Carcinoma of Unknown Primary Treatment

Prognosis and Survival

The prognosis for patients with CUP is poor. Approximately 30% of patients are alive at 1 year.[1,7] CUP is represented by a heterogeneous group of diseases, all of which have presented with metastasis as the primary manifestation. Although most diseases are relatively refractory to cytotoxic treatments, molecular and genetic diagnostics can identify targeted therapies that may result in a much better prognosis.[1] In each instance, the clinician must consider distinct clinical and pathological details when selecting appropriate, and potentially curative, management.

Survival is worse for patients with any of the following characteristics: [8-10]

• Adenocarcinoma or undifferentiated carcinoma histology.
• Extranodal presentation.
• Older age.
• Hepatic or adrenal involvement.
• Poor performance status.
• Elevated serum lactate dehydrogenase (LDH).

Lymph node involvement or neuroendocrine histology were associated with longer survival in retrospective reviews.[8-10]

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.[10]

A review of five case control studies and 14 cohort studies found a clear increased risk of CUP with smoking.[11]

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.[12-16] Pathological evaluations provide guidance for an appropriate clinical evaluation.

The following tests may be used to diagnose CUP:

• Gene expression profiling: Gene expression profiling and NGS may identify a potential site of origin in patients with CUP.[5,12-14,17]
• Beta-human chorionic gonadotropin (beta-hCG) and alpha-fetoprotein (AFP) analysis: Beta-hCG and AFP are not absolutely specific for germ cell tumors, and AFP is not specific for hepatoma. However, abnormal levels of these proteins are an important finding in young men with a mediastinal or retroperitoneal mass. Prognosis is improved for patients with germ cell tumors treated with site-specific therapy.[18]
• Other tumor marker tests include prostate-specific antigen (prostate cancer) in men; CA-125 (ovarian or gynecologic cancers), CA 15-3 (breast cancer), and CA 27.29 (breast cancer) in women; and carcinoembryonic antigen (CEA), CA 19-9, CA 72-4 (adenocarcinoma), and chromogranin A (neuroendocrine cancer). Elevation of less specific tumor-specific markers such as CEA, CA 19-9, and CA 72-4 can be used to monitor progression or tumor response.
• Magnetic resonance imaging is used for head and neck presentations, brain metastases, suspected pelvic neoplasms, suspected breast cancer (with isolated axillary lymph nodes or isolated bone metastases), prostate lesions, and adrenal lesions.
• For patients with presumed CUP, a prior diagnosis of malignancy should be evaluated by pathological comparison, using genomic sequencing in both tissue and circulating tumor DNA, when available.[19]

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.[5] 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 (including when no primary site is evident with metastases). Examples include tumors with a high mutational burden or elevated PD-1 or PD-L1, HER2 expression, NTRK expression, BRAF V600E expression, RET expression, EGFR mutations, ROS1 fusion, MET amplification, hormone receptor positivity, or homologous repair deficiency/microsatellite instability.[20-27]

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.[28,29] There was no advantage to site-specific therapy in median progression-free survival (PFS) (5 months) or median overall survival (OS) (10–12 months) in either trial. However, most novel targeted therapies, including checkpoint inhibitors, were not available at that time.[28,29][Level of evidence B1]

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).[30][Level of evidence B1] Isolated benefit was seen in patients with more responsive tumors with an identified specifically targeted therapy.

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).[31] Combination matched therapies based on these alterations might improve patient outcomes.[31] A matching score (MS) (roughly equivalent to the number of alterations targeted/total number of deleterious alterations) was calculated post hoc to quantify the degree of the tumor-to-drug match. Outcomes were compared for evaluable patients determined to be MS high (>50%; n = 15) or MS low (≤50%; n = 47). The median PFS was 10.4 months for MS-high patients and 2.8 months for MS-low patients (HR, 0.27; 95% CI, 0.11–0.64; P = .002). The OS was 15.8 months for MS-high patients and 6.9 months for MS-low patients (HR, 0.45; 95% CI, 0.17–1.16; P = .09).[31][Level of evidence C2]

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.[1][Level of evidence C3] Anecdotal reports also support localized therapy for patients with fewer than five metastases, or even re-treatment with radiation therapy or surgery for patients with localized recurrence.[2][Level of evidence C3] A patient staged with CUP and a single brain metastasis may also do well with radiation therapy with or without surgery, as was reported in a prospective study of 33 patients.[3,4][Level of evidence C3]

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.[5]

Transoral robotic surgery may replace pan-endoscopy in the search for a primary site in the head and neck region.[6] Pathological studies should include testing for p16 expression to assess human papillomavirus status, Epstein-Barr virus status, and PD-L1 expression.[7]

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.[8]

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.[9] Initial pathological studies should include estrogen-receptor, progesterone-receptor, and human epidermal growth factor (HER2) status, with further molecular and genetic studies done subsequently. Surgery, radiation therapy, neoadjuvant or adjuvant chemotherapy, and/or hormonal therapy are given according to guidelines for conventional breast cancer.[10-13]

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.[14] This is considered a primary peritoneal serous carcinoma.

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.[15-22]

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.[23,24] Somatostatin receptor PET-CT scans are highly effective at identifying primary sites and metastatic sites for well-differentiated NETs, while fluorine F 18-fludeoxyglucose–PET is more appropriate for NEC.[25-27]

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.[28]

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.[29]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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/molecular targeted therapy.
• Immunological therapy.
• Chemotherapy.

Palliative care and hospice are options for patients with a poor performance status and relapsing disease.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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 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:

• be discussed at a meeting,
• 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 reviewers for Cancer of Unknown Primary (CUP) Treatment are:

• Jacob Adashek, DO (Johns Hopkins University)
• Eric J. Seifter, MD (Johns Hopkins University)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. 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.

Permission to Use This Summary

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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: https://www.cancer.gov/types/unknown-primary/hp/unknown-primary-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389252]

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