Cancer of an unknown primary site (Cup)

Cancer of an unknown primary site (CUPS) is a metastatic tumor with no obvious source. It is detected by a biopsy that shows cancer from a part of the body that does not produce that type of malignancy, and no site of origin is identified despite a thorough physical examination, blood tests, X-rays, and other imaging studies.

No primary site of origin can be identified in 2 to 5 percent of patients diagnosed with metastatic cancer. This is often because the primary tumor is so small that it is undetectable or the primary site is difficult to see directly or by using imaging techniques.

Since by definition the disease is diagnosed at a metastatic stage, the prognosis is generally poor. A significant percentage of patients, however, can have symptoms relieved and can occasionally be cured. For example, germ cell tumors, choriocarcinomas, lymphomas, and certain sarcomas are potentially curable even in their metastatic stages. Other tumors such as prostate cancer, breast cancer, and endometrial carcinomas are amenable to hormonal therapy.

Unfortunately, many of the cancers that can present as CUPS are relatively resistant to treatment when they are advanced. Examples of such tumor types include lung cancer and tumors originating in the gastrointestinal tract (particularly the pancreas). Although there has been modest recent improvement in the treatment of these cancers, they remain incurable when advanced. Most patients with CUPS are also incurable, with an average survival of six to eight months. However, there is an extremely wide range of treatment outcomes, and identification of subgroups of patients for specific treatments is very important.

Finding the Primary Site

In trying to discover the primary site, there are two important considerations:

1. Some primary cancers are much more treatable than others. These include cancers of the breast, prostate, thyroid, and ovary; lymphomas (including Hodgkin’s disease); and germ cell tumors similar to those that develop in the testes. Great efforts are made to determine if one of these is the primary site. Not only is the prognosis much better with these types of cancer, but the treatment has to be specific for that cancer.

2. There are important clues your doctor can use to discover the primary site:

• One clue is the location of the metastases. A woman with a tumor that develops in glands (adenocarcinoma) and is found in the lymph nodes of the armpit, for example, is more likely to have carcinoma of the breast. A woman who develops fluid in the abdomen (ascites) or has a tumor involving the lining of the abdominal cavity (peritoneum) should be suspected of having ovarian cancer.

• The most common sites of CUPS are metastases to the lung(s), lymph nodes, bone, and liver. When CUPS is found in the upper part of the body (above the diaphragm), the most common source is the lung. When it appears in the liver, the usual primary site is the gastrointestinal tract, including the pancreas.

• Another clue is the type of pathology. If a person has epidermoid (squamous) carcinoma in lymph glands high in the neck, for example, the primary site is most often in the nasopharynx, the throat, or the tonsils. Special endoscopic procedures and biopsies can be used to look for the primary site, and even if it is not found, such people should be treated using guidelines for head and neck cancer. Epidermoid cancer involving lymph nodes in the lower neck is usually of lung origin. Cervical lymph nodes with metastases of other pathological appearance may represent breast cancer, lymphoma, melanoma, or other tumors (see also “Special Pathologic Methods,” in this post).

Possible primary sources of cancer first diagnosed in a metastatic site

Table 1. Treatable Cancers That May Present as CUPSCHANCE OF SIGNIFICANT REMISSION

Diagnosis

People with CUPS undergo certain standard methods of medical evaluation to discover the primary site (if possible) and other potential areas of spread. Evaluation will include a history as well as a specific work-up for the major potential sites of the cancer’s origin that can be treated—breast cancer, germ cell tumors, lymphomas, and cancers of the head and neck, lung (especially small cell), prostate, thyroid, and ovary. A consensus about the minimal investigation that has to be performed includes the following.

Physical Examination

• When CUPS is found in high cervical (neck) lymph nodes, a thorough examination of the nasopharynx, throat, and upper respiratory tract should be done, usually by an ear, nose, and throat specialist.

• A gynecological examination, including a rectal examination, a Pap smear, and a pelvic ultrasound or CT, should be done for any woman with CUPS, especially if the inguinal (groin) lymph nodes are enlarged or there is fluid in the abdomen (ascites).

Blood and Other Tests

• Complete blood counts.

• Urinalysis to check for blood.

• Test for hidden (occult) blood in the stool.

• Blood chemistry tests to assess liver and kidney function.

• Tests for serum tumor markers that may be elevated with specific cancers, such as prostate-specific antigen (prostate), alpha-fetoprotein (hepatomas, germ cell tumors), HCG (choriocarcinomas, germ cell tumors), and thyroglobulin and calcitonin (thyroid gland). Other commonly used serum tumor markers (e.g., CEA, CA-125, CA 15-3, CA 19-9) are frequently elevated but nonspecific. However, they may be useful in following response to treatment.

