What is the differential diagnosis for a 56-year-old male with abdominal distention and ascites, no evidence of lesions on endoscopy and computed tomography (CT) scan, but mild Fluorodeoxyglucose (FDG) avidity on positron emission tomography (PET) CT at the subdiaphragm?

Differential Diagnosis of Ascites with Mild Subdiaphragmatic FDG Avidity

The most likely differential diagnoses in this 56-year-old male with ascites, negative endoscopy/CT, and mild subdiaphragmatic FDG uptake include peritoneal tuberculosis, occult peritoneal carcinomatosis (particularly from gastrointestinal or hepatobiliary malignancy), and less likely, inflammatory conditions such as serositis or peritoneal infection. 1

Primary Diagnostic Considerations

Peritoneal Tuberculosis

• Peritoneal tuberculosis is a critical consideration as it can markedly accumulate FDG and closely mimic peritoneal carcinoma on PET/CT imaging. 1
• This condition presents with ascites and can show FDG-avid peritoneal thickening without obvious mass lesions on conventional CT 1
• The subdiaphragmatic location is consistent with tuberculous peritonitis, which commonly involves the peritoneal surfaces including the diaphragmatic peritoneum 2
• Diagnostic confirmation requires laparoscopy with peritoneal biopsy for histology, acid-fast bacilli staining, and mycobacterial culture 2

Occult Peritoneal Carcinomatosis

• FDG PET/CT demonstrates superior sensitivity (86.4%) compared to CT alone (27.3%) for detecting abdominal cavity metastasis in patients with ascites of undetermined origin. 1
• Malignancy was identified as the primary cause in 63.3% of cases with ascites when evaluated by PET/CT 1
• The mild (rather than intense) FDG avidity suggests either early-stage disease, low-grade malignancy, or small-volume disease below CT detection thresholds 1, 3
• Cholangiocarcinoma can present with ascites and may produce a negative serum-ascites albumin gradient (SAAG), making it particularly difficult to diagnose 4
• Gastrointestinal malignancies (gastric, pancreatic, or colonic) can present with peritoneal seeding without obvious primary lesions on initial imaging 2, 1

Inflammatory/Infectious Processes

• Inflammatory processes account for 73.3% of benign lesions showing increased FDG uptake on PET/CT 3
• Serositis from autoimmune conditions or other inflammatory etiologies can produce mild FDG avidity 3
• Secondary peritonitis from occult perforation should be considered, though typically presents more acutely 2

Essential Diagnostic Workup Algorithm

Immediate Ascitic Fluid Analysis

• Perform diagnostic paracentesis immediately with analysis including cell count with differential, total protein, albumin, and calculate SAAG. 2, 5, 6
• Send ascitic fluid for bacterial culture in blood culture bottles inoculated at bedside 2, 6
• Add mycobacterial culture and acid-fast bacilli staining given the FDG-avid findings suggestive of possible tuberculosis 2, 1
• Measure ascitic glucose (<50 mg/dL suggests secondary peritonitis), LDH, CEA (>5 ng/mL suggests malignancy), and alkaline phosphatase 2
• Cytology should be sent, though sensitivity is limited for peritoneal malignancy 1

Interpretation of SAAG Results

• SAAG ≥1.1 g/dL indicates portal hypertension with 97% accuracy, suggesting cirrhosis, cardiac ascites, or hepatic vein thrombosis. 5, 6
• SAAG <1.1 g/dL suggests peritoneal carcinomatosis, tuberculosis, nephrotic syndrome, or serositis 2, 5, 4
• A negative SAAG (as can occur with cholangiocarcinoma) indicates high-protein ascites from malignancy 4

Advanced Imaging Considerations

• The mild FDG avidity warrants correlation with SUVmax values, as malignant lesions typically demonstrate significantly higher SUVmax than benign processes 1
• SUVmax demonstrated superior diagnostic ability (area under curve 0.803) compared to tumor markers CA19-9 and CA12-5 for differentiating malignant from benign ascites 1
• Consider contrast-enhanced CT if not already performed, as IV contrast significantly improves detection of peritoneal implants and bowel wall abnormalities 2

Definitive Diagnostic Procedures

• If ascitic fluid analysis is non-diagnostic and clinical suspicion remains high, laparoscopy with peritoneal biopsy is the gold standard for diagnosis. 2
• Laparoscopy allows direct visualization of peritoneal surfaces, targeted biopsy of abnormal areas (including subdiaphragmatic regions), and comprehensive staging 2
• This approach is particularly important given that approximately 5% of ascites cases have multiple simultaneous causes 2

Critical Pitfalls to Avoid

Do Not Dismiss Mild FDG Avidity

• Even mild or moderate FDG uptake can represent significant pathology, including malignancy or tuberculosis 1, 3
• The absence of lesions on conventional CT does not exclude malignancy, as PET/CT detects occult disease missed by CT alone in a substantial proportion of cases 1
• False-negative lesions on imaging are typically smaller in size, but can still be clinically significant 1

Do Not Delay Paracentesis

• Paracentesis should never be delayed for coagulopathy correction, as routine FFP/platelet transfusion is not evidence-based and complications occur in only ~1% of cases. 6
• Delaying diagnostic paracentesis can result in missed spontaneous bacterial peritonitis (SBP), which increases mortality 6

Do Not Assume Single Etiology

• Approximately 5% of patients with ascites have two or more simultaneous causes (e.g., cirrhosis plus peritoneal carcinomatosis or tuberculosis) 2
• The combination of cirrhosis with superimposed malignancy or infection requires identification of all contributing factors 2

Do Not Overlook Tuberculosis

• Peritoneal tuberculosis deserves special attention as it can be highly FDG-avid and is frequently misdiagnosed as peritoneal carcinoma. 1
• This diagnosis is particularly important in patients from endemic areas or with risk factors for tuberculosis 2
• Empiric anti-tuberculous therapy should not be initiated without tissue diagnosis, as this can confound subsequent diagnostic efforts 2

Additional Workup Based on Initial Findings

If SAAG <1.1 g/dL (Non-Portal Hypertensive)

• Proceed urgently to laparoscopy with peritoneal biopsy for histology and culture 2
• Send tissue for both routine pathology and mycobacterial studies 2
• Consider tumor marker panel including CEA, CA19-9, and CA125, though these have limited specificity 1

If SAAG ≥1.1 g/dL (Portal Hypertensive)

• Investigate for underlying liver disease with hepatitis serologies, autoimmune markers, and liver imaging 2, 6
• Consider cardiac evaluation with BNP (median 6100 pg/mL in heart failure vs 166 pg/mL in cirrhosis) and echocardiography 6
• The presence of FDG avidity in portal hypertensive ascites suggests superimposed malignancy or infection requiring further investigation 1