AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Miscellaneous
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Miscellaneous
• References

Background

In spite of the increasing sophistication in the diagnostic workup for malignancies, detailed investigations fail to reveal a primary site of origin for a subset of patients with metastatic cancer. This is often referred to as carcinoma of unknown primary origin (CUP) or occult primary malignancy. In 2007, the American Cancer Society estimates that 32,100 persons (15,720 males; 16,380 females) will be diagnosed with cancers of unspecified primary sites.¹ This would suggest that cancer of unknown primary origin constitutes about 2% of all cancers diagnosed in the United States. However, deaths due to cancer of unknown primary site are estimated to be 45,230 in 2007 (24,440 males; 20,790 females).¹ This discrepancy between incidence and mortality is believed to be due to a lack of specificity in the listing of cause of death on death certificates.

The exact incidence of cancer of unknown primary origin in the United States is, then, not precisely known. It is almost certainly underreported, and its true incidence is most probably between 2% and 6%. In 15-25% of cases, the primary site cannot be identified even on postmortem examination. The inability to identify a primary site of cancer poses many challenges. The primary site of cancer usually dictates the treatment, expected outcome, and overall prognosis. The diagnosis of carcinoma of unknown primary thus generates anxiety among patients and care givers, who may feel that the evaluation has been incomplete.

Pathophysiology

Cancers are thought to arise from a single cell that escapes the controls of normal cell replication, forms a tumor at the site of origin, and ultimately metastasizes to other organs. In some cases the original tumor may remain small or undetectable at the time of metastasis, leading to the clinical presentation of cancer of unknown primary origin. Whether a specific genetic or mutational factor plays a role in cancer of unknown primary origin remains uncertain.

Frequency

United States

Cancer of unknown primary origin represents 2-6% of all cancers diagnosed in the United States.

International

Cancer of unknown primary origin accounts for 2-9% of cancers diagnosed worldwide.

Mortality/Morbidity

Median survival ranges from 11 weeks to 11 months. The 5-year overall survival rate is about 11%.

Sex

Most series reporting on or reviewing cancer of unknown primary origin patient groups give an approximate equal incidence for men and women.

Age

The median age on presentation for both men and women ranges from 59-66 years.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Miscellaneous
• References

History

Because most patients with malignant neoplasms of unknown origin have fairly advanced-staged cancers, the constitutional symptoms of malaise, weakness, fatigue, and weight loss are present in nearly all patients.

Physical

The clinical presentation of cancer of unknown primary origin is extremely variable, and depends on the extent and type of organ involvement. Most patients present with multiple areas of involvement in multiple visceral sites, the most common sites of involvement being lung, bone, lymph nodes, and liver. Attempts have been made to subclassify patients based on histologic type, involved organ sites, and sensitivity to treatment.

The definition of cancer of unknown primary origin varies depending on the study, but most studies involve some minimum investigations before the term is used. The patient should have a biopsy-proven malignancy. The evaluation should include a detailed history and physical examination, including head and neck, rectal, testicular, pelvic, and breast examinations. Lab and radiological studies should include a complete blood cell count (iron deficiency may point toward an occult gastrointestinal malignancy leading to chronic blood loss), urinalysis (microscopic hematuria may be a sign of occult genitourinary malignancy), liver and renal function tests, stool for occult blood, chest radiograph, computed tomography of abdomen and pelvis, mammography in women, and measurement of prostate-specific antigen (PSA) in men.

Patients have early dissemination of their cancer without symptoms at the primary site. The symptoms are often at the site of metastases.

• Ascites should lead one to evaluate for a GI or an ovarian primary.
• An axillary mass in a female should make the clinician check for breast cancer.
• A cervical node should lead to a thorough ENT examination.
• A brain metastasis should lead to a search for a lung, breast, or kidney primary.
• Bone metastasis should lead to evaluation for prostate, breast, lung, renal, or thyroid primary.
• A testicular mass should lead to measurement of tumor markers such as beta-human chorionic gonadotropin (beta-HCG) and alpha-fetoprotein (AFP).

Further investigations are dictated by any positive findings on initial evaluation. Depending on the clinical situation, these may include computed tomography of the chest, breast magnetic resonance imaging, upper or lower endoscopy. In suspected head and neck malignancies, panendoscopy of the upper aerodigestive pathways should be performed with even as indicated blind biopsies of the lymphoid tissue in these areas. Diagnostic tonsillectomy may be warranted.

Intensive testing also adds to the morbidity for the weak and frail patient. A large negative cost-to-benefit ratio exists for an extensive unguided clinical evaluation, with one study quoting a 9.5% increase in 1-year survival at a cost of 2-8 million dollars. When these investigations fail to reveal a potential primary lesion, a cancer of unknown primary origin is assumed. The goal of initial evaluation should be to detect the small subset of patients who warrant potentially curative management.

