What is the best approach to further evaluate and manage a patient with multiple liver metastases, ascites positive for malignancy, elevated Carcinoembryonic Antigen (CEA) and Cancer Antigen 19-9 (CA 19-9), and a Fine Needle Aspiration Cytology (FNAC) suggesting metastatic squamous cell carcinoma, despite a negative Upper Gastrointestinal (UGI) endoscopy for malignancy in a small fundal growth?

Diagnostic Evaluation and Management Approach

This patient requires immediate comprehensive imaging with contrast-enhanced MRI/MRCP of the abdomen and contrast-enhanced CT of the chest to identify the primary tumor source, as the combination of squamous cell carcinoma on FNAC with elevated CEA and CA 19-9 suggests a pancreaticobiliary or upper gastrointestinal primary rather than a typical squamous cell source. 1

Primary Tumor Identification Strategy

The discordance between FNAC showing squamous carcinoma and elevated CEA/CA 19-9 (typically associated with adenocarcinomas) requires systematic evaluation:

Immediate Imaging Protocol

• Obtain contrast-enhanced MRI with MRCP as the optimal investigation for detecting pancreaticobiliary malignancies, which has superior sensitivity to CT for liver metastases and can evaluate biliary anatomy 1, 2
• Perform contrast-enhanced CT of chest, abdomen, and pelvis using protocols optimized for hepatobiliary imaging to identify the primary tumor and assess extent of metastatic disease 1, 3
• Consider hepatocyte-specific contrast-enhanced liver MRI to better characterize liver metastases, particularly helpful in detecting lesions that may have been missed on initial CT 3

Endoscopic Re-evaluation

The negative fundal growth biopsy warrants repeat evaluation given the clinical context:

• Perform EUS (endoscopic ultrasound) with EUS-guided biopsy if pancreaticobiliary malignancy is suspected, as this has 84% sensitivity and 100% specificity for tissue diagnosis 1
• Repeat upper endoscopy with multiple biopsies of the fundal growth, as initial sampling may have been inadequate 1
• Consider ERCP-guided biopsies if biliary stricture or periampullary lesion is identified on MRCP 3

Tumor Marker Interpretation

The elevation of both CEA and CA 19-9 provides important diagnostic clues:

• CEA elevation occurs in up to 90% of colorectal liver metastases and strongly suggests adenocarcinoma rather than squamous cell carcinoma 4, 5
• CA 19-9 levels >1000 U/mL are particularly concerning for advanced pancreaticobiliary malignancy, though levels can be falsely elevated by biliary obstruction alone 1, 2
• The combination of elevated CEA, CA 19-9, and malignant ascites has high sensitivity for gastrointestinal adenocarcinoma, making the squamous cell diagnosis on FNAC questionable 2, 6
• Recheck CA 19-9 after biliary decompression if obstruction is present, as persistent elevation strongly suggests malignancy 1

Critical Diagnostic Consideration

The FNAC diagnosis of squamous cell carcinoma is likely incorrect or represents a sampling error, as squamous cell carcinomas rarely produce CEA and CA 19-9 elevations 7. This discordance mandates:

• Obtain core needle biopsy of liver metastasis before initiating systemic therapy, as recommended by ESMO, to establish definitive histologic diagnosis 1
• Request immunohistochemistry panel including CK7, CK20, CDX2, TTF-1 to determine primary site 1

Molecular Profiling Requirements

Once adenocarcinoma is confirmed (as expected):

• Mandatory molecular analysis for all advanced pancreaticobiliary cancers suitable for systemic treatment, including testing for actionable mutations: FGFR2 fusions, IDH1/2 mutations, BRAF V600E, HER2 amplification, and NTRK fusions 1
• Assess MSI status via IHC for mismatch repair proteins (MLH1, MSH2, MSH6, PMS2) 1
• Evaluate homologous recombination deficiency markers (BRCA1/2, PALB2) 1

Ascites Management

The malignant ascites requires specific evaluation:

• Ascitic fluid CEA, CA 19-9, and CA 125 levels should be measured, as combining cytology with tumor markers increases positive predictive value 3
• Ascites/serum ratios of CEA, CA 19-9, CA 125, and AFP have diagnostic value, with combined detection sensitivity of 98.4% for malignant ascites 6
• Diagnostic paracentesis should be repeated if initial cytology was inadequate, as yield for positive cytology ranges from 0-96.7% depending on tumor site 3

Prognostic Assessment

This patient has multiple poor prognostic factors:

• Multiple liver metastases and malignant ascites indicate advanced disease with limited curative options 3, 1
• Elevated CA 19-9 and CEA levels are associated with poorer prognosis 3, 1
• The magnitude of CA 19-9 elevation (if >1000 U/mL) is particularly concerning for advanced disease 1

Management Algorithm

1. Immediate multidisciplinary team discussion with hepatobiliary surgeon, medical oncologist, and gastroenterologist 1
2. Complete staging with MRI/MRCP and CT chest/abdomen/pelvis 1, 2
3. Core needle biopsy of liver metastasis for definitive histology and molecular profiling 1
4. EUS with tissue sampling if pancreaticobiliary primary suspected 1
5. Initiate systemic chemotherapy once molecular profiling complete, as resection is not feasible with multiple liver metastases and malignant ascites 1

Common Pitfalls to Avoid

• Do not rely on FNAC diagnosis alone when tumor markers are discordant with histology 1
• Do not biopsy hepatic lesions without discussion with the regional hepatobiliary unit 3
• Do not interpret CA 19-9 in isolation if biliary obstruction is present, as this causes false elevation 2
• Do not delay molecular profiling, as actionable mutations may significantly alter treatment strategy 1