Imaging

• Chest X-ray may reveal the most common tumor origin, carcinoma of the lung. It is often impossible, however, to distinguish between a primary lung cancer and a metastatic lesion within the lung. Sometimes chest CT is also helpful.

• Mammograms for all women diagnosed with CUPS. For women with clinical features suggesting breast cancer, a breast MRI scan should also be performed. For example, over half of the women with isolated metastases in the lymph nodes in the armpit will have a primary breast cancer. However, this will not always be seen even with a mammogram and a breast MRI (false negative results).

• Abdominal CT scan sometimes identifies a primary site in the abdomen, particularly in the pancreas, and frequently provides additional information regarding the location of metastases.

• PET scanning is a new technique that is sometimes successful in detecting cancers not evident on the CT scan. When used in conjunction with CT scanning, the PET scan can detect a primary site in 20 to 30 percent of patients.

• It is not helpful to do extensive X-rays—bowel X-rays, for example—to look for a primary site unless there is a specific complaint in that area, such as constipation or gastrointestinal bleeding.

The following imaging studies are occasionally done:

• CT, MRI, and ultrasound studies of the area of known tumor and likely primary sites.

• Nuclear scans of bone, liver, and thyroid.

Endoscopy and Biopsy

• Endoscopic evaluation of the colon, urinary tract, or lung is performed when indicated either by symptoms or by results of the previous studies.

• Biopsy of suspicious lesions identified by X-rays may establish a primary site; breast, prostate, and pancreas may need special studies on biopsy; hormone-receptor, DNA, and other studies may also be performed.

Special Pathologic Methods

The pathologist has a crucial role in the diagnosis, evaluating the biopsy specimen and determining not only if it is malignant, but, on the basis of his or her experience and the tissue’s appearance under the microscope, the most likely source.

The pathologist is often consulted before the biopsy is done because some special immunohistochemistry studies require frozen tissue, or tissue may have to be specially prepared for examination by an electron microscope. These methods offer a significant advantage in obtaining an accurate diagnosis, particularly when tumors appear “poorly differentiated” under the regular microscope. The limited material obtained with a needle biopsy may not be adequate for specialized pathologic studies. In such cases, a larger biopsy, obtained surgically, is recommended.

Immunohistochemistry Along with the usual tissue stains used to examine the tumor tissue under the microscope, special stains using monoclonal antibodies are directed against specific tumor antigens. These can reliably identify several treatable types, particularly lymphoma, thereby allowing therapy to be more specific and improving the chance of remission or even cure.

Electron Microscopy (EM) Regular microscopes magnify tissues up to 1,000 times. The electron microscope can magnify tissues 50,000 to 100,000 times. Very small structures inside and on the surfaces of cells, often characteristic of certain types of cancer cells, can be seen. There are structures characteristic of squamous cell cancers, cancers of neuroendocrine origin, muscle tumors, and most melanomas. Besides suggesting likely sites, EM studies are useful in eliminating certain tumor types.

Polymerase Chain Reaction (PCR) This new method detects minute amounts of genetic material (DNA or RNA). PCR may detect abnormal DNA or RNA structures in the biopsy specimen. A few of these abnormalities are specific for certain cancers and, thus, will suggest the origin of the tumor.

Tissue Stains Many new tissue stains are being developed and are rapidly enlarging the diagnostic capability of the modern pathologist (see Table 2).

Table 2. Special Stains Used for Specific Tissues• The presence of keratin, a protein found in epithelium (surface tissue), indicates the tumor is a carcinoma rather than a sarcoma or lymphoma.• S-100 and HMB-45 are useful in the diagnosis of melanomas.• Chromogranin and synaptophysin are positive in small cell (oat cell) lung cancer and other neuroendocrine tumors.• Leukocyte-common antigen, found on the surface of leukocytes, is positive in leukemia and lymphoma.• Prostate-specific antigen (PSA) is positive in prostate cancer.• Alpha-fetoprotein (AFP) is present in primary liver cancer and certain germ cell tumors.• Estrogen receptors are present in breast cancer and cancer of the lining of the uterus (endometrial cancer). Finding estrogen receptors not only helps in the diagnosis, but suggests that hormonal therapy may be useful.

Staging

The actual tumor origin is the most important thing in planning treatment and assessing the prognosis. By definition, all CUPS are in an advanced stage because the cancer has already metastasized. It has been suggested that doctors caring for patients with CUPS should refrain from extensive investigations, since the cost of the evaluation financially and with respect to time and discomfort is not worth the results and may not affect survival anyway.

The results of exhaustive tests are also sometimes misleading. The tests may sometimes seem to show a positive finding when none is really there (false positive) or may instead fail to show an abnormality that is present, but not detectable (false negative).

Treatment Overview

There is no generally recommended treatment for all patients with CUPS. Whenever there is a likely primary origin, based on the opinion of the pathologist as well as the clinical, laboratory, and imaging studies, the treatment will be given according to that probable diagnosis.

