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A cancer of unknown primary (CUP) is defined as a biopsy-confirmed malignancy with no established primary site after pathological evaluation and radiographic studies. With the advent of comprehensive genomic profiling and positron emission tomography–computed tomography scanning, less than 1% of new cancer diagnoses are designated as CUP.[
Most CUPs are adenocarcinomas or undifferentiated tumors. Less commonly, squamous cell carcinomas, melanomas, sarcomas, germ cell tumors, and neuroendocrine tumors present with an undetermined primary site of origin.[
Prognosis and Survival
The prognosis for patients with CUP is poor. Approximately 30% of patients are alive at 1 year.[
Survival is worse for patients with any of the following characteristics: [
Lymph node involvement or neuroendocrine histology were associated with longer survival in retrospective reviews.[
Patients who present with a normal LDH and an Eastern Cooperative Oncology Group performance status of 0 or 1 have a much better prognosis than those with a high LDH or worse performance status.[
A review of five case control studies and 14 cohort studies found a clear increased risk of CUP with smoking.[
Patterns of Metastases
Conceptually, CUP is a type of tumor that tends to metastasize early, unlike more common cases, in which the primary tumor is apparent, with or without metastasis. 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 sites below the diaphragm. A cancer presenting as CUP may have a significantly different pattern of metastasis than what is typically expected. For instance, when presenting as CUP, bone metastases are more common from pancreatic cancer and less common from lung cancer, unlike their typical presentation.
Diagnostic Evaluation
The pathologist has a central role in the evaluation of CUP. A thorough evaluation of an adequate specimen for histological, immunohistochemical, molecular diagnostics, next-generation sequencing (NGS), and, when appropriate, electron microscopic evaluations provides the most important clues in the diagnosis of CUP.[
The following tests may be used to diagnose CUP:
Clinical, pathological, and molecular genetic tests have two goals. The first is to identify tumors that are responsive to available therapies. The second is to identify novel targeted therapies that might be applicable to the particular genetic profile.[
Two randomized prospective trials published in 2019 compared standard chemotherapy (carboplatin and paclitaxel or cisplatin and gemcitabine) versus site-specific therapy using gene expression profiling.[
A meta-analysis of five studies including 1,114 patients compared site-specific therapy from genomic profiling versus empiric therapy. There was no improvement in PFS (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.74–1.17; P = .534) or OS (HR, 0.75; 95% CI, 0.55–1.03; P = .069).[
In a retrospective analysis, a cohort of 97 patients with CUP underwent NGS of tissue- or blood-derived cell-free DNA (cfDNA). The median number of pathogenic genomic alterations found in tissue was four (range, 0–25), and the median number of genomic alterations found in cfDNA was two (range, 0–9).[
References:
A positron emission tomography–computed tomography (PET-CT) scan of the whole body can reveal the extent of disease and is especially useful in single-site or oligometastatic presentations, especially for patients with cervical lymph node metastases suspicious for a head and neck primary.[
PET-CT can be combined with somatostatin receptor PET-CT scans for neuroendocrine neoplasms or prostate-specific membrane antigen for suspected prostate cancer. A meta-analysis of 20 studies including 1,942 patients found a biopsy confirmed or clinically confirmed positive PET-CT scan in 40.9% of patients (95% confidence interval [CI], 40.0%–42.9%).[
A meta-analysis of 38 studies including 2,795 patients found that a fluorine F 18-fludeoxyglucose–PET or PET-CT scan led to management changes in 35% of patients (95% CI, 31%–40%).[
After staging with a PET-CT scan and magnetic resonance imaging of the head, the next step is molecular characterization and next-generation sequencing, preferably on the tissue biopsy or alternatively by analyzing circulating tumor cells on a blood sample (so-called liquid biopsy).
