- General Information About Carcinoma of Unknown Primary
- Cellular Classification of Carcinoma of Unknown Primary
- Stage Information for Carcinoma of Unknown Primary
- Newly Diagnosed Carcinoma of Unknown Primary
- Recurrent Carcinoma of Unknown Primary
- Changes to This Summary (02 / 23 / 2012)
- About This PDQ Summary
- Get More Information From NCI
Carcinoma of Unknown Primary Treatment (PDQ®): Treatment - Health Professional Information [NCI]
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Carcinoma of Unknown Primary Treatment
General Information About Carcinoma of Unknown Primary
The site of origin of a histologically documented carcinoma is not identified clinically in approximately 3% of patients; this situation is often referred to as carcinoma of unknown primary (CUP) origin or occult primary malignancy.[1,2,3,4,5,6]
The definition of a CUP varies from study to study; however, at a minimum, this determination should include a biopsy of the tumor and a thorough history and complete physical examination that includes head and neck, rectal, pelvic, and breast examinations; chest x-rays; a complete blood cell count; urinalysis; and an examination of the stool for occult blood. The value of other radiographic tests will be discussed in the stage information section. When these results do not reveal signs of a potential primary lesion and the biopsy is not consistent with a primary tumor at the biopsy site, a CUP must be assumed. The majority of CUP are adenocarcinomas or undifferentiated tumors; less commonly, squamous cell carcinoma, melanoma, sarcoma, and neuroendocrine tumors can also present with a primary site of origin that cannot be determined. In approximately 15% to 25% of patients, the primary site cannot be identified even at postmortem examination.
The prognosis for patients with CUP is poor. As a group, the median survival is approximately 3 to 4 months with less than 25% and 10% of patients alive at 1 and 5 years, respectively. CUP is represented by a heterogeneous group of diseases all of which have presented with metastasis as the primary manifestation. Although the majority of diseases are relatively refractory to systemic treatments, certain clinical presentations of CUP carry a much better prognosis. In each instance, distinct clinical and pathologic details require consideration for appropriate, potentially curative, management.[7,8,9,10]
A retrospective review of 657 consecutive patients with CUP (270 additional patients were excluded as a result of identification of a primary malignancy, a noncarcinoma cell type, or no malignancy) reported several variables of significant prognostic importance identified by multivariate analysis. Lymph node involvement and neuroendocrine histology were associated with longer survival; male sex, increasing number of involved organ sites, adenocarcinoma histology, and hepatic involvement were unfavorable prognostic factors. Adrenal involvement has also been noted to be a poor prognostic finding.
Conceptually, CUP represents a tumor that has a greater propensity for early dissemination than the more common presentation in which the primary tumor is apparent with or without metastasis.
The distribution of primary sites that are likely to result in CUP contrasts with the distribution of major primary adenocarcinomas as reported in the Surveillance, Epidemiology, and End Results data. Most large studies have shown that carcinoma of the lung and pancreas are the most common primary carcinomas that initially present as CUP. Other common malignancies such as colorectal, breast, and prostate cancers infrequently present as CUP.[7,8,9,10]
The pattern of spread of CUP at diagnosis can provide clues to the likelihood of the primary site being above or below the diaphragm. Lung metastases are twice as common in primary sites ultimately found to be above the diaphragm. Liver metastases are more common from primary disease below the diaphragm. The pattern of metastasis from a carcinoma presenting as CUP may be significantly different from that which would be expected from the usual presentation. For instance, bone metastases are approximately three times more common in pancreatic cancer presenting as CUP, while osseous metastasis from lung cancer is about 10 times less common when it presents as CUP compared with the usual presentation. The biologic bases for these differences in presentation, incidence, and pattern of metastases are unknown.
Although only a minority of patients will have curable disease or a disease for which there is substantial palliative benefit, the appropriate use of special diagnostic pathology and selected radiologic studies will identify patients for whom directed therapy will provide the best possible chance for response.