The prognosis for people with CUPS is highly variable because so many different tumors may be involved. However, a number of subgroups recognized by typical clinical or pathologic features are now known to benefit from specific treatments. Some of the patients who do not fit into any of these subgroups can benefit from empiric combination chemotherapy treatment.

Treatment for Specific Presentations

Certain rules have been recommended for a number of specific presentations of CUPS.

“Midline” Tumors

These tumors originate in the middle part of the body such as the mediastinum (chest) or midabdominal lymph nodes. Some people with these tumors who are under fifty years of age, have lung and lymph node metastases, and have a poorly differentiated histology respond well to combination chemotherapy that contains cisplatin and etoposide.

Sixty percent of the patients in one such group had a significant response to therapy and 15 percent were apparently cured. Some of these patients had blood markers (HCG or AFP) suggesting that they had a germ cell tumor.

CUPS in the Neck Lymph Nodes

When epidermoid (squamous) carcinoma is found in the neck (upper cervical) lymph nodes, patients should be treated as if they had a tumor of the upper respiratory area even though a thorough ear, nose, and throat evaluation—including blind biopsies of the base of the tongue and the nasopharynx—may have been negative.

Treatment is potentially curative and may include

• Chemotherapy combined with radical radiotherapy to the cervical lymph nodes and pharyngeal areas or

• a combination of surgery (to remove lymph nodes in the neck) and radiotherapy.

CUPS in the Armpit Lymph Nodes

Women with this site of involvement are frequently curable if no other sites are involved. Over half of such women actually have breast cancer, with an undetectable primary site. Treatment will emphasize

• surgery, including removal of all axillary nodes in the involved site;

• total mastectomy or radiation to the breast;

• hormonal therapy, especially if hormone receptors are present in tumor tissue; and/or

• chemotherapy, sometimes with trastuzumab (Herceptin) added, as recommended for treatment of Stage II breast cancer.

CUPS Involving the Peritoneum

In women, CUPS involving the lining of the abdominal cavity should be treated following the recommendations for ovarian cancer, even if the ovaries are normal or have been removed. Treatment will include

• initial exploratory surgery with removal of all tumor possible, and

• chemotherapy, usually with a taxane (paclitaxel [Taxol] or docetaxel [Taxotere]) and carboplatin [Paraplatin].

CUPS Presenting with a Single Metastasis

Occasionally, only one metastasis is found, even after complete evaluation. A variety of such presentations have been described, including isolated involvement of lymph nodes, lung, brain, adrenal gland, and liver. Involvement of a single lymph node is one of the more common of these presentations. Special care should be made to rule out other types of tumors (lymphoma, melanoma) that frequently involve lymph nodes. When metastatic carcinoma involves a single site, surgical excision is the treatment of choice if possible. Usually other metastases will eventually appear but sometimes after a long delay.

Neuroendocrine CUPS

Neuroendocrine carcinomas are a family of tumors identifiable by the pathologist. The most common neuroendocrine carcinoma in adults is small cell lung cancer. Occasionally, neuroendocrine carcinomas present with unknown primary sites. Most are rapidly growing tumors. It is important to identify these cancers, since they respond well to chemotherapy. About two-thirds of patients have major tumor shrinkage following treatment with paclitaxel (Taxol) and carboplatin (Paraplatin); a few patients have long-term remissions.

Multiple Skeletal Lesions

In males, a prostatic cancer should be suspected. This diagnosis can usually be confirmed by detecting elevated blood levels of PSA or by detecting PSA in the tumor biopsy of special stains. Hormonal therapy is usually of benefit and should be given if prostate cancer is suspected.

In females, breast cancer is a possibility.

In both sexes, a thyroid cancer should be kept in mind, since both tumors may be treated effectively even in the metastatic stage (with hormonal therapy and chemotherapy for breast cancer and with radioiodine for thyroid cancer). Metastatic thyroid cancer that does not resemble normal thyroid tissue (poorly differentiated or undifferentiated), however, seldom responds to treatment with radioactive iodine.

Empiric Chemotherapy

Patients who do not fit into any of the above subgroups should receive a trial of combination therapy unless they are already very ill (confined to bed) as a result of their cancer. Regimens containing new drugs such as paclitaxel (Taxol), docetaxel (Taxotere), and gemcitabine (Gemzar) have produced substantial tumor shrinkage in 40 to 50 percent of patients, with improved survival. New chemotherapy programs and several of the new targeted agents are being evaluated in clinical trials.

The Most Important Questions You Can Ask

• How much investigation is really needed to increase my chance of survival or to improve my quality of life?

• Has the pathologist used any of the special studies described here?

• What is the most probable diagnosis?

• Can I benefit from surgery, radiotherapy, chemotherapy, or hormonal therapy?