Causes

See Pathophysiology.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Miscellaneous
• References

Other Problems to be Considered

All chronic debilitating diseases are among the initial differential diagnoses for 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

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Miscellaneous
• References

Lab Studies

Lab studies should include a complete blood cell count (iron deficiency may point toward an occult gastrointestinal malignancy leading to chronic blood loss), urinalysis (microscopic hematuria may be a sign of occult genitourinary malignancy), liver and renal function tests, stool examination for occult blood, and measurement of PSA in men.

Imaging Studies

Imaging studies should include chest radiograph, computed tomography of abdomen and pelvis, and mammography in women.

Positron emission tomography with 18F-fluoro-2-deoxy-D-glucose (18F-FDG-PET) is increasingly being used in the evaluation of metastatic malignancies. This may be especially the case in suspected head and neck malignancies. However, this testing lacks specificity and may only be useful to identify promising sites for biopsy. Although promising, high cost and false positive rates of 20% limit its utility in cases of cancer of unknown primary origin. The combination of PET/CT may reduce the false-positive rate.

Depending on the clinical situation, further imaging studies may include computed tomography of the chest or breast magnetic resonance imaging.

The high level of inaccuracy of unguided radiographic studies raises the issue of cost effectiveness for intensive diagnostic workup of this disorder.

Other Tests

The role of tumor markers like AFP, beta-HCG, CA125, CA 27.29, CA 19.9, and carcinoembryonic antigen (CEA) to establish a specific primary site or to identify patients who respond to chemotherapy remains unclear and should probably be limited to cases in which a particular primary site is favored. Most tumor markers are nonspecific and may not be used to establish definitive diagnoses.

Procedures

Often the diagnostic procedure of choice is a biopsy of the metastatic site and a careful evaluation of the pathology, which lead the clinician to a cost-effective diagnostic evaluation of the disease.

Depending on the clinical situation, upper or lower endoscopy may be warranted. In suspected head and neck malignancies, panendoscopy of the upper aerodigestive pathways should be performed with even as indicated blind biopsies of the lymphoid tissue in these areas. Diagnostic tonsillectomy may be warranted.

Histologic Findings

The pathologist has an indispensable role in the evaluation of cancer of unknown primary origin. The help of a pathologist familiar with cancer of unknown primary origin is essential. Tumors provided for pathological review should come from tissue that has whenever possible been excised if such tissue is available and accessible. Needle biopsy specimens may provide insufficient tissue for diagnosis or provide tissue that has been too damaged or distorted by the biopsy procedure for accurate diagnosis.

Various immunoperoxidase stains are available for providing a differential diagnosis for cancer of unknown primary origin. An experienced and knowledgeable pathologist will be familiar with appropriate DNA microarray techniques and proteonomic studies to establish a definitive diagnosis. The pathologist typically puts the tissue specimen through 1-4 steps, depending on the need. These studies include light microscopy, immunohistochemical stains, electron microscopy, and chromosomal analysis including cytogenetics.  

• Light microscopy: After initial light microscopic evaluation, most tumors are classifiable as epithelial cancers, lymphomas, sarcomas, melanomas, or germ cell tumors. When cytologic distinguishing features are limited, the tumor may be classified as undifferentiated or poorly differentiated carcinoma.
• Immunohistochemistry: These tests help define tumor lineage by using peroxidase-labeled antibody against specific tumor antigens. These include stains for keratin, leukocyte common antigen and S-100 (expressed in melanomas), thyroid transcription factor TTF-1 (for lung and thyroid cancer), PSA, HCG (for germ cell tumors), AFP (for germ-cell tumors and hepatomas), ER, PR, and Her-2 (for breast cancer).
• Electron microscopy: This study has limited utility in identification of the primary site of cancer of unknown primary origin but may rarely be used in poorly differentiated tumors.
• Chromosomal studies: In cases of cancer of unknown primary origin with suspected occult nasopharyngeal carcinoma, DNA amplification of Epstein Barr virus (EBV) in tissue may clinch the diagnosis. The presence of iso-chromosome 12p, i(12p), a specific chromosomal marker characteristic of germ cell tumors can help diagnose extragonadal germ cell tumors in patients with cancer of unknown primary origin.

The majority of cancers of unknown primary origin are adenocarcinomas or undifferentiated tumors (up to 58% in some studies). Less commonly, squamous cell carcinoma, melanoma, sarcoma, and neuroendocrine tumors can also present as metastasis with an unknown primary site of origin. Most studies exclude sarcomas and melanomas from their analysis.

In the approximately 30% of cancers of unknown primary origin in which a full workup establishes a clear pathological diagnosis, the most common epithelial malignancies are lung (15%), pancreas (13%), colon/rectum (6%), kidney (5%), and breast (4%). Sarcomas, melanomas, and lymphomas each contribute 6-8%. The remaining primary tumors are those of stomach (4%), ovary (3%), liver (3%), esophagus (3%), prostate (2%), and a variety of other malignancies (22%).

Staging

Patients with cancer of unknown primary origin are presumed to all have stage IV disease at the time of initial presentation.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Miscellaneous
• References

Medical Care

The treatment of cancer of unknown primary origin continues to evolve. The most common scenario is a patient with progressive, metastatic adenocarcinoma with multiple organ involvement. The treatment of this group of patients remains suboptimal.

The overall prognosis of patients with cancer of unknown primary origin with multiple organ involvement and poor performance status is grave; the median survival is only 3-4 months. The 1-year survival rate is less than 15%, with a 5-year survival of 5-10%. Certain clinical factors, like male sex, multiple brain metastases, pleural/lung involvement, liver involvement, adrenal involvement, and adenocarcinoma histology are poor prognostic markers. Others, like lymph node involvement and neuroendocrine histology, are associated with a longer survival.

In contrast, some favorable subsets have been identified that respond well to certain specific treatment strategies. These are discussed below.

Metastasis to cervical lymph nodes

A histologic diagnosis of metastatic carcinoma in the cervical nodes warrants a careful evaluation of the upper aerodigestive tract, including direct visualization of the hypopharynx, nasopharynx, larynx, and upper esophagus. Most of these tumors are squamous cell carcinoma on histology, but adenocarcinoma, melanoma, or anaplastic tumors can also be seen in this location. In patients with squamous or undifferentiated carcinoma, tonsillectomies should be considered. Cervical adenopathy can be the primary disease manifestation in 2-5% of patients with primary squamous cell carcinoma of the head and neck region. In the absence of localization of a primary site, aggressive local therapy is indicated. This may involve any of the following:

• Radical radiation therapy with curative intent to the neck and possible site of origin
• Preoperative radiation therapy followed by radical neck dissection
• Radical neck dissection
• Radical neck dissection followed by radiation to possible sites of origin

Five-year survival rates as high as 30-50% have been achieved with this approach. Role of chemotherapy is debated. One randomized study showed improved response rate and median survival with cisplatin and 5-fluorouracil—based chemotherapy when compared to radiation alone. A single adenocarcinoma-involved  lymph node in either the cervical or inguinal areas with no evidence of disease elsewhere may be managed with surgical excision alone and watchful  expectation. Radiation therapy to the involved and local fields may be provided as well. Combination therapy may be superior to monotherapy with 5-year survival rates of 35% reported.

• Patient younger than 50 years 
• Midline distribution, with elevated levels of beta-HCG or AFP
• Beta-HCG/AFP positive on immunohistochemistry
• Neuroendocrine granules
• Rapid tumor growth
• Iso-chromosome 12p in midline tumors

Platinum-based combination chemotherapy regimens specific for germ cell tumors have been employed in these patients with a response rate of 63%, a complete response rate of 26%, and a 10-year survival rates of 16%.

Poorly differentiated neuroendocrine carcinomas

These tumors are characterized by positive histochemical stains for chromogranin or neuron-specific enolase. These patients often present with extensive liver or bone metastases. In a series of 29 patients, 19 were treated with intensive cisplatin-based chemotherapy, and 6 others received doxorubicin-based combinations. Complete responses were achieved in 6 patients, and 4 of these patients were alive 19-100 months after diagnosis.
 
Inguinal node metastasis

Metastatic carcinoma in inguinal nodes from an unknown site can be found in 1-3.5% of patients. Squamous cell histology in this area is usually metastatic from the genital/anorectal area. The anorectal area should be carefully inspected in both sexes. Vulvar, vaginal, and cervical examination in women and penile examination in men is warranted. Treatment can involve groin dissection alone or with radiation and chemotherapy. In some patients, local excision with or without radiation may be adequate.

Cancer of unknown primary origin in unselected patients

The results from the favorable patient subsets do not apply to most of the patients with cancer of unknown primary origin. The most effective chemotherapy regimens for this group of patients involve combination therapy with a platinum compound (cisplatin or carboplatin) and a taxane (preferably paclitaxel).This combination gives a response rate of about 12-26% and a median survival of 5-7 months. Triple drug therapy does not appear to offer any additional benefit.

Patients in whom combination therapy fails may benefit from single-agent treatment with gemcitabine with median time to progression of 5 months. A recent phase II clinical trial with bevacizumab and erlotinib has given a median survival of 7-8 months with 33% of patients alive at 1 year. A confirmation and extension of this trial is anticipated within the next 1-2 years.

Surgical Care

See Medical Care.

MEDICATION

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Miscellaneous
• References

See Medical Care.

MISCELLANEOUS

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Miscellaneous
• References

Medical/Legal Pitfalls

It is always important to communicate clearly the goals of the diagnostic plan to the patient and his next of kin. Always make sure that the patient is always informed of his options once a diagnosis is made. The therapeutic choices should be thoroughly reviewed and complications must be mentioned.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Miscellaneous
• References

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Article Last Updated: Jul 12, 2007