Cellular Classification of Carcinoma of Unknown Primary
The pathologist has a central role in the evaluation of carcinoma of unknown primary (CUP). A thorough evaluation of an adequate specimen for histologic, immunohistochemical, and, when appropriate, electron microscopic evaluations is probably the most important clue in the diagnostic puzzle of CUP. Pathologic evaluations provide guidance for an appropriate clinical evaluation. An obvious corollary to the pathologist's role is the critical interaction between the pathologist, oncologist, and primary physician.
The complexity of the pathologic evaluation tends to be inversely related to the degree of differentiation of the tumor. For well- or moderately differentiated tumors, the pathologic diagnosis of an epithelial cancer versus lymphoma, sarcoma, melanoma, or a germ cell tumor, for instance, is often readily apparent. Commonly used histologic stains such as mucicarmine or diastase-sensitive Periodic Acid Schiff can be important in confirming the diagnosis of certain tumors of gastrointestinal or renal origin.
Special studies can help in distinguishing tumors that are poorly differentiated;[2,3] the generic distinction between a poorly differentiated tumor of epithelial, hematopoietic, or neuroectodermal origin (i.e., melanoma) is important. Microsatellite analysis has been used to assess genetic alterations in cervical lymph nodes. These alterations were identical in 18 patients with normal mucosal histology and malignant nodes, suggesting a site of primary tumor origin.
Other diagnostic tests:
- Immunohistochemical analysis: Several studies can be important in making these broad distinctions; in particular, studies that evaluate staining for keratins, leukocyte common antigen, and S-100, a neuroectodermal antigen expressed in melanomas.
- Gene expression profiling: Gene expression profiling using an immunohistochemical panel may allow identification of a potential site of origin in patients with adenocarcinoma of unknown origin. One study reported identification of a potential primary site in 14 of 22 patients. This modality has not been validated against the gold standard and has not been studied prospectively.
- Prostate-specific antigen (PSA) analysis: This histochemical study can accurately differentiate tumors of prostatic origin from other types of cancer. Prostate cancer is most often found by digital rectal examination. Approximately 3% of CUPs are ultimately shown to be prostate cancer. These cancers, as mentioned above, appear to have a different metastatic distribution than the predominant bony distribution that is generally encountered in prostate cancer. When the primary disease may be suspected to have arisen from the prostate, prostate cancer-specific tests should be performed to rule out a diagnosis of primary prostate cancer.
- Human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP) analysis: Immunohistochemical stains are available for both of these proteins. Although neither protein is absolutely specific for germ cell tumors, and AFP is not specific for hepatoma, they are important because germ cell tumors are effectively treated with combination chemotherapy; appropriate therapy may lead to cure. The finding of germ cell tumors by genetic analysis has been associated with a high response rate to cisplatin therapy, thus suggesting that molecular or cytogenetic studies may be useful in identifying undifferentiated tumors that are otherwise unclassifiable.
Polymerase chain reaction (PCR) analysis: In patients with suspected nasopharyngeal carcinoma, DNA amplification of Epstein-Barr virus (EBV) genomes can be used for diagnosis with tissue provided by fine-needle aspiration biopsy. The presence of EBV in metastases from an occult primary tumor suggests the development of overt nasopharyngeal carcinoma. A single study has shown that the i(12p) marker chromosome may be used as a diagnostic tool in patients with suspected midline germ cell tumors.
Another study used a molecular assay to evaluate ten tissue type–specific gene markers, using quantitative reverse transcriptase PCR technology to detect tumors originating from the lung, breast, colon, ovary, pancreas, and prostate. About 60% of patients had the putative site of origin identified, thus allowing for administration of treatment-specific therapy.
Electron microscopic analysis: Electron microscopy (EM) evaluation can sometimes aid in the diagnosis of CUP. In particular, the presence of desmosomes and bundles of tonofilaments are characteristic of squamous cell cancers. The presence of core granules that are diagnostic of neuroendocrine origin is seen in poorly differentiated neuroendocrine tumors of unknown primary site.
Acinar spaces and microacinic spaces are seen with adenocarcinomas. Electron dense secretory granules are seen in tumors of neuroectodermal origin. Premelanosomes can be found in most amelanotic melanomas.
The features mentioned above are generally associated with differentiation along a particular line. Often poorly differentiated tumors do not display such characteristics, making the EM evaluation of little value. It is estimated that EM may aid in distinguishing a primary diagnosis that has not been obtained by light microscopy approximately 10% of the time.[14,15,16] Because of the development of immunohistochemical stains, EM is rarely needed.
Stage Information for Carcinoma of Unknown Primary
Opinions are divergent concerning the value and extent of evaluation that should be performed to determine the primary tumor in patients who present with carcinoma of unknown primary (CUP). Clinical and pathological investigations to detect tumors that are potentially responsive to treatment (e.g., lymphoma, germ cell tumor, breast, or ovarian tumor) may be undertaken.
The chest radiograph has become an almost routine procedure in general medical practice. Although chest radiography is routinely performed, in the setting of CUP no distinguishing feature clearly separates primary from metastatic disease within the chest. The abdominal computed tomographic (CT) scan is the only radiographic test that may frequently be of value in defining the primary site, because of the inordinately high representation of pancreatic cancer in the CUP process. With the exception of ovarian cancer, however, CT scans rarely identify treatable primary cancers.[2,3]
The clinical biology of the disease, the types of tumors most often encountered, and the high level of inaccuracy of unguided radiographic studies raise issues of cost effectiveness for intensive diagnostic work-up. Two studies have indicated that a large negative cost/benefit ratio exists for an extensive unguided clinical evaluation, with a single study citing a 9.5% increase in 1-year survival at a cost of 2 to 8 million dollars. The most reasonable approach is to develop a comprehensive knowledge of the manner in which CUP patients present and to remember that this presentation is associated with tremendous heterogeneity regarding outcome.[4,5,6,7,8,9]
Cervical Lymph Nodes
A histologic diagnosis of metastatic carcinoma in cervical nodes requires a meticulous examination of the upper aerorespiratory tract. Histologically, these tumors are usually squamous cell carcinoma, but occasionally may be adenocarcinoma, melanoma, or anaplastic tumors. Metastatic adenocarcinoma is generally associated with a poor prognosis. Approximately 2% to 5% of patients with primary squamous cell carcinoma of the head and neck region will present with cervical adenopathy as the primary disease manifestation; about 10% of this group will present with bilateral adenopathy. The 3-year survival rate ranges from 35% to 59% when patients with squamous or undifferentiated tumors are treated with radical radiation therapy, surgery, or both.[10,11,12]
Poorly Differentiated Carcinomas
Investigators have defined a subpopulation of potentially curable patients with 1 or more of the following characteristics:
- Age younger than 50 years.
- Midline tumor distribution, multiple pulmonary nodules or lymph nodes, elevated serum levels of beta human chorionic gonadotropins (HCG) or alpha-fetoprotein (AFP).
- Cells positive for beta HCG or AFP by immunohistochemical stain.
- The presence of neuroendocrine granules.
- Clinical evidence for rapid tumor growth.
- Tumors that were very responsive to chemotherapy or radiation therapy.
In retrospective review, many of these patients, including some complete responders to chemotherapy, did not have any recognizable histopathologic features of germ cell tumors.[13,14,15] A single study has shown that the i(12p) marker chromosome may be used as a diagnostic tool in patients with suspected midline germ cell tumors.
Metastatic Melanoma to a Single Nodal Site
Approximately 5% of patients with malignant melanoma will present without a documented primary site. Special stains and electron microscopy may be important in establishing the diagnosis. Patients with this diagnosis should, like those with stage II melanoma, have a radical lymph node dissection. Survival is actually slightly better than that seen in patients with stage II melanoma with a documented primary site.[5,17,18,19] (Refer to the PDQ summary on Melanoma Treatment for more information.)
