Metastatic Cancer, Unknown Primary Site

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


INTRODUCTION

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.

Frequency:

• In the US: This entity comprises 5-15% of all malignancies.

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.

• The signs and symptoms provide clues to the underlying organ affected by the tumor; sometimes, further investigation reveals the primary site of origin.

• Obtaining a good history is the most important aspect of the initial workup of any patient with tumor of unknown primary origin.

• The history should be complete, with a detailed and comprehensive review of systems. Special attention should be given to past medical history. Any previous surgery should be documented, and pathology reports of previous surgical specimens should be obtained.

• 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.

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

• Similarly, positive signs provide clues to the organ system affected by the neoplasms and, in some cases, can reveal the underlying primary site of origin.

• All patients should have a complete physical examination, including breast and pelvic examinations in female patients and testicular and prostate examinations in male patients.

• Whenever cervical lymphadenopathy is present with a squamous cell or undifferentiated histology, a thorough evaluation by an ear, nose, and throat surgeon should be performed, even in the absence of symptoms, to find the primary site of origin.

• In female patients with inguinal lymphadenopathy consistent with squamous cell histology, a Papanicolaou smear test and a colposcopic examination of the cervix should be performed.

Causes: See Pathophysiology.

DIFFERENTIALS

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.

WORKUP

Lab Studies:

• Laboratory investigation initially should be limited to the following:

• CBC count

• Electrolytes

• Hepatic and renal function tests

• Calcium, albumin, and phosphate evaluations

• Remember, the detection of a primary cancer may have a favorable influence on patient survival or quality of life if the underlying cancer is amenable to effective treatment. Therefore, costly and invasive investigations should be used intelligently.

• Tumor markers

• Routine use of tumor markers is not justified in all patients. Only in specific circumstances do tumor markers help in the treatment of the underlying malignancy.

• Cancer antigen 125 test: Use this only in women with a peritoneal presentation of adenocarcinoma of unknown primary origin. If elevated at diagnosis, it can be used to gauge response to therapy.

• Prostate-specific antigen: Use this in men with adenocarcinoma (especially with bone metastases).

• Beta human chorionic gonadotropin and alpha-fetoprotein: Use this only in men with undifferentiated malignancy (especially with midline tumors).

Imaging Studies:

• The initial radiological tests should be limited to a chest x-ray. All other tests should be justified clinically.

• This is the most controversial area in the management of cases of tumor of unknown primary origin. Although many physicians feel uncomfortable limiting initial investigations, enormous amounts of data published in medical literature support such an approach.

• The goal of an effective diagnostic strategy for tumor of unknown origin is to identify patients with treatable (sometimes curable) underlying primary malignancies. This should be accomplished using minimal investigations without overlooking patient complaints and abnormal clinical signs.

• Extensive searches usually are fruitless, costly, and have no major impact on the overall survival of the patient with cancer.

• CT scans, nuclear scans, and other endoscopic evaluations should be limited to special cases and should not be ordered in all cases.

• Special circumstances

• CT scan of the head and neck: This should be performed in patients with metastatic squamous cell carcinoma of high cervical lymph nodes.

• CT scan of the chest, abdomen, and pelvis in patients with either poorly differentiated adenocarcinoma or an undifferentiated carcinoma: Some of these patients have underlying germ cell cancers that may respond to treatment.

• CT scan of the abdomen and pelvis in female patients with abdominal presentation of adenocarcinoma: Many of these patients have underlying ovarian carcinoma, another treatable disease.

• Mammogram: This should be performed in all female patients with adenocarcinoma (especially when the tumor is estrogen and progesterone receptor-positive).

• Routine bone scan: No role exists for routine bone scans. Bone scans should be performed only in patients with complaints of bone pain or abnormal calcium and alkaline phosphatase levels in their serum.

Procedures:

• No role exists for routine endoscopic examinations.

• Upper and lower GI endoscopy should be performed only to investigate either clinical GI signs and symptoms or specific abnormal laboratory results. Routine use of endoscopic procedures in asymptomatic patients is fruitless and usually does not reveal the primary site.

