Are there reported cases of cancer in a female patient with a stented common bile duct stricture, mild intra‑hepatic biliary dilation, an atrophic pancreas with a dilated pancreatic duct, and an incidental left adrenal nodule, despite normal immunoglobulin G4 levels and negative initial biopsies?

Can Cancer Present Despite Normal IgG4 and Negative Biopsies?

Yes, cholangiocarcinoma and other malignancies frequently present with normal IgG4 levels and negative initial biopsies—this scenario is well-documented and represents a critical diagnostic pitfall that demands aggressive repeat tissue sampling and advanced diagnostic modalities. 1

The Diagnostic Reality of Biliary Malignancies

Standard Biopsy Techniques Have Poor Sensitivity

The evidence is unequivocal about the limitations of initial tissue sampling:

• Standard brush cytology detects malignancy in less than 50% of cholangiocarcinoma cases, with an overall sensitivity of only 41.6% and negative predictive value of just 58%. 1
• Forceps biopsy performs similarly poorly, with pooled sensitivity of 45-48.1%, though specificity approaches 99-100%. 1
• Even combining both techniques only increases sensitivity to 59.4%—meaning over 40% of malignancies remain undetected after initial ERCP-based sampling. 1

The reasons for these false negatives include submucosal tumor growth, extrinsic pathologies, tumor-associated fibrosis, and inadequate cellularity of obtained tissue. 1

IgG4 Levels Do Not Exclude Malignancy

Normal IgG4 levels provide no reassurance against cholangiocarcinoma. 1, 2

• IgG4 testing is recommended to exclude IgG4-related sclerosing cholangitis (a benign mimic), not to rule out cancer. 1
• The guideline explicitly states: "IgG4 cholangiopathy should be excluded in suspected cases of CC"—this means checking IgG4 to identify the benign condition, not using it as a cancer marker. 1
• Cholangiocarcinoma and IgG4-related disease are distinct entities; normal IgG4 simply means the stricture is not autoimmune in origin. 2, 3

Your Patient's High-Risk Features

Given the clinical context described (stented CBD stricture, intrahepatic biliary dilation, atrophic pancreas with dilated pancreatic duct, adrenal nodule):

The "Double-Duct Sign" Carries High Malignancy Risk

• Dilation of both the pancreatic duct and common bile duct is highly suggestive of pancreatic malignancy, with 85.5% of patients with obstructive jaundice having cancer. 4
• Even without jaundice, 5.9% still have malignancy—a clinically significant rate that mandates thorough evaluation. 4

Atrophic Pancreas Raises Additional Concerns

• An atrophic pancreas with ductal dilation can represent chronic pancreatitis but also occurs with chronic obstruction from periampullary malignancy. 5, 4
• The combination of biliary stricture, pancreatic duct dilation, and pancreatic atrophy requires exclusion of cholangiocarcinoma or pancreatic adenocarcinoma. 5, 4

The Adrenal Nodule Cannot Be Ignored

• While potentially incidental, an adrenal nodule in the setting of suspected biliary malignancy raises concern for metastatic disease. 1
• This finding increases the urgency for definitive tissue diagnosis. 5

What Must Be Done Next

EUS-Guided Tissue Acquisition Is Critical

When ERCP-based sampling is negative or nondiagnostic, EUS-guided fine needle aspiration dramatically increases diagnostic yield and should be performed urgently. 1, 4

• EUS-FNA has 92.8-98.5% accuracy for diagnosing malignancy in patients with double-duct sign. 4
• EUS is superior to CT for detecting cholangiocarcinoma and should be the next diagnostic step. 5
• In one study of indeterminate biliary strictures, EUS-FNA provided histological diagnosis in 58% of cases where conventional sampling failed. 1

Cholangioscopy-Guided Biopsy for Persistent Uncertainty

If EUS remains nondiagnostic, cholangioscopy with direct visualization and targeted biopsy should be performed. 1

• Cholangioscopy-guided biopsy improves diagnosis of biliary strictures after prior negative conventional sampling. 1
• This allows direct visualization of the stricture and targeted tissue acquisition under direct vision. 1

Advanced Molecular Testing on Tissue Samples

When tissue is obtained, request:

• Fluorescence in situ hybridization (FISH) for chromosomal abnormalities associated with cholangiocarcinoma. 6
• Free DNA mutation profiling to detect malignant mutations. 6
• These techniques increase sensitivity beyond standard cytology. 6, 3

Critical Pitfalls to Avoid

Never Accept Negative Biopsies as Definitive

The most dangerous error is assuming negative initial biopsies exclude malignancy in a high-risk clinical scenario. 1, 6

• With sensitivity below 50%, negative brushings or biopsies mean "insufficient tissue" not "no cancer." 1
• Repeat sampling with advanced techniques is mandatory when clinical suspicion remains high. 1, 6

Do Not Delay Based on Normal Tumor Markers

• CA 19-9 has only 40-70% sensitivity for cholangiocarcinoma. 1
• Normal CA 19-9 does not exclude malignancy, particularly in the 15-20% of patients who are Lewis antigen-negative and cannot produce CA 19-9. 1
• Tumor markers should be measured after biliary obstruction is relieved, as cholestasis itself elevates CA 19-9. 1

Recognize That Imaging Alone Cannot Differentiate Benign from Malignant

MRI/MRCP characteristics (wall thickening, long-segment involvement, asymmetry, luminal irregularity, hyperenhancement) favor malignancy but are not diagnostic. 7

• Multiple benign conditions (IgG4-SC, PSC, infectious strictures) can mimic cholangiocarcinoma on imaging. 7, 2, 3
• Tissue diagnosis remains essential when imaging and clinical features suggest malignancy. 1, 3

The Bottom Line for Your Patient

This clinical presentation—CBD stricture requiring stenting, double-duct sign, pancreatic atrophy, and adrenal nodule—carries substantial malignancy risk that is NOT excluded by normal IgG4 or negative initial biopsies. 1, 5, 4

The documented cases you're asking about are not rare exceptions—they represent the expected diagnostic challenge in biliary strictures, where initial sampling fails in the majority of malignancies. 1

Proceed immediately to EUS-FNA, and if nondiagnostic, to cholangioscopy with targeted biopsy and molecular testing. 1, 4 Only after exhausting these advanced modalities—and ideally with multidisciplinary tumor board review—can you consider this an indeterminate stricture requiring close surveillance rather than presumed malignancy. 1, 5