How can a patient with an IgG4‑negative pancreatic inflammatory process, refractory to three months of high‑dose prednisone, and negative endoscopic ultrasound‑guided fine‑needle aspiration biopsies still have pancreatic cancer?

How Cancer Can Exist Despite Negative Biopsies

In a patient with an IgG4-negative pancreatic inflammatory process unresponsive to steroids and negative EUS-FNA biopsies, pancreatic cancer remains highly likely and should not be excluded—proceed with surgical resection or repeat invasive investigation without delay if clinical and radiologic features strongly suggest malignancy. 1, 2, 3

The Fundamental Limitation of Pancreatic Biopsies

EUS-FNA has inherent sampling limitations that result in false-negative rates of 13-30% for pancreatic adenocarcinoma. 1, 3, 4 The National Comprehensive Cancer Network explicitly states that negative biopsies should be confirmed by at least one repeat EUS biopsy, but even after two negative attempts, treatment may proceed if imaging and clinical features are consistent with malignancy. 1

Why Biopsies Fail in Pancreatic Cancer

• Sampling error from tumor heterogeneity: Pancreatic adenocarcinoma elicits intense desmoplastic stromal reaction, and the needle may sample only fibrotic tissue rather than malignant cells. 1, 5

• Low cellularity specimens: EUS-FNA samples often lack adequate cellularity, particularly in well-differentiated adenocarcinomas that closely mimic non-neoplastic glands. 1

• Technical factors: The degree of dysplasia in aspirates frequently underestimates the actual degree present in resection specimens due to considerable tumor heterogeneity. 1

• Contamination issues: Samples can be contaminated by non-neoplastic tissues such as gastric mucosa, reducing diagnostic accuracy. 1

Your Specific Clinical Scenario: IgG4-Negative and Steroid-Refractory

This presentation is particularly concerning because:

• Autoimmune pancreatitis typically responds to corticosteroids within weeks: The lack of response after three months of high-dose prednisone strongly argues against autoimmune pancreatitis. 1

• IgG4 negativity does not exclude cancer: While elevated serum IgG4 is the most sensitive and specific laboratory indicator for autoimmune pancreatitis, its absence in a steroid-refractory case makes pancreatic cancer the leading diagnosis. 1

• Pancreatic cancer can mimic autoimmune pancreatitis: Autoimmune pancreatitis presents with clinical and radiologic characteristics identical to pancreatic cancer, including jaundice, weight loss, elevated CA 19-9, and focal pancreatic masses. 1

The Critical Management Algorithm

When clinical suspicion remains high despite negative biopsies, the following approach is mandated:

Step 1: Reassess Imaging with Structured Reporting

• Obtain multiphasic contrast-enhanced CT or MRI with pancreas protocol to detail tumor characteristics, vessel involvement, and metastatic disease. 1, 6
• Use standardized reporting templates, as structured reports significantly reduce missing morphological features compared to free-text reports. 1

Step 2: Consider Repeat Biopsy (One Attempt Only)

• Perform one additional EUS-FNA if not previously done twice. 1, 2
• Do not delay treatment beyond one repeat attempt—after two inconclusive biopsies, proceed with definitive management if multidisciplinary tumor board discussion, imaging, and CA 19-9 are consistent with malignancy. 1

Step 3: Proceed to Surgical Resection or Laparoscopy

• For potentially resectable disease: Proceed directly to laparotomy and resection without further tissue diagnosis. 1, 2, 6, 3
• For borderline resectable or locally advanced disease: Consider diagnostic laparoscopy with biopsy if repeat FNA is negative. 1
• The National Comprehensive Cancer Network explicitly states that treatment may be recommended after two negative biopsies if clinical and radiographic evidence strongly suggests pancreatic cancer. 1

Critical Caveats to Avoid Delayed Diagnosis

The most dangerous pitfall is allowing negative biopsies to delay definitive treatment in a patient with high clinical suspicion. 1, 2, 3

• Approximately 5% of pancreaticoduodenal resections are performed for benign disease, which is an acceptable risk when perioperative mortality is low. 1

• A nondiagnostic biopsy should never delay surgical resection when clinical suspicion for pancreatic cancer is high. 1, 2

• Real-world case series demonstrate that patients with negative EUS-FNA cytology but worrisome imaging features, biochemical factors, and clinical presentation who underwent upfront resection were all ultimately diagnosed with pancreatic ductal adenocarcinoma on final pathology. 3

The Evidence Supporting Proceeding Without Tissue Diagnosis

• The European Society for Medical Oncology states that biopsy is not routinely required before surgical resection, and proof of malignancy through biopsy is not required before surgery when clinical suspicion is high. 1, 2

• The American Society of Clinical Oncology confirms that failure to obtain histological confirmation does not exclude malignancy and should not delay appropriate surgical treatment. 7, 2

• Sensitivity of EUS-FNA ranges from 70-87%, meaning 13-30% of cancers will be missed. 6, 4