisional skin biopsy can sometimes provide diagnostic tissue with relatively low risk.

Open or excisional surgical biopsy
When needle or endoscopic approaches can’t safely get enough tissue—or when a larger tissue sample is needed—surgeons may perform an open or excisional biopsy to secure adequate tissue for diagnosis.

Why pathology matters so much in IgG4‑RD

Pathology is the medical specialty that studies tissues and cells to understand what is causing disease. By examining samples under a microscope, pathologists help doctors make accurate diagnoses and guide treatment decisions.

IgG4-related disease cannot be diagnosed by any single test. Instead, doctors integrate:

• Your symptoms and which organs are involved

• Imaging findings (CT, MRI, PET)

• Blood tests, including serum IgG4

• Pathology from a biopsy

Among these, pathology often plays the most decisive role. Not because it gives a simple yes‑or‑no answer, but because it helps doctors assemble the case correctly.

Pathology does two equally important jobs:

• Supports a diagnosis of IgG4‑RD when the right features are present

• Excludes IgG4‑RD when features point to something else

That second role—ruling things out—is just as critical in reaching an accurate diagnosis.

What pathologists look for under the microscope

When a pathologist examines a biopsy from someone suspected of having IgG4‑RD, they look for a pattern, not a single abnormality. Let’s review some of the examples we saw in the video.

1. Lymphoplasmacytic inflammation

What is it? A dense infiltrate of lymphocytes and plasma cells within the tissue.

This means the tissue is crowded with immune cells, especially plasma cells. Plasma cells are the cells that B cells evolve into at the conclusion of their development.

Plasma cells have:

• An abundant cytoplasm (the area around the cell nucleus)

• A nucleus with a “clock‑face” pattern

• A pale area near the nucleus called a hof, reflecting active antibody production

Seeing many plasma cells raises suspicion—but it’s only the first step.

2. IgG4‑positive plasma cells

Pathologists use special stains to see whether plasma cells are producing IgG4 antibodies.

• An IgG4 immunostain turns IgG4-producing cells brown

• The pathologist counts how many IgG4‑positive cells appear in high‑power fields

• They also estimate the ratio of IgG4‑positive cells to all plasma cells

Keep in mind: Even very high numbers of IgG4‑positive plasma cells are not diagnostic by themselves. Other diseases, such as certain forms of vasculitis or chronic inflammation, can also be associated with large numbers of IgG4‑positive plasma cells.

3. Fibrosis with a storiform pattern

What is it? Fibrosis arranged in a swirling, cartwheel-like (“storiform”) pattern.

This is scar-like tissue laid down in curving, woven bands, rather than straight lines.

In small biopsies, this pattern can be subtle or distorted by surgical instruments. That’s why experience—and caution—matter so much when interpreting fibrosis.

4. What should not be there

Just as important as what is present is what is absent.

Pathologists carefully look for features that argue against IgG4‑RD, including:

• Granulomas (which suggest other inflammatory diseases)

• Prominent neutrophils and necrosis (which raise concern for infection or vasculitis)

• Features of cancer or lymphoma

As Dr. Stone noted in the video, many patient referrals for IgG4‑RD are ultimately excluded because these findings are present.

Three real biopsy stories

The video outlined three important cases in which biopsy was integral to being able to make sense of complex or atypical presentations.

Case 1: Pericardial disease

A patient with inflammation of the tissue around the heart under went pericardial removal.

• The biopsy showed numerous plasma cells

• IgG4 staining revealed many IgG4-positive plasma cells

• There were no granulomas or necrosis

This provided strong pathologic support for the diagnosis of IgG4‑RD. Other things that the clinician will look for to substantiate the diagnosis of IgG4‑RD are the levels of IgG4 in the blood and evidence of IgG4‑RD in other organs, perhaps identified by imaging.

Case 2: Isolated pituitary involvement

A young woman had disease only in the pituitary gland. The pituitary gland, which lies just beneath the brain in the center of the head, produces some of the body’s most critical hormones—hormones that ultimately govern the function of the thyroid and adrenal glands and the ovaries, among others.

• The biopsy showed heavy plasma cell infiltration

• IgG4 stain met pathologic thresholds

• Blood IgG4 levels were normal

• No other organs were involved

Despite the unusual presentation, the combination of positive findings and absence of exclusions supported IgG4-RD. The biopsy was very helpful in providing evidence against certain other diagnoses that can occur in the pituitary gland, such as sarcoidosis, ANCA-associated vasculitis, lymphoma, and Erdheim-Chester disease.

The biopsy findings might strengthen the clinicians’ resolve to proceed with IgG4‑RD treatment, with the goal of preserving pituitary function.

Case 3: Disease revealed over time

A woman had:

• Uterine inflammation years earlier

• Later developed an aortic aneurysm

When the aorta was examined:

• Inflammation centered in the adventitia (outer vessel layer)

• Dense plasma cells were present

• IgG4 staining showed high counts and high ratios

Looking back, the earlier uterine biopsy fit the same pattern. Only with time—and pathology—did the full diagnosis become clear.

How biopsies support more accurate diagnosis

Many IgG4-RD patients are initially told they might have:

• Cancer

• Infection

• Sarcoidosis

• Vasculitis

Biopsies help avoid:

• Unnecessary surgeries

• Over-treatment with toxic therapies

• Missed alternative diagnoses

As Dr. Stone says plainly: pathology doesn’t just help diagnose IgG4‑RD—it often protects patients from the wrong diagnosis.

How biopsy findings fit into the big picture

A biopsy never stands alone. Doctors always ask:

• Does this match the symptoms?

• Does imaging support this pattern?

• Are blood tests consistent—or misleading?

This process is called clinical‑pathologic correlation, and it’s at the heart of IgG4‑RD diagnosis.

References

1. Stone JH, Zen Y, Deshpande V. IgG4-Related Disease. N Engl J Med. 2012;366:539 – 551. URL: https://www.nejm.org/doi/full/10.1056/NEJMra1104650

2. Peyronel F, Della - Torre E, Maritati F, et al. IgG4-related disease and other fibro-inflammatory conditions. Nat Rev Rheumatol. 2025;21:275 – 290. URL: https://doi.org/10.1038/s41584-025-01240-x

3. Lang D, Zwerina J, Pieringer H. IgG4 - related disease: current challenges and future prospects. Ther Clin Risk Manag. 2016;12:189 – 199. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC4760655/