References:
Twenty percent of patients with cancer of unknown primary (CUP) have favorable CUP. Favorable CUP is defined by the following characteristics:
Single-Site or Oligometastatic Disease Amenable to Surgery or Radiation Therapy
According to a consensus paper, when a single site of metastasis can be confirmed by positron emission tomography–computed tomography (PET-CT) scan and magnetic resonance imaging (MRI) of the brain, local treatment with surgery or radiation therapy is an option. Local treatment has resulted in anecdotal cure in a few patients and several months to years of anecdotal relapse-free survival in a few patients.[
Cervical Lymph Node(s) With Squamous Cell Histology (Head and Neck Paradigm)
PET-CT, MRI, and pan-endoscopy for biopsies and bilateral tonsillectomies are performed when squamous cell carcinoma is identified in cervical lymph nodes (not supraclavicular) in patients with CUP.[
Transoral robotic surgery may replace pan-endoscopy in the search for a primary site in the head and neck region.[
For more information, see Metastatic Squamous Neck Cancer with Occult Primary Treatment.
Inguinal Lymph Nodes With Squamous Cell Histology (Genitourinary or Anorectal Source)
Squamous cell carcinoma in an inguinal or iliac site is usually associated with a genital or anorectal primary. Examinations should focus on the vulva, vagina, and cervix in women, and the penis in men. In both sexes, the anorectal area should be examined, and any suspicious areas should be biopsied. Anecdotal cures have been reported in a few cases of isolated inguinal or iliac sites with an occult primary after staging studies.[
Axillary Lymph Node(s) With Adenocarcinoma Histology (Breast Paradigm)
Less than 1% of female patients present with histological breast cancer in an axillary lymph node with an occult primary even after MRI of the breast.[
For more information, see Breast Cancer Treatment.
Bone Metastases if Blastic (Breast Paradigm for Women, Prostate Paradigm for Men)
The presence of blastic bone metastases or mixed blastic/lytic lesions will usually suggest breast cancer in women and prostate cancer in men. Diagnostic procedures and therapeutic options should proceed in these directions.
For more information, see Breast Cancer Treatment or Prostate Cancer Treatment.
Elevated AFP and/or Beta-hCG (Germ Cell Paradigm)
The presence of elevated serum or tissue levels of AFP and/or beta-hCG suggests testicular cancer or extragonadal germ cell tumor in males. Men younger than 50 years with mediastinal adenopathy and pulmonary metastases have immunohistochemical evidence of AFP and/or beta-hCG in the extragonadal presentation. Diagnostic procedures and therapeutic options should proceed in these directions.
For more information, see Testicular Cancer Treatment and Extragonadal Germ Cell Tumors Treatment.
Peritoneal Carcinomatosis if Adenocarcinoma (Ovarian Paradigm)
Women with peritoneal carcinomatosis of an undifferentiated adenocarcinoma or serous histology in the absence of an ovarian, fallopian tube, or uterine primary site should undergo diagnostic testing and a therapeutic approach for ovarian cancer.[
For more information, see Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment.
Targeted Therapy Defined by Molecular Markers or by Next-Generation Sequencing (Including PD-L1, HRD, MSI)
Clinical, pathological, and molecular genetic tests have two goals. The first is to identify tumors that are responsive to available therapies. The second is to identify novel targeted therapies that might be applicable to the particular genetic profile. The U.S. Food and Drug Administration has approved some novel targeted therapies when a molecular target is identified in a cancer, regardless of primary site or when no primary site is evident. Examples include tumors with high mutational burden, elevated PD-L1, elevated HER2, NTRK mutations, BRAF mutations, RET mutations, ROS1 fusion, MET amplification, HRD, MSI, and EGFR mutations.[
Neuroendocrine Neoplasms
Neuroendocrine neoplasms are classified as well-differentiated neuroendocrine tumors (NETs) and slow progression neuroendocrine carcinomas (NEC). Well-differentiated NETs exhibit relatively indolent behavior. Slow progression NECs may exhibit highly aggressive behavior, with a rapid metastatic spread that is clinically indistinguishable from pancreatic adenocarcinoma or small cell lung cancer. The Ki-67 proliferative index rate is used to subclassify well-differentiated NETs into low, intermediate, and high-grade, while NECs are by default high-grade and poorly differentiated and divided into small- and large-cell NEC.
NETs of unknown primary origin may derive from the small bowel, pancreas, appendix, colon, rectum, or ovary.[
For more information, see Gastrointestinal Neuroendocrine Tumors Treatment.
Merkel cell carcinoma is a rare, aggressive, cutaneous malignancy of neuroendocrine origin, usually with primary lesions in the head and neck or in the extremities. However, it may present in the lymph nodes only, with no evident primary site.[
For more information, see Merkel Cell Carcinoma Treatment.
Melanoma (Melanotic or Amelanotic) Occurring in a Single Lymph Node Site
Approximately 5% of patients with malignant melanoma will present without a documented primary site. Diagnostic studies and therapeutic options should proceed with the paradigm of malignant melanoma.[
For more information, see Melanoma Treatment.
Current Clinical Trials
Use our
References:
Most patients with newly diagnosed cancer of unknown primary (CUP) are considered to have an unfavorable prognosis.
Treatment Options for Newly Diagnosed Unfavorable CUP
Treatment options for newly diagnosed unfavorable CUP include the following:
Site-directed therapy based on molecular tissue of origin or molecular targeted therapy
Clinical, pathological, and molecular genetic tests have two goals. The first is to identify tumors that are responsive to available therapies. The second is to identify novel targeted therapies that might be applicable to the particular genetic profile. The U.S. Food and Drug Administration (FDA) has approved some novel targeted therapies when a molecular target is identified in a cancer, regardless of primary site or when no primary site is evident. Examples include tumors with high mutational burden, elevated PD-L1, elevated human epidermal growth factor (HER2), NTRK mutations, BRAF mutations, RET mutations, ROS1 fusion, MET amplification, homologous repair deficiency, microsatellite instability, and EGFR mutations.[
Immunological therapy
Immunological therapy using checkpoint inhibitors such as nivolumab has been given to a general population with unfavorable CUP, resulting in a 22% overall response rate.[
Chemotherapy
Patients with unfavorable CUP who are not candidates for molecular targeted therapy or immunotherapy are candidates for clinical trials. Cytotoxic chemotherapy can be a palliative therapy, but the choice of drugs has been based on a few small clinical studies, with no randomized trials establishing their benefit over best supportive care.[
Palliative care and hospice are options for patients with a poor performance status and relapsing disease.
Current Clinical Trials
Use our
References:
The use of follow-up studies including computed tomography or magnetic resonance imaging, is extrapolated from paradigms of other related malignancies with known primary sites. No prospective trials evaluating clinical surveillance have been conducted for patients with cancer of unknown primary.
Current Clinical Trials
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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.
General Information About Cancer of Unknown Primary
Revised text to state that for patients with presumed cancer of unknown primary (CUP), a prior diagnosis of malignancy should be evaluated by pathological comparison, using genomic sequencing in both tissue and circulating tumor DNA, when available.
Added text about a retrospective analysis in which a cohort of 97 patients with CUP underwent next-generation sequencing of tissue- or blood-derived cell-free DNA. Combination matched therapies based on these alterations might improve patient outcomes. The median number of pathogenic genomic alterations found in tissue was determined and a matching score was calculated to compare the progression-free and overall survival of evaluable treated patients (cited Kato et al. as reference 31 and level of evidence C2).
This summary is written and maintained by the
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of cancer of unknown primary. It is intended as a resource to inform and assist clinicians in the care of their 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
Board members review recently published articles each month to determine whether an article should:
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 reviewers for Cancer of Unknown Primary (CUP) Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's
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.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Cancer of Unknown Primary (CUP) Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at:
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Last Revised: 2024-05-06
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