• Panendoscopy of the head and neck area should be performed in all patients with squamous cell or undifferentiated carcinoma of high cervical lymph nodes.

• Pathological evaluation of the biopsy specimen of the tumor is very important in the workup of patients with tumor of unknown primary origin. Every attempt should be made to obtain a good-sized biopsy specimen for pathological evaluation. If the specimen is inadequate for quality assessment, then a second core or excisional biopsy should be performed.

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.

TREATMENT

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.

• The 3 modes of therapy are as follows:

• Surgery

• Chemotherapy

• Radiation therapy

• All 3 modes can be used as isolated treatments or in combination with the other 2.

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:

• Female patients with adenocarcinoma of the axillary lymph nodes of unknown primary origin should undergo ipsilateral mastectomy.

• Patients with squamous cell carcinoma of cervical lymph nodes can undergo cervical lymph node dissection if radiation is contraindicated.

• In any patient with a solitary isolated metastatic tumor, complete excision should be performed.

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.

MEDICATION

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 Dose	Combination therapy: 300 mg/m2 q4wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; bone marrow suppression
Interactions	Nephrotoxicity increases with aminoglycosides and other nephrotoxic drugs
Pregnancy	D - Unsafe in pregnancy
Precautions	Monitor bone marrow function

Drug Name	Cisplatin (Platinol) -- Inhibits DNA synthesis and thus cell proliferation by causing DNA crosslinks and denaturation of double helix.
Adult Dose	20 mg/m2 IV days 1-5; repeat q3-4 wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; preexisting renal insufficiency; myelosuppression; hearing impairment
Interactions	Increases toxicity of bleomycin and ethacrynic acid
Pregnancy	D - Unsafe in pregnancy
Precautions	Administer 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 Dose	30 U qwk/cycle
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; significant renal function impairment; compromised pulmonary function
Interactions	May decrease plasma levels of digoxin and phenytoin; cisplatin may increase toxicity of bleomycin when administered systemically
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution 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 Dose	175 mg/m2 IV over 3 h q3wk or 135 mg/m2 IV over 24 h q3wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; peripheral neuropathy; bone marrow suppression; liver failure; severe cardiac disease
Interactions	Coadministration with cisplatin may further increase myelosuppression
Pregnancy	D - Unsafe in pregnancy
Precautions	Premedicate 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 Dose	100 mg/m2 IV days 1-5
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; IT administration may cause death
Interactions	May 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
Precautions	Bleeding and severe myelosuppression may occur

FOLLOW-UP

In/Out Patient Meds:

• All patients on chemotherapy should be prescribed antiemetics to control and prevent nausea and vomiting.

Prognosis:

• In most cases, the overall prognosis is poor. The median survival is less than 1 year. However, certain groups of patients do well and can achieve prolonged survival.

• Squamous cell carcinoma of cervical lymph nodes: With radiation therapy (with or without neck dissection), some patients achieve long-term survival.

• Squamous cell carcinoma of inguinal lymph nodes: Radical dissection or external radiation therapy can lead to long-term survival in some patients.

• Adenocarcinoma of the axilla in a female patient: With proper treatment (ie, ipsilateral mastectomy and adjuvant chemotherapy), survival is the same as that associated with stage II breast cancer.

• Adenocarcinoma of the peritoneal cavity: Survival is the same as stage III ovarian cancer with carboplatin- and paclitaxel-based chemotherapy.

• In males, adenocarcinoma with bone-only metastases can be treated with androgen deprivation therapy and survival can be the same as with D2 prostate cancer.

• Undifferentiated neoplasms or poorly differentiated carcinomas: Some patients can be cured with systemic cisplatin-based chemotherapy because some of these patients can have an underlying germ cell neoplasm.

• Well-differentiated and moderately differentiated adenocarcinomas: Treatment with systemic carboplatin, paclitaxel, and oral etoposide chemotherapy can lead to responses in as many as 40% of patients.

Patient Education:

• Education is directed mainly at the primary care physician. The physician should realize that too many investigations have no effect on patient survival. Excessive investigation only adds to the cost of health care and has no bearing on the treatment.