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Dowell JE. Cancer from an unknown primary site. Am J Med Sci. 2001l; 326: 35-46.
Hainsworth and Greco. Treatment of patients with cancer of an unknown primary site. NEJM 1993;329:257-263
Take home points:
1. Cancer of unknown primary site (CUPS) can be further identified and treated based on histologic type.
2. Immunohistochemical staining is important because it can identify potentially treatable cancers.
3. Use a systematic and evidence-based approach when confronted with CUPS.
First, some background:
• Cancers of unknown primary site (CUPS) account for approximately 5% of cancers.
• Patients present with symptoms that originate from the involved site of metastasis.
• Initial evaluation including history, physical exam, and radiographic imaging fails to identify primary site.
Step 1: Sutton’s Law – go for the money (get some tissue).
• This step is implied, because you are dealing with a cancer of unknown primary site.
• Therefore, if you haven’t gotten tissue yet, get it because the histology is important.
Step 2: What is the histology of the CUPS?
• Histologic analysis of biopsy material separates CUPS into 3 types: adenocarcinoma (60%), poorly
differentiated (35%), and squamous cell carcinoma (5%).
Step 3: Based on the histology, follow steps to identify and treat the primary site.
• Adenocarcinoma:
- Primary site identified in only 15-20% of patients. Pancreas, hepatobiliary tree, and lung account for
40-50%. GI sites are also common. Breast and prostate only rarely present as CUPS.
- Immunohistochemistry can be used to diagnose prostate cancer (PSA stain) and thyroid cancer
(thyroglobulin stain). ER/PR stains are not specific
- Diagnostic testing: history, physical, abdominal CT, PET, serum PSA, mammography. Routine
radiologic or endoscopic evaluation that is not symptom-directed may be misleading. Tumor
markers are not useful diagnostically.
- Groups with specific treatment options:
o Woman with peritoneal mets? Treat for epithelial ovarian cancer
o Woman with axillary lymph node mets? Treat for breast cancer.
o Man with elevated PSA? Treat for prostate cancer with hormonal therapy.
o Mets involving a single peripheral node? Long term survival reported with excision and/or local XRT.
Poorly differentiated cancers:
- Use immunoperoxidase staining to diagnose specific tumors like lymphoma, carcinomas (prostate,
thyroid, neuroendocrine, germ-cell tumors), melanoma, and sarcoma.
- Is the CUPS a non-Hodgkin lymphoma? Potentially curable.
- Is the CUPS an atypical germ cell tumor, neuroendocrine tumor, or a tumor located predominantly
in the retroperitoneum or peripheral lymph node? These tumors are potentially highly responsive to
Squamous cell cancers:
- Cervical node involved? Primary tumor in head and neck should be sought with panendoscopy. Even without an
identified primary site, patients should be treated for locally advanced SCC of head and neck with long term disease free
survival of 30 to 68%.
- Lower cervical or supraclavicular node involved? Usually primary lung cancer and poor prognosis
- Inguinal node involved?: primary site almost always identified (genital or anorectal) and therefore usually treatable.
Evaluation of patients with CUPS whose tumor may be treatable:
Differential diagnosis of miliary opacities on chest radiography:
• Tuberculosis
• Histoplasmosis
• Metastases (e.g. thyroid carcinoma, adenocarcinoma of the pancreas, breast, colon, etc.)
• Pneumoconiosis (silicosis, coal-worker’s pneumoconiosis)
• Talc granulomatosis
• Eosinophilic granuloma
For more information and resources developed by UCSF medical housestaff,
please browse the following links:
UCSF Department of Medicine, Housestaff Website:
• Resources and information for our housestaff
• Location:
UCSF Department of Medicine Hospitalist Handbook:
• Available free of charge for download to PDA
• Updated annually and written by UCSF medical residents
• Location:
UCSF Chief Medical Residents’ Cover Sheets:
• Covering a wide array of topics that were discussed at morning report
• Location: