Archives: Cancer Types

Cancer of Unknown Primary (CUP) Treatment (PDQ®)–Health Professional Version

Cancer of Unknown Primary (CUP) Treatment (PDQ®)–Health Professional Version

General Information About Cancer of Unknown Primary

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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.[1–5]

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.[6] In some patients, the primary site cannot be identified even at postmortem examination.

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 LDH levels within the reference range and an Eastern Cooperative Oncology Group performance status of 0 or 1 have better prognoses than those with high LDH levels or worse performance statuses.[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 using histology, immunohistochemistry, molecular diagnostics, next-generation sequencing (NGS), and, when appropriate, electron microscopy 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 the following actionable targets:[20–27]

  • High tumor mutational burden.
  • Elevated PD-1 or PD-L1 expression.
  • HER2 expression.
  • Pathogenic variants in NTRK, RET, or EGFR.
  • BRAF V600E pathogenic variant.
  • ROS1 gene fusion.
  • MET amplification.
  • Homologous recombination repair deficiency/microsatellite instability.

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]

References
  1. Binder C, Matthes KL, Korol D, et al.: Cancer of unknown primary-Epidemiological trends and relevance of comprehensive genomic profiling. Cancer Med 7 (9): 4814-4824, 2018. [PUBMED Abstract]
  2. Kwee TC, Kwee RM: Combined FDG-PET/CT for the detection of unknown primary tumors: systematic review and meta-analysis. Eur Radiol 19 (3): 731-44, 2009. [PUBMED Abstract]
  3. Burglin SA, Hess S, Høilund-Carlsen PF, et al.: 18F-FDG PET/CT for detection of the primary tumor in adults with extracervical metastases from cancer of unknown primary: A systematic review and meta-analysis. Medicine (Baltimore) 96 (16): e6713, 2017. [PUBMED Abstract]
  4. Woo S, Becker AS, Do RKG, et al.: Impact of 18F-Fluorodeoxyglucose positron emission tomography on management of cancer of unknown primary: systematic review and meta-analysis. Eur J Cancer 159: 60-77, 2021. [PUBMED Abstract]
  5. Conway AM, Mitchell C, Kilgour E, et al.: Molecular characterisation and liquid biomarkers in Carcinoma of Unknown Primary (CUP): taking the ‘U’ out of ‘CUP’. Br J Cancer 120 (2): 141-153, 2019. [PUBMED Abstract]
  6. Krämer A, Bochtler T, Pauli C, et al.: Cancer of unknown primary: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 34 (3): 228-246, 2023. [PUBMED Abstract]
  7. Varadhachary GR, Raber MN: Cancer of unknown primary site. N Engl J Med 371 (8): 757-65, 2014. [PUBMED Abstract]
  8. Hess KR, Abbruzzese MC, Lenzi R, et al.: Classification and regression tree analysis of 1000 consecutive patients with unknown primary carcinoma. Clin Cancer Res 5 (11): 3403-10, 1999. [PUBMED Abstract]
  9. Hemminki K, Bevier M, Hemminki A, et al.: Survival in cancer of unknown primary site: population-based analysis by site and histology. Ann Oncol 23 (7): 1854-63, 2012. [PUBMED Abstract]
  10. Culine S, Kramar A, Saghatchian M, et al.: Development and validation of a prognostic model to predict the length of survival in patients with carcinomas of an unknown primary site. J Clin Oncol 20 (24): 4679-83, 2002. [PUBMED Abstract]
  11. Hermans KEPE, Kazemzadeh F, Loef C, et al.: Risk factors for cancer of unknown primary: a literature review. BMC Cancer 23 (1): 314, 2023. [PUBMED Abstract]
  12. Horlings HM, van Laar RK, Kerst JM, et al.: Gene expression profiling to identify the histogenetic origin of metastatic adenocarcinomas of unknown primary. J Clin Oncol 26 (27): 4435-41, 2008. [PUBMED Abstract]
  13. Handorf CR, Kulkarni A, Grenert JP, et al.: A multicenter study directly comparing the diagnostic accuracy of gene expression profiling and immunohistochemistry for primary site identification in metastatic tumors. Am J Surg Pathol 37 (7): 1067-75, 2013. [PUBMED Abstract]
  14. Ross JS, Wang K, Gay L, et al.: Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Site: New Routes to Targeted Therapies. JAMA Oncol 1 (1): 40-9, 2015. [PUBMED Abstract]
  15. Selves J, Long-Mira E, Mathieu MC, et al.: Immunohistochemistry for Diagnosis of Metastatic Carcinomas of Unknown Primary Site. Cancers (Basel) 10 (4): , 2018. [PUBMED Abstract]
  16. Pauli C, Bochtler T, Mileshkin L, et al.: A Challenging Task: Identifying Patients with Cancer of Unknown Primary (CUP) According to ESMO Guidelines: The CUPISCO Trial Experience. Oncologist 26 (5): e769-e779, 2021. [PUBMED Abstract]
  17. Ross JS, Sokol ES, Moch H, et al.: Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Origin: Retrospective Molecular Classification Considering the CUPISCO Study Design. Oncologist 26 (3): e394-e402, 2021. [PUBMED Abstract]
  18. Motzer RJ, Rodriguez E, Reuter VE, et al.: Molecular and cytogenetic studies in the diagnosis of patients with poorly differentiated carcinomas of unknown primary site. J Clin Oncol 13 (1): 274-82, 1995. [PUBMED Abstract]
  19. Bochtler T, Endris V, Leichsenring J, et al.: Comparative genetic profiling aids diagnosis and clinical decision making in challenging cases of CUP syndrome. Int J Cancer 145 (11): 2963-2973, 2019. [PUBMED Abstract]
  20. Adashek JJ, Menta AK, Reddy NK, et al.: Tissue-Agnostic Activity of BRAF plus MEK Inhibitor in BRAF V600-Mutant Tumors. Mol Cancer Ther 21 (6): 871-878, 2022. [PUBMED Abstract]
  21. Subbiah V, Wolf J, Konda B, et al.: Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. Lancet Oncol 23 (10): 1261-1273, 2022. [PUBMED Abstract]
  22. Subbiah V, Cassier PA, Siena S, et al.: Pan-cancer efficacy of pralsetinib in patients with RET fusion-positive solid tumors from the phase 1/2 ARROW trial. Nat Med 28 (8): 1640-1645, 2022. [PUBMED Abstract]
  23. Le DT, Uram JN, Wang H, et al.: PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 372 (26): 2509-20, 2015. [PUBMED Abstract]
  24. Overman MJ, McDermott R, Leach JL, et al.: Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 18 (9): 1182-1191, 2017. [PUBMED Abstract]
  25. Luchini C, Bibeau F, Ligtenberg MJL, et al.: ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann Oncol 30 (8): 1232-1243, 2019. [PUBMED Abstract]
  26. Marcus L, Lemery SJ, Keegan P, et al.: FDA Approval Summary: Pembrolizumab for the Treatment of Microsatellite Instability-High Solid Tumors. Clin Cancer Res 25 (13): 3753-3758, 2019. [PUBMED Abstract]
  27. Tanizaki J, Yonemori K, Akiyoshi K, et al.: Open-label phase II study of the efficacy of nivolumab for cancer of unknown primary. Ann Oncol 33 (2): 216-226, 2022. [PUBMED Abstract]
  28. Fizazi K, Maillard A, Penel N: A phase III trial of empiric chemotherapy with cisplatin and gemcitabine or systemic treatment tailored by molecular gene expression analysis in patients with carcinomas of an unknown primary (CUP) site (GEFCAPI 04). [Abstract] Ann Oncol 30 (Suppl 5): A-LBA15_PR, v851, 2019.
  29. Hayashi H, Kurata T, Takiguchi Y, et al.: Randomized Phase II Trial Comparing Site-Specific Treatment Based on Gene Expression Profiling With Carboplatin and Paclitaxel for Patients With Cancer of Unknown Primary Site. J Clin Oncol 37 (7): 570-579, 2019. [PUBMED Abstract]
  30. Ding Y, Jiang J, Xu J, et al.: Site-specific therapy in cancers of unknown primary site: a systematic review and meta-analysis. ESMO Open 7 (2): 100407, 2022. [PUBMED Abstract]
  31. Kato S, Gumas S, Adashek JJ, et al.: Multi-omic analysis in carcinoma of unknown primary (CUP): therapeutic impact of knowing the unknown. Mol Oncol 18 (4): 956-968, 2024. [PUBMED Abstract]

Stage Information for Cancer of Unknown Primary

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.[1–4]

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%).[5]

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%).[6] In this meta-analysis, PET-CT identified a primary site in 22% of patients (95% CI, 18%–28%) and other metastases in 14% of patients (95% CI, 10%–19%).[6]

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
  1. Lievens Y, Guckenberger M, Gomez D, et al.: Defining oligometastatic disease from a radiation oncology perspective: An ESTRO-ASTRO consensus document. Radiother Oncol 148: 157-166, 2020. [PUBMED Abstract]
  2. Albertson M, Chandra S, Sayed Z, et al.: PET/CT Evaluation of Head and Neck Cancer of Unknown Primary. Semin Ultrasound CT MR 40 (5): 414-423, 2019. [PUBMED Abstract]
  3. de Braud F, al-Sarraf M: Diagnosis and management of squamous cell carcinoma of unknown primary tumor site of the neck. Semin Oncol 20 (3): 273-8, 1993. [PUBMED Abstract]
  4. Smith KA, Dort JC, Hall SF, et al.: Cost-effectiveness of positron emission tomography-CT in the evaluation of cancer of unknown primary of the head and neck. Head Neck 37 (12): 1781-7, 2015. [PUBMED Abstract]
  5. Burglin SA, Hess S, Høilund-Carlsen PF, et al.: 18F-FDG PET/CT for detection of the primary tumor in adults with extracervical metastases from cancer of unknown primary: A systematic review and meta-analysis. Medicine (Baltimore) 96 (16): e6713, 2017. [PUBMED Abstract]
  6. Woo S, Becker AS, Do RKG, et al.: Impact of 18F-Fluorodeoxyglucose positron emission tomography on management of cancer of unknown primary: systematic review and meta-analysis. Eur J Cancer 159: 60-77, 2021. [PUBMED Abstract]

Treatment of Newly Diagnosed Favorable Cancer of Unknown Primary

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.[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 the following actionable targets:[15–22]

  • High tumor mutational burden.
  • Elevated PD-1 or PD-L1 expression.
  • HER2 expression.
  • Pathogenic variants in NTRK, RET, or EGFR.
  • BRAF V600E pathogenic variant.
  • ROS1 gene fusion.
  • MET amplification.
  • HRD/MSI.

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]

For more information, see Melanoma Treatment.

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.

References
  1. Lievens Y, Guckenberger M, Gomez D, et al.: Defining oligometastatic disease from a radiation oncology perspective: An ESTRO-ASTRO consensus document. Radiother Oncol 148: 157-166, 2020. [PUBMED Abstract]
  2. Pouyiourou M, Wohlfromm T, Kraft B, et al.: Local ablative treatment with surgery and/or radiotherapy in single-site and oligometastatic carcinoma of unknown primary. Eur J Cancer 157: 179-189, 2021. [PUBMED Abstract]
  3. Bartelt S, Lutterbach J: Brain metastases in patients with cancer of unknown primary. J Neurooncol 64 (3): 249-53, 2003. [PUBMED Abstract]
  4. Rudà R, Borgognone M, Benech F, et al.: Brain metastases from unknown primary tumour: a prospective study. J Neurol 248 (5): 394-8, 2001. [PUBMED Abstract]
  5. de Braud F, al-Sarraf M: Diagnosis and management of squamous cell carcinoma of unknown primary tumor site of the neck. Semin Oncol 20 (3): 273-8, 1993. [PUBMED Abstract]
  6. Al-Lami A, Gao C, Saddiq M, et al.: Reducing the unknowns: A systematic review & meta-analysis of the effectiveness of trans-oral surgical techniques in identifying head and neck primary cancer in carcinoma unknown primary. Oral Oncol 126: 105748, 2022. [PUBMED Abstract]
  7. Machiels JP, René Leemans C, Golusinski W, et al.: Squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 31 (11): 1462-1475, 2020. [PUBMED Abstract]
  8. Matsuyama S, Nakafusa Y, Tanaka M, et al.: Iliac lymph node metastasis of an unknown primary tumor: report of a case. Surg Today 36 (7): 655-8, 2006. [PUBMED Abstract]
  9. de Bresser J, de Vos B, van der Ent F, et al.: Breast MRI in clinically and mammographically occult breast cancer presenting with an axillary metastasis: a systematic review. Eur J Surg Oncol 36 (2): 114-9, 2010. [PUBMED Abstract]
  10. Kim H, Park W, Kim SS, et al.: Prognosis of patients with axillary lymph node metastases from occult breast cancer: analysis of multicenter data. Radiat Oncol J 39 (2): 107-112, 2021. [PUBMED Abstract]
  11. McCartan DP, Zabor EC, Morrow M, et al.: Oncologic Outcomes After Treatment for MRI Occult Breast Cancer (pT0N+). Ann Surg Oncol 24 (11): 3141-3147, 2017. [PUBMED Abstract]
  12. Van den Bruele AB, Chen I, Sevilimedu V, et al.: Management of ipsilateral breast tumor recurrence following breast conservation surgery: a comparative study of re-conservation vs mastectomy. Breast Cancer Res Treat 187 (1): 105-112, 2021. [PUBMED Abstract]
  13. Thompson JL, Sinco BR, McCaffrey RL, et al.: Prophylactic mastectomy and occult malignancy: Surgical and imaging considerations. J Surg Oncol 127 (1): 18-27, 2023. [PUBMED Abstract]
  14. Pentheroudakis G, Pavlidis N: Serous papillary peritoneal carcinoma: unknown primary tumour, ovarian cancer counterpart or a distinct entity? A systematic review. Crit Rev Oncol Hematol 75 (1): 27-42, 2010. [PUBMED Abstract]
  15. Adashek JJ, Menta AK, Reddy NK, et al.: Tissue-Agnostic Activity of BRAF plus MEK Inhibitor in BRAF V600-Mutant Tumors. Mol Cancer Ther 21 (6): 871-878, 2022. [PUBMED Abstract]
  16. Subbiah V, Wolf J, Konda B, et al.: Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. Lancet Oncol 23 (10): 1261-1273, 2022. [PUBMED Abstract]
  17. Subbiah V, Cassier PA, Siena S, et al.: Pan-cancer efficacy of pralsetinib in patients with RET fusion-positive solid tumors from the phase 1/2 ARROW trial. Nat Med 28 (8): 1640-1645, 2022. [PUBMED Abstract]
  18. Le DT, Uram JN, Wang H, et al.: PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 372 (26): 2509-20, 2015. [PUBMED Abstract]
  19. Overman MJ, McDermott R, Leach JL, et al.: Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 18 (9): 1182-1191, 2017. [PUBMED Abstract]
  20. Luchini C, Bibeau F, Ligtenberg MJL, et al.: ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann Oncol 30 (8): 1232-1243, 2019. [PUBMED Abstract]
  21. Marcus L, Lemery SJ, Keegan P, et al.: FDA Approval Summary: Pembrolizumab for the Treatment of Microsatellite Instability-High Solid Tumors. Clin Cancer Res 25 (13): 3753-3758, 2019. [PUBMED Abstract]
  22. Tanizaki J, Yonemori K, Akiyoshi K, et al.: Open-label phase II study of the efficacy of nivolumab for cancer of unknown primary. Ann Oncol 33 (2): 216-226, 2022. [PUBMED Abstract]
  23. Kotteas EA, Pavlidis N: Neuroendocrine Merkel cell nodal carcinoma of unknown primary site: management and outcomes of a rare entity. Crit Rev Oncol Hematol 94 (1): 116-21, 2015. [PUBMED Abstract]
  24. Begum N, Wellner U, Thorns C, et al.: CUP Syndrome in Neuroendocrine Neoplasia: Analysis of Risk Factors and Impact of Surgical Intervention. World J Surg 39 (6): 1443-51, 2015. [PUBMED Abstract]
  25. Ma H, Kan Y, Yang JG: Clinical value of 68Ga-DOTA-SSTR PET/CT in the diagnosis and detection of neuroendocrine tumors of unknown primary origin: a systematic review and meta-analysis. Acta Radiol 62 (9): 1217-1228, 2021. [PUBMED Abstract]
  26. Menda Y, O’Dorisio TM, Howe JR, et al.: Localization of Unknown Primary Site with 68Ga-DOTATOC PET/CT in Patients with Metastatic Neuroendocrine Tumor. J Nucl Med 58 (7): 1054-1057, 2017. [PUBMED Abstract]
  27. De Dosso S, Treglia G, Pascale M, et al.: Detection rate of unknown primary tumour by using somatostatin receptor PET/CT in patients with metastatic neuroendocrine tumours: a meta-analysis. Endocrine 64 (3): 456-468, 2019. [PUBMED Abstract]
  28. Broida SE, Chen XT, Baum CL, et al.: Merkel cell carcinoma of unknown primary: Clinical presentation and outcomes. J Surg Oncol 126 (6): 1080-1086, 2022. [PUBMED Abstract]
  29. De Andrade JP, Wong P, O’Leary MP, et al.: Multidisciplinary Care for Melanoma of Unknown Primary: Experience in the Era of Molecular Profiling. Ann Surg Oncol 27 (13): 5240-5247, 2020. [PUBMED Abstract]

Treatment of Newly Diagnosed Unfavorable Cancer of Unknown Primary

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 the following actionable targets:[1–8]

  • High tumor mutational burden (TMB-H).
  • Elevated PD-1 or PD-L1 expression.
  • HER2 expression.
  • Pathogenic variants in NTRK, RET, or EGFR.
  • BRAF V600E pathogenic variant.
  • ROS1 gene fusion.
  • MET amplification.
  • Homologous recombination repair deficiency/microsatellite instability (MSI).

