Understanding Cancer of Unknown Primary Site: A Patient's Guide to Diagnosis and Treatment

Table of Contents

• Introduction: The Clinical Challenge
• The Clinical Problem
• Key Points About Cancer of Unknown Primary
• Clinical Evaluation Process
• Immunophenotyping: How Pathologists Identify Cancer Types
• Molecular Profiling: Advanced Genetic Testing
• Treatment Approaches and Strategies
• Prognosis and Survival Outlook
• Clinical Recommendations for Patients
• Source Information

Introduction: The Clinical Challenge

Imagine a 47-year-old previously healthy woman who develops abdominal bloating and discomfort that worsens over three months. Her examination reveals abdominal distention with fluid buildup (ascites). Testing shows anemia (hemoglobin level of 10.4 g/dL compared to the normal 12.0-14.0 range), elevated cancer markers (CA-125 at 168 U/mL, normal <38; CEA at 14.7 ng/mL, normal <3.8), and CT scans revealing tumors in her liver, lymph nodes, and abdominal lining with ascites.

A biopsy shows poorly differentiated carcinoma with specific protein markers suggesting gastrointestinal origin, yet comprehensive testing including mammography, colonoscopy, and endoscopy cannot locate the original cancer site. Molecular profiling also fails to identify the tissue of origin. This case illustrates the complex challenge facing patients and doctors when dealing with cancer of unknown primary site.

The Clinical Problem

Cancer of unknown primary site represents one of the most difficult diagnoses in oncology. This term describes a diverse group of cancers that have spread (metastasized) by the time they're discovered, but the original site remains hidden despite standard diagnostic testing. Patients with this diagnosis typically require more healthcare resources including additional tests, emergency visits, and hospitalizations compared to patients with known primary cancers.

This condition accounts for 2-4% of all cancers, with approximately 37,370 new cases expected in the United States in 2025. Worldwide incidence ranges between 2-15 cases per 100,000 person-years, and rates have been declining due to improved diagnostic methods and molecular profiling that can better identify primary sites.

Risk factors include smoking, alcohol consumption, diabetes, and family history of cancer. Patients typically present with symptoms of widespread cancer involvement, and imaging reveals diverse cancer types: adenocarcinoma (59% of cases), poorly differentiated or undifferentiated carcinoma (31%), and squamous carcinoma (9%). The cancer spreads to multiple sites (33% of cases), liver (25%), or lymph nodes (7%) among other locations.

Key Points About Cancer of Unknown Primary

Several important facts patients should know about this condition:

• Heterogeneous nature: This represents a diverse group of metastatic cancers where the original site remains unidentified after standard testing
• Comprehensive evaluation needed: Diagnosis requires detailed history, physical exam, laboratory tests, imaging (preferably contrast-enhanced CT scans), and thorough pathological examination of adequate tumor tissue
• Advanced testing: While immunophenotyping (protein marker analysis) remains central to diagnosis, molecular profiling now plays a key role in predicting tissue of origin and identifying targetable genetic changes
• Treatment options: Both site-specific therapy (treating based on suspected primary site) and empirical chemotherapy (standard platinum-based regimens) are acceptable approaches
• Prognostic challenges: Overall prognosis remains poor, and participation in clinical trials should be encouraged

Clinical Evaluation Process

The diagnostic process for cancer of unknown primary begins with a comprehensive evaluation aimed at finding any primary lesion. However, the extent of testing may be limited by resource constraints, other medical conditions, and the urgency of treatment dictated by how rapidly the disease is progressing.

The clinical evaluation starts with a careful history, including family and personal history of previous cancers. Physical examination and baseline laboratory tests help guide further workup. All patients should undergo imaging, ideally contrast-enhanced CT scans of the chest, abdomen, and pelvis.

Additional diagnostic methods may include PET scans, MRI, mammography, testicular ultrasound (in young men with midline lymphadenopathy), or invasive procedures like endoscopy, colonoscopy, bronchoscopy, laryngoscopy, or cystoscopy. These are guided by symptoms, imaging findings, or pathological results that suggest a possible primary origin.

Since no single test is highly effective due to the atypical nature of these cancers, developing a management plan based on the overall disease presentation and multidisciplinary team expertise is crucial.

Immunophenotyping: How Pathologists Identify Cancer Types

Microscopic examination of tumor tissue with immunophenotyping (analysis of protein markers) remains the foundation of diagnosing cancer of unknown primary. The accuracy of immunohistochemical testing for determining tissue type is high, especially when adequate tumor tissue is available.

