What is the best approach for a patient with ascites, unknown primary malignancy, and cytology suggestive of cytokeratin (CK) positive only?

Management of Malignant Ascites with Cytokeratin-Positive Cytology and Unknown Primary

For a patient with malignant ascites showing only cytokeratin (CK) positivity without identification of a primary tumor, you must first complete additional immunohistochemical staining to exclude lymphoma and guide site-specific workup, followed by systematic evaluation for the most likely primary sites based on the clinical presentation—particularly ovarian cancer in women and gastrointestinal/pancreatic sources in both sexes.

Critical First Step: Exclude Non-Carcinomatous Malignancies

Before proceeding with a cancer of unknown primary (CUP) workup, you must definitively exclude lymphoma, which has dramatically different treatment and prognosis:

• Check LCA (CD45) status immediately on the ascitic fluid cytology specimen. If LCA-positive and cytokeratin-negative, this is virtually diagnostic of non-Hodgkin lymphoma and requires lymphoma-directed chemotherapy rather than carcinoma protocols 1.
• Misdiagnosing lymphoma as carcinoma results in inappropriate therapy with significantly worse outcomes, whereas appropriately treated aggressive B-cell lymphomas can achieve >70% 5-year survival with R-CHOP 1.

Essential Immunohistochemical Panel

Once carcinoma is confirmed (CK-positive, LCA-negative), expand the immunohistochemical workup to narrow the differential:

• CK7 and CK20 staining patterns provide critical diagnostic clues 2:

  • CK7+/CK20- suggests lung, breast, thyroid, endometrial, cervical, pancreatic, or biliary origin
  • CK7-/CK20+ suggests colorectal or Merkel cell carcinoma
  • CK7+/CK20+ suggests urothelial, ovarian, pancreatic, or biliary cancer
  • CK7-/CK20- suggests hepatocellular, renal cell, prostate, or squamous cell carcinoma

• Additional targeted markers based on patient demographics 2:

  • Women: Estrogen receptor (ER), progesterone receptor (PgR), GCDFP-15, WT-1, CA-125
  • Men >40 years: PSA (prostate-specific antigen)
  • All patients: TTF-1, NapsinA (lung), chromogranin A and synaptophysin (neuroendocrine), AFP and β-hCG (germ cell)

Sex-Specific Workup Priorities

For Women with Peritoneal/Ascitic Presentation:

Ovarian cancer is the primary concern and must be aggressively pursued 2:

• Serum CA-125 measurement is recommended for all women with peritoneal/ascitic malignancy 2.
• Gynecologic oncology consultation should be obtained 2.
• CT imaging of abdomen and pelvis (if not already performed) 2.
• Mammography and consideration of breast MRI to exclude breast cancer, which can present with peritoneal carcinomatosis 2.

Even without identifying an ovarian primary on imaging, women with adenocarcinoma in the peritoneal cavity should often be treated as presumed ovarian cancer (peritoneal papillary serous carcinoma), as this approach improves outcomes 2.

For Men with Ascites:

• PSA testing is mandatory for men >40 years with adenocarcinoma (except those with metastases limited to liver or brain) 2.
• Men with bone metastases should have PSA checked regardless of age 2.

Systematic Imaging and Laboratory Evaluation

Standard Imaging:

• CT chest, abdomen, and pelvis constitutes the minimal basic workup for all CUP patients 2.
• PET/CT has limited utility in patients with diffuse peritoneal carcinomatosis/ascites and is not mandatory in this setting 2.

Selective Serum Tumor Markers:

• AFP and β-hCG in patients with midline disease or those <65 years to exclude extragonadal germ cell tumors 2.
• Chromogranin A if neuroendocrine features are suspected 2.

Endoscopic Evaluation:

Colonoscopy is NOT routinely recommended for patients presenting with malignant ascites 2. The diagnostic yield is <5% in the absence of positive fecal occult blood testing or other clinical factors suggesting colonic origin 2.

• Endoscopy should be symptom-guided or laboratory abnormality-guided only 2.

Important Caveats and Pitfalls

Ascitic Fluid Analysis Limitations:

• While cytology can confirm malignancy, negative cytology does not exclude malignant ascites—sensitivity ranges from 50-65% even with optimal technique 3.
• Tumor markers in ascitic fluid (CA-125, CYFRA21-1) have high specificity (96-98%) but modest sensitivity (40-50% individually, 65% combined) 3.
• The serum-ascites albumin gradient (SAAG) helps distinguish portal hypertensive from non-portal hypertensive causes but doesn't differentiate malignant from other low-gradient causes 2, 4, 5.

Diagnostic Laparoscopy Consideration:

If the above workup remains non-diagnostic, laparoscopy with directed peritoneal biopsies establishes the diagnosis in 86% of cases with ascites of unknown origin and can identify unsuspected tuberculosis (which can mimic carcinomatosis) 6.

Prognosis and Treatment Planning

• Malignant ascites carries a poor prognosis with median survival typically 6-10 months for most CUP patients 2.
• However, identifying favorable subsets (such as presumed ovarian primary in women with peritoneal carcinomatosis) can improve outcomes with site-specific therapy 2.
• Patients with good performance status (ECOG 0-1) and normal LDH have better prognosis (median survival ~12 months) compared to those with poor performance status or elevated LDH (median survival ~4 months) 2.

Treatment Approach:

• If a likely primary is identified through the workup, treat according to site-specific guidelines 2.
• For true CUP without identifiable primary, empiric platinum-based chemotherapy (such as carboplatin/paclitaxel) is standard, though outcomes remain modest 2.
• Gene expression profiling assays are commercially available but their impact on survival through site-directed therapy remains unproven in randomized trials 2.