Isolated Axillary Metastasis
Most patients who present with nodal metastasis above the diaphragm ultimately are documented to have lung cancer, the most common supradiaphragmatic primary malignancy. The presence of isolated axillary metastasis in females, however, raises another possibility. A few studies involving a small number of patients have shown that approximately 50% of patients who present with isolated axillary metastasis of an adenocarcinoma will ultimately be shown to have breast cancer. Although some of these patients will have a positive mammogram after the initial evaluation, approximately 50% of the patients will not. When these patients are treated with local excision, or as having primary breast cancer, 2- to 10-year survival has been obtained in approximately 50% of patients. The availability of estrogen-receptor (ER) and progesterone-receptor (PR) assays may aid in this diagnosis, and these studies should be performed in this setting. If the clinical setting is consistent with breast cancer, and ER and/or PR levels are elevated, CUP with this distribution should be treated as breast cancer.[1,4,20] (Refer to the PDQ summary on Breast Cancer Treatment for more information.)
Inguinal Node Metastasis
Squamous carcinoma detected in the inguinal lymph nodes is almost always metastatic from the genital or anal/rectal area. In females, careful examination of the vulva, vagina, and cervix is indicated, with biopsy of any suspicious areas. The penis of uncircumcised males should be carefully inspected. In both sexes, the anorectal area should be carefully examined, including biopsy of suspicious areas. Isolated metastases present in the central nervous system, the liver, and the genitourinary tract. Information about these presentations may be found in PDQ summaries that specifically detail their management.
In addition to the above situations, significant palliation can be achieved in certain instances in patients with CUP. Breast, prostate, ovarian, and thyroid cancers are all treatable malignancies, even when metastatic, and they represent approximately 15% of all CUP tumors. As with other CUP presentations, the pattern of spread of these malignancies is somewhat atypical. For instance, patients with prostate cancer who present with CUP have an inordinately high incidence of metastases to nonosseous sites such as lung (75%), liver (50%), and brain (25%). Bone metastases are also less common than lung metastases in thyroid cancer presenting as CUP.
Newly Diagnosed Carcinoma of Unknown Primary
The overwhelming majority of patients presenting with carcinoma of unknown primary (CUP) have disseminated disease that is relatively chemoresistant. Potentially curative treatment can be delivered, however, in a few situations.
Cervical Lymph Nodes
All patients should undergo a careful head, neck, and lung evaluation including coronal computed tomography and/or magnetic resonance imaging of the head and neck and directed biopsies of the nasopharynx and tongue base. In those patients with squamous cell or undifferentiated carcinoma, tonsillectomies have been recommended and should be considered if the tonsils have not been previously removed. Fluorodeoxyglucose F 18-positron emission tomography scan may identify an occult primary site in the head and neck area.[2,3] If no primary site can be determined, the following approaches should be considered:
- Radical radiation therapy with curative intent to the cervical lymph nodes and possible sites of origin. Intensity-modulated radiation therapy (IMRT) may have less short- and long-term toxicity than conventional radiation therapy in terms of xerostomia, acute dysphagia, and skin fibrosis.[5,6]
- Preoperative radiation therapy followed by radical neck dissection.
- Radical neck dissection.
- Radical neck dissection followed by postoperative radiation therapy to possible sites of origin.
(Refer to the PDQ summary on Metastatic Squamous Neck Cancer with Occult Primary Cancer Treatment for more information.)
Poorly Differentiated Carcinomas
Patients who have poorly differentiated carcinomas with or without serologic or histologic evidence of beta human chorionic gonadotropins or alpha-fetoprotein should be treated with intensive chemotherapy as used in the treatment of disseminated germ cell tumors.
In a series, more than 220 patients with excellent performance status were treated with aggressive combination chemotherapy. This chemotherapy generally consisted of vinblastine, bleomycin, and cisplatin; however, some patients received a doxorubicin-containing modification of this regimen and some received etoposide instead of vinblastine. The response rate was 63%, with a complete response rate of 26%, and a long-term disease-free survival of 16%. Carboplatin-containing regimens were found to have equal activity. A paclitaxel-based combination yielded a 48% response rate in 71 patients with various histologic types of carcinoma of unknown origin.
Poorly Differentiated Neuroendocrine Carcinomas
In a series of 29 patients with poorly differentiated neuroendocrine carcinomas, 19 were treated with intensive cisplatin-based combination chemotherapy, and six additional patients received doxorubicin combinations. Six patients achieved complete response and four of these patients were alive 19 to 100 months after diagnosis.
Women with peritoneal carcinomatosis of an adenocarcinoma serous histologic type have a favorable response to chemotherapy and improved prognosis. Response and survival rates in these patients approach those seen in ovarian cancer patients, and therapy appropriate for ovarian cancer should be used.[12,13] (Refer to the PDQ summary on Ovarian Epithelial Cancer Treatment for more information.)
Isolated Axillary-Nodal Metastasis
The most common primary site for isolated axillary metastasis is the breast. Mammography should be performed in all patients with isolated axillary-nodal metastasis. After an adequate evaluation of the breast and lung to rule out these primary sites, the following treatment options should be considered:
- Lymph node dissection with or without mastectomy or radiation therapy to the breast with curative intent.
- Lymph node dissection with or without mastectomy or radiation therapy to the breast with curative intent plus adjuvant chemotherapy with an accepted therapeutic adjuvant approach for breast cancer. This option should be considered especially if breast cancer is proven or if other lymph nodes show adenocarcinoma.
Inguinal Node Metastasis
Metastatic carcinoma in inguinal nodes from an unknown primary source occurs in approximately 1% to 3.5% of patients. A diagnostic excisional-node biopsy should be performed when no primary source of carcinoma can be found. The most common pathologic diagnosis in this instance is Hodgkin lymphoma or non-Hodgkin lymphoma, with CUP being less frequent.
- Superficial groin dissection alone.
- Local excisional biopsy with or without radiation, inguinal node dissection, or chemotherapy.
In a small proportion of patients, local excision alone is sufficient therapy. Initial therapy with radiation may be used successfully in some patients, depending on extent of disease and individual patient characteristics. Isolated metastases also present in the central nervous system, liver, and genitourinary tract. More information can be found in the PDQ summaries for these malignancies.
Melanoma (Melanotic or Amelanotic) Occurring in a Single Nodal Site
Approximately 5% of patients present with no detectable primary site.
- Radical lymph node dissection. For patients who present with a single site of nodal metastasis, this treatment will yield a survival that is slightly better than that obtained in conventional stage II melanoma.
When patients present with widespread metastatic disease and special studies reveal a probable primary tumor for which standard systemic therapy is available, such therapy should be administered. This may include hormonal therapy for prostate and breast cancer, I131 for thyroid cancer, or cytotoxic single-agent or combination chemotherapy for hormone-refractory breast and ovarian cancers. Standard approaches for such diseases are available in the specific PDQ summaries for each diagnosis.
The majority of patients will not have a definable primary source. For such patients, a variety of combination chemotherapy approaches have been tried with little success. No treatment can be considered standard at present. Therefore, such patients should be considered for available clinical trials. Information about ongoing clinical trials is available from the NCI Web site.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with newly diagnosed carcinoma of unknown primary. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Recurrent Carcinoma of Unknown Primary
The prognosis for any treated cancer patient with progressing, recurring, or relapsing disease is poor, regardless of cell type or stage. Deciding on further treatment depends on many factors, including the specific cancer, prior treatment, and site of recurrence, as well as individual patient considerations. Treatments that are under clinical evaluation are appropriate and should be considered when possible. Information about ongoing clinical trials is available from the NCI Web site.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent carcinoma of unknown primary. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Changes to This Summary (02 / 23 / 2012)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Cellular Classification of Carcinoma of Unknown Primary
Updated Greco et al. as reference 8.
Newly Diagnosed Carcinoma of Unknown Primary
Added Sher et al. as reference 6.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of carcinoma of unknown primary. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
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- be cited with text, or
- replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewer for Carcinoma of Unknown Primary Treatment is:
- James P. Neifeld, MD (Medical College of Virginia Hospital & Virginia Commonwealth University)
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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National Cancer Institute: PDQ® Carcinoma of Unknown Primary Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/unknownprimary/HealthProfessional. Accessed <MM/DD/YYYY>.
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