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.[8] Better response rates can be seen when checkpoint inhibitors are given to patients with tumors expressing high levels of MSI (MSI-H) or deficient mismatch repair (dMMR).[7] Patients with TMB-H disease, defined as at least 7.75 mutations [8] or 10 mutations [9] per megabase, also have higher response rates to immunotherapy.[6] The FDA has approved pembrolizumab in a tumor-agnostic situation (which includes CUP) for tumors with MSI-H, dMMR, or TMB-H.[7] High PD-L1 expression also correlates with higher response rates in patients who receive immunotherapy.[8] Further trials for patients with CUP are required to assess when to give checkpoint inhibitors and to define optimal cutoffs (1% to 50%) and scoring systems (cancer cell tumor proportion score vs. cancer-plus-surrounding cell combined positive score) to guide treatment.[10]

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.[10] Several randomized prospective studies demonstrate that platinum-based doublet chemotherapy combined with a taxane or gemcitabine is equivalent to other chemotherapy in response rate and progression-free survival.[11–14][Level of evidence B1] Although most patients in these trials had adenocarcinoma or poorly differentiated carcinoma, patients with poorly differentiated squamous cell carcinoma were included.

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.

References
  1. Adashek JJ, Menta AK, Reddy NK, et al.: Tissue-Agnostic Activity of BRAF plus MEK Inhibitor in BRAF V600-Mutant Tumors. Mol Cancer Ther 21 (6): 871-878, 2022. [PUBMED Abstract]
  2. Subbiah V, Wolf J, Konda B, et al.: Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. Lancet Oncol 23 (10): 1261-1273, 2022. [PUBMED Abstract]
  3. Subbiah V, Cassier PA, Siena S, et al.: Pan-cancer efficacy of pralsetinib in patients with RET fusion-positive solid tumors from the phase 1/2 ARROW trial. Nat Med 28 (8): 1640-1645, 2022. [PUBMED Abstract]
  4. Le DT, Uram JN, Wang H, et al.: PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 372 (26): 2509-20, 2015. [PUBMED Abstract]
  5. Overman MJ, McDermott R, Leach JL, et al.: Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 18 (9): 1182-1191, 2017. [PUBMED Abstract]
  6. Luchini C, Bibeau F, Ligtenberg MJL, et al.: ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann Oncol 30 (8): 1232-1243, 2019. [PUBMED Abstract]
  7. Marcus L, Lemery SJ, Keegan P, et al.: FDA Approval Summary: Pembrolizumab for the Treatment of Microsatellite Instability-High Solid Tumors. Clin Cancer Res 25 (13): 3753-3758, 2019. [PUBMED Abstract]
  8. Tanizaki J, Yonemori K, Akiyoshi K, et al.: Open-label phase II study of the efficacy of nivolumab for cancer of unknown primary. Ann Oncol 33 (2): 216-226, 2022. [PUBMED Abstract]
  9. Hellmann MD, Ciuleanu TE, Pluzanski A, et al.: Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N Engl J Med 378 (22): 2093-2104, 2018. [PUBMED Abstract]
  10. Krämer A, Bochtler T, Pauli C, et al.: Cancer of unknown primary: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 34 (3): 228-246, 2023. [PUBMED Abstract]
  11. Huebner G, Link H, Kohne CH, et al.: Paclitaxel and carboplatin vs gemcitabine and vinorelbine in patients with adeno- or undifferentiated carcinoma of unknown primary: a randomised prospective phase II trial. Br J Cancer 100 (1): 44-9, 2009. [PUBMED Abstract]
  12. Gross-Goupil M, Fourcade A, Blot E, et al.: Cisplatin alone or combined with gemcitabine in carcinomas of unknown primary: results of the randomised GEFCAPI 02 trial. Eur J Cancer 48 (5): 721-7, 2012. [PUBMED Abstract]
  13. Lee J, Hahn S, Kim DW, et al.: Evaluation of survival benefits by platinums and taxanes for an unfavourable subset of carcinoma of unknown primary: a systematic review and meta-analysis. Br J Cancer 108 (1): 39-48, 2013. [PUBMED Abstract]
  14. Hainsworth JD, Spigel DR, Clark BL, et al.: Paclitaxel/carboplatin/etoposide versus gemcitabine/irinotecan in the first-line treatment of patients with carcinoma of unknown primary site: a randomized, phase III Sarah Cannon Oncology Research Consortium Trial. Cancer J 16 (1): 70-5, 2010. [PUBMED Abstract]

Follow-Up Treatment of Cancer of Unknown Primary in Remission

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

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.

Latest Updates to This Summary (05/07/2025)

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.

Editorial changes were made to this summary.

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® Cancer Information for Health Professionals 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 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 (Consultant)
  • 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

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

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

Carcinoma of Unknown Primary—Health Professional Version

Carcinoma of Unknown Primary—Health Professional Version

Treatment

PDQ Treatment Information for Health Professionals

More information

Causes & Prevention

NCI does not have PDQ evidence-based information about prevention of carcinoma of unknown primary.

More information

Screening

NCI does not have PDQ evidence-based information about screening for carcinoma of unknown primary.

More information

Supportive & Palliative Care

We offer evidence-based supportive and palliative care information for health professionals on the assessment and management of cancer-related symptoms and conditions.

Cancer Pain Nausea and Vomiting Nutrition in Cancer Care Transition to End-of-Life Care Last Days of Life View all Supportive and Palliative Care Summaries

Carcinoma of Unknown Primary—Patient Version

Carcinoma of Unknown Primary—Patient Version

Overview

Cancer of unknown primary (CUP) occurs when cancer cells have spread in the body and formed metastatic tumors but the site of the primary cancer is not known. Explore the links on this page to learn more about CUP, how it is treated, and clinical trials that are available.

Treatment

PDQ Treatment Information for Patients

More information

Causes & Prevention

NCI does not have PDQ evidence-based information about prevention of carcinoma of unknown primary.

More information

Screening

NCI does not have PDQ evidence-based information about screening for carcinoma of unknown primary.

More information

Coping with Cancer

The information in this section is meant to help you cope with the many issues and concerns that occur when you have cancer.

Emotions and Cancer Adjusting to Cancer Support for Caregivers Survivorship Advanced Cancer Managing Cancer Care

Metastatic Cancer: When Cancer Spreads

What Is Metastatic Cancer?

Bethany ross from the back with a "survivor neuroendocrine cancer" shirt
The Challenges of Living with Metastatic Cancer

Survivors describe “scanxiety,” financial concerns, and other issues.

Cancer that spreads from where it started to a distant part of the body is called metastatic cancer. For many types of cancer, it is also called stage 4 cancer. The process by which cancer cells spread to other parts of the body is called metastasis.

When observed under a microscope and tested in other ways, metastatic cancer cells have features like that of the primary cancer and not like the cells in the place where the metastatic cancer is found. This is how doctors can tell that it is cancer that has spread from another part of the body.

Metastatic cancer has the same name as the primary cancer. For example, breast cancer that spreads to the lung is called metastatic breast cancer, not lung cancer. It is treated as stage 4 breast cancer, not as lung cancer.

Sometimes when people are diagnosed with metastatic cancer, doctors cannot tell where it started. This type of cancer is called cancer of unknown primary origin, or CUP. See Carcinoma of Unknown Primary for more information.

How Cancer Spreads

Metastasis: How Cancer Spreads

During metastasis, cancer cells spread from the place in the body where they first formed to other parts of the body.

Play the audio-described version of this video.

Cancer cells spread through the body in a series of steps. These steps include:

  1. growing into, or invading, nearby normal tissue
  2. moving through the walls of nearby lymph nodes or blood vessels
  3. traveling through the lymphatic system and bloodstream to other parts of the body
  4. stopping in small blood vessels at a distant location, invading the blood vessel walls, and moving into the surrounding tissue
  5. growing in this tissue until a tiny tumor forms
  6. causing new blood vessels to grow, which creates a blood supply that allows the metastatic tumor to continue growing

Most of the time, spreading cancer cells die at some point in this process. But, as long as conditions are favorable for the cancer cells at every step, some of them are able to form new tumors in other parts of the body. Metastatic cancer cells can also remain inactive at a distant site for many years before they begin to grow again, if at all.

Where Cancer Spreads

Cancer can spread to almost any part of the body, