January 17, 2007

Metastatic Cancer, Unknown Primary Site

Synonyms and related keywords: tumor of unknown primary, cancer of unknown origin


Background: Tumor of unknown origin is a distinct clinicopathological entity defined as the presence of a metastatic cancer without a known primary site of origin. This entity can be diagnosed only if the histology of the tumor is not consistent with the known tumors of the organ from which the biopsy was taken.

This entity is a diagnostic dilemma and a therapeutic challenge. It creates anxiety among not only patients and their families but also physicians, who feel uncomfortable informing patients that they have an advanced disease of unknown origin.

Pathophysiology: All cancers are monoclonal in origin, ie, they arise from a single cell. As cells start to replicate, they first form a clinically detectable mass at the site of origin and ultimately metastasize to other organs. However, in some situations, replicating cells tend to metastasize to distant sites early and fail to grow at the site of origin. This accounts for the absence of a detectable primary tumor, while secondary sites become clinically detectable.


Mortality/Morbidity: With few exceptions, cancers of unknown primary site have a grave prognosis, with a median survival of 5-6 months. The overall 5-year survival rate is less than 10%.

Sex: Tumor of unknown primary origin is slightly more common in males than in females. This is in proportion to the fact that males are affected with cancer more commonly than females.

Age: The median age of presentation is 59 years.

History: The clinical features of tumor of unknown primary origin depend on the organ or area affected by the metastatic lesions. Therefore, these are variable from patient to patient.

Physical: Like the history, physical examination findings also vary from patient to patient.

Causes: See Pathophysiology.


Other Problems to be Considered:

Because most patients with malignant neoplasms of unknown origin have fairly advanced-staged cancers, the constitutional symptoms of malaise, weakness, fatigue, and weight loss usually are present in all patients. Therefore, all chronic debilitating diseases are in the initial differential diagnosis of all cases of advanced cancers. However, once a histological diagnosis of a malignancy is made, the list of differential diagnoses is narrowed to neoplastic conditions.


Lab Studies:

Imaging Studies:


Histologic Findings: With light microscopy, the initial histologic subgroups of tumors are as follows: (1) well-differentiated and moderately differentiated adenocarcinoma (60%), (2) squamous cell carcinoma (5%), (3) poorly differentiated adenocarcinoma or undifferentiated carcinoma (30%), and (4) poorly differentiated malignant neoplasm (5%).

Well-differentiated and moderately differentiated adenocarcinomas are the most common tumors found on biopsy specimens, followed by poorly differentiated adenocarcinoma, undifferentiated carcinoma, and finally, squamous cell carcinoma and poorly differentiated neoplasms.

Occasionally, a patient may have obvious histologic features of sarcoma or melanoma and, therefore, should be treated and evaluated appropriately. When the light microscopic features are nondiagnostic for any particular histologic types (eg, when a diagnosis of poorly differentiated adenocarcinoma or an undifferentiated neoplasm is suggested), further specialized tests are needed to identify the exact histologic type, to identify the underlying primary site of origin, and to guide proper therapy.

Using immunohistochemical staining, electron microscopy, and molecular and cytogenetic techniques, sometimes a definitive histology of lymphoma, germ cell neoplasm, melanoma, or Hodgkin disease is diagnosed.

Staging: Staging studies must be individualized according to the histologic diagnosis of the tumor and the condition of the patient. The idea of staging in tumors of unknown primary origin is completely different from other tumors. The goal is to locate the primary site of origin because it already is known that the cancer is metastatic. Therefore, all staging tests should be selected carefully and should be based on the specific tumor histology and the overall condition of the patient.


Medical Care: Treatment begins with a frank and open discussion with the patient. All patients should be informed about the nature of their disease and the limitations of diagnostic tests and cancer therapy. Without this full disclosure, their decision or consent regarding therapy cannot be considered informed.

Surgical Care: The main role of surgery is in the initial biopsy of the tumor mass. This is the most important aspect in the treatment of carcinoma of unknown primary origin. A large excisional or core biopsy of the tumor is needed for a complete pathological evaluation to determine the site of origin. A fine-needle aspiration specimen is not adequate for pathological assessment. In terms of treatment, the role of surgery is as follows:

Diet: All patients with underlying malignancy should maintain a normal balanced diet. Restrictive diets and parental nutrition have no role in the treatment of cancer of unknown primary origin.


The goals of pharmacotherapy are to reduce morbidity, prevent complications, and eradicate the disease.

Drug Category: Antineoplastic agents -- Chemotherapy is the main therapy for any underlying malignancy. This involves cytotoxic agents specifically designed to cause tumor lysis. If during investigation, a primary cancer is discovered, the treatment is based on the treatment of that site. Otherwise, therapy is not fully standardized. Carboplatin, paclitaxel, and etoposide are used together. Cisplatin, etoposide, and bleomycin also are used as combination therapy.
Drug Name
Carboplatin (Paraplatin) -- Analog of cisplatin. Has same efficacy as cisplatin but with better toxicity profile.
Dose is based on the following formula: Total dose (mg) = (target AUC) X (GFR = 25), where AUC (area under plasma concentration-time curve) is expressed in mg/mL/min and GFR (glomerular filtration rate) is expressed in mL/min.
Adult DoseCombination therapy: 300 mg/m2 q4wk
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; bone marrow suppression
InteractionsNephrotoxicity increases with aminoglycosides and other nephrotoxic drugs
Pregnancy D - Unsafe in pregnancy
PrecautionsMonitor bone marrow function
Drug Name
Cisplatin (Platinol) -- Inhibits DNA synthesis and thus cell proliferation by causing DNA crosslinks and denaturation of double helix.
Adult Dose20 mg/m2 IV days 1-5; repeat q3-4 wk
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; preexisting renal insufficiency; myelosuppression; hearing impairment
InteractionsIncreases toxicity of bleomycin and ethacrynic acid
Pregnancy D - Unsafe in pregnancy
PrecautionsAdminister adequate hydration before and 24 h after cisplatin to reduce risk of nephrotoxicity; myelosuppression, ototoxicity, nausea, and vomiting may occur
Drug Name
Bleomycin (Blenoxane) -- Glycopeptide antibiotic that inhibits DNA synthesis. For palliative measures in the treatment of several neoplasms.
Adult Dose30 U qwk/cycle
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; significant renal function impairment; compromised pulmonary function
InteractionsMay decrease plasma levels of digoxin and phenytoin; cisplatin may increase toxicity of bleomycin when administered systemically
Pregnancy D - Unsafe in pregnancy
PrecautionsCaution in patients with renal impairment; possibly secreted in breast milk; may cause mutagenesis and pulmonary toxicity (10%); idiosyncratic reactions similar to anaphylaxis (1%) may occur; monitor for adverse effects during and after treatment; vasoocclusive phenomenon with distal necrosis of digit; permanent damage to nail matrix may occur
Drug Name
Paclitaxel (Taxol) -- Mechanisms of action are tubulin polymerization and microtubule stabilization.
Adult Dose175 mg/m2 IV over 3 h q3wk or 135 mg/m2 IV over 24 h q3wk
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; peripheral neuropathy; bone marrow suppression; liver failure; severe cardiac disease
InteractionsCoadministration with cisplatin may further increase myelosuppression
Pregnancy D - Unsafe in pregnancy
PrecautionsPremedicate with steroids and H1 and H2 blockers to decrease risk of hypersensitivity reactions; myelosuppression, alopecia, arthralgias/myalgias, and cardiac arrhythmia may occur
Drug Name
Etoposide (Toposar, VePesid) -- Inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation to arrest in late S or early G2 portion of the cell cycle.
Adult Dose100 mg/m2 IV days 1-5
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; IT administration may cause death
InteractionsMay prolong effects of warfarin and increase clearance of methotrexate; cyclosporine and etoposide have additive effects in cytotoxicity of tumor cells
Pregnancy D - Unsafe in pregnancy
PrecautionsBleeding and severe myelosuppression may occur


In/Out Patient Meds:


Patient Education:

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