Pathologists typically use an average of 8.8 different protein stains (ranging from 0 to 20) when evaluating metastatic tumors. Unfortunately, nearly two-thirds of patients will have insufficient tissue left for molecular profiling during their clinical care due to the extensive testing required.

Despite heavy reliance on immunohistochemical testing, its accuracy in identifying a primary organ is limited, particularly with poorly differentiated tumors. Since no single protein stain definitively identifies tissue origin, pathologists often use a panel of tests performed in a stepwise fashion. The future may involve deep-learning methods to improve tissue of origin determination.

Molecular Profiling: Advanced Genetic Testing

Molecular profiling serves two important purposes in cancer of unknown primary: predicting a putative primary site (tissue-of-origin profiling) and identifying targetable genetic alterations amenable to targeted therapies.

Several tissue-of-origin assays have been developed based on the premise that cancers of unknown primary share similarities with metastases from known primary sites. These assays examine RNA, microRNA, DNA, and methylation patterns combined with machine learning, achieving accuracy rates ranging from 65% to 99% in predicting tissue of origin.

Among these strategies, only gene-expression profiling has been evaluated in randomized trials, with mixed results. This advanced testing represents a significant development in managing this challenging condition.

Treatment Approaches and Strategies

Treatment for most patients with cancer of unknown primary is primarily palliative due to the widespread nature of the disease, except for a small subgroup with single-site or limited metastatic disease where a multidisciplinary approach incorporating radiation or surgery might be potentially curative.

Site-Specific Therapy and Molecular Profiling

Patients who present with characteristic patterns analogous to specific known cancers can be treated according to guidelines for those specific tumors. For example:

• Blastic bone metastases with elevated PSA in men → treated as prostate cancer
• Serous carcinoma with peritoneal involvement in women → treated as ovarian cancer
• Carcinoma with isolated axillary lymphadenopathy in women → treated as breast cancer
• Squamous-cell carcinoma with cervical lymphadenopathy → treated as head/neck cancer

For cancers with specific molecular features:

• BRAF V600E mutation → treated with dabrafenib and trametinib
• NTRK fusions → treated with entrectinib, larotrectinib, or repotrectinib
• HER2 amplification → treated with trastuzumab deruxtecan
• Mismatch repair deficiency → treated with PD-1/PD-L1 inhibitors
• High tumor mutational burden → treated with pembrolizumab

Several retrospective studies and prospective trials have investigated the benefit of site-specific therapy versus empirical chemotherapy with conflicting results. Two multicenter trials (CUP-NGS with 130 patients and GEFCAPI 04 with 395 patients) are currently evaluating molecular profiling-guided treatment versus empirical chemotherapy.

Prognosis and Survival Outlook

Cancer of unknown primary has been classified into "favorable" and "unfavorable" subsets, though these categories are evolving with advances in molecular diagnostics and targeted therapies. The favorable subset comprises approximately 20% of cases and is associated with better prognosis than unfavorable disease.

The larger unfavorable subset is associated with poor survival, though modest improvements have been noted in recent years. Survival outcomes appear worse than for metastatic cancers of known primary site, suggesting more aggressive behavior.

Negative prognostic factors include:

• Male sex
• Poor performance status
• Adenocarcinoma histology
• High number of metastases
• Liver or peritoneal metastases
• High neutrophil-to-lymphocyte ratio
• Specific molecular alterations (KRAS or NRAS mutations, CDKN2A deletion)

Clinical Recommendations for Patients

Based on current evidence, patients with cancer of unknown primary should:

1. Undergo comprehensive evaluation: Complete history, physical exam, laboratory tests, and imaging (preferably contrast-enhanced CT of chest, abdomen, and pelvis)
2. Ensure adequate tissue sampling: Core-needle biopsy is preferred to preserve tissue architecture and allow for extensive testing
3. Receive multidisciplinary care: Collaboration between oncologists, pathologists, and other specialists is essential
4. Consider molecular profiling: This can help predict tissue of origin and identify targetable alterations
5. Discuss treatment options: Both site-specific therapy and empirical chemotherapy are acceptable approaches
6. Explore clinical trials: Participation in research studies should be encouraged given the poor prognosis
7. Seek palliative support: Symptom management and quality of life considerations are important components of care

Source Information

Original Article Title: Cancer of Unknown Primary Site

Author: Kanwal Raghav, M.D.

Publication: The New England Journal of Medicine, 2025;392:2035-47

DOI: 10.1056/NEJMcp2402691

This patient-friendly article is based on peer-reviewed research originally published in The New England Journal of Medicine. It maintains all significant findings, data points, and clinical recommendations from the original work while making the information accessible to patients and caregivers.