What is the diagnosis and treatment approach for adenocarcinoma (adenocarcinoma) that is positive for pankeratin (pankeratin) and CK7 (cytokeratin 7), but negative for TTF1 (thyroid transcription factor 1), CDX2 (caudal type homeobox 2), PSA (prostate-specific antigen), and CK20 (cytokeratin 20)?

Adenocarcinoma CK7+/CK20-/TTF1-/CDX2-/PSA-: Cancer of Unknown Primary

This immunoprofile (pankeratin+/CK7+/CK20-/TTF1-/CDX2-/PSA-) represents a cancer of unknown primary (CUP) requiring immediate additional immunohistochemical workup and clinical correlation to identify the primary site, as this pattern is consistent with multiple possible origins including pancreaticobiliary, breast, ovarian, endometrial, gastric, or TTF1-negative lung adenocarcinoma. 1

Differential Diagnosis Based on Immunoprofile

The CK7+/CK20- pattern narrows the differential to lung, breast, thyroid, pancreatic, ovarian, endometrioid, gastric, urothelial, or endocervical carcinomas. 1 However, the negative TTF1 and CDX2 significantly alter this differential:

Most Likely Primary Sites

Pancreaticobiliary adenocarcinoma is a leading consideration with this profile (CK7+/CK20-/TTF1-/CDX2-), particularly if the patient has liver metastases. 1, 2

Breast carcinoma must be excluded, especially in female patients, as 98% of breast cancers are CK7+ and 92% are CK20-. 1, 3

Ovarian adenocarcinoma (non-mucinous) typically shows CK7+/CK20-/TTF1-/CDX2-/CEA- pattern. 2

Gastric adenocarcinoma can present with CK7+/CK20-/CDX2+ or CDX2- patterns, with CDX2 expression more common in intestinal-type tumors (61% overall). 2, 4

TTF1-negative lung adenocarcinoma remains possible, as only ~60% of poorly differentiated and metastatic lung adenocarcinomas stain positive for TTF1. 1

Mandatory Next-Step Immunohistochemistry

For Female Patients

GATA3 must be performed immediately to screen for breast cancer. 1

SOX10 should be added to evaluate for triple-negative breast cancer. 1

ER/PR (estrogen receptor/progesterone receptor) are essential breast markers with high specificity. 1, 2

WT1 positivity would suggest ovarian serous carcinoma. 1

For Male Patients

PSMA and/or NKX3.1 are mandatory to exclude metastatic prostate cancer, even though PSA is negative (as PSA can be negative in poorly differentiated prostate cancer). 1

Universal Additional Markers

MUC5AC and CEA together suggest pancreaticobiliary origin when both positive in the setting of CK7+/TTF1-/CDX2-. 2, 5

CK17 and MUC1 are highly specific for pancreaticobiliary adenocarcinomas, with CK17 showing 83% sensitivity for pancreatic ductal carcinoma and 71% for cholangiocarcinoma. 5

SMARCA4 staining should be considered if lung primary is suspected despite TTF1 negativity, as many TTF1-negative lung adenocarcinomas show loss of SMARCA4 nuclear staining. 1

HepPar1, glypican-3, and Arginase-1 must be performed if liver metastases are present to exclude hepatocellular carcinoma. 6

Synaptophysin and/or INSM1 should be added if the tumor shows solid, trabecular, or regular glandular growth pattern to exclude neuroendocrine differentiation. 1

Essential Clinical Workup

CT scans of chest, abdomen, and pelvis are mandatory baseline imaging for all CUP patients. 1

Mammography is required for all female patients given the high likelihood of breast primary. 1

Upper gastrointestinal endoscopy should be performed if pancreaticobiliary or gastric origin is suspected based on additional IHC markers or clinical presentation. 6

FDG-PET/CT may identify the primary site in patients with single metastasis or cervical adenopathy, but has limited utility in other CUP presentations. 1

Serum CA19-9 elevation would support pancreaticobiliary origin. 1

Treatment Approach

Empiric platinum-based chemotherapy (paclitaxel 200 mg/m² + carboplatin AUC=6 every 3 weeks) is the standard treatment for adenocarcinoma CUP with unfavorable features. 1

Site-specific therapy should be administered if additional IHC and clinical workup identify a likely primary:

• Breast origin: Treat as metastatic breast cancer with endocrine therapy if ER/PR+ or HER2-targeted therapy if HER2+. 1
• Pancreaticobiliary origin: Consider gemcitabine-based or FOLFIRINOX regimens. 1
• Ovarian origin: Treat as advanced ovarian cancer with platinum/taxane combinations. 1

Molecular profiling with next-generation sequencing should be performed to identify actionable mutations (EGFR, ALK, ROS1, BRAF, NTRK, MSI-high/dMMR) that may guide targeted therapy. 1

Critical Prognostic Information

Median survival for adenocarcinoma CUP with unfavorable features (multiple organ metastases) is approximately 3 months without treatment, with 1-year survival <20%. 1

Extranodal disease (liver, lung, bone metastases) carries significantly worse prognosis than lymph node-only disease. 1

Performance status is the most important factor determining treatment candidacy—only patients with PS 0-2 should receive chemotherapy. 1

Common Pitfalls to Avoid

Do not assume colorectal origin is excluded by CK20 negativity alone—approximately 20% of colorectal cancers are CK20-negative, though the CDX2 negativity makes this very unlikely. 4

Do not rely on TTF1 negativity to exclude lung primary—40% of lung adenocarcinomas are TTF1-negative, particularly poorly differentiated tumors. 1

Do not perform extensive IHC panels blindly—use a stepwise algorithmic approach guided by clinical context and initial markers. 1

Do not overlook breast cancer in males—while rare, male breast cancer can present as CUP and requires GATA3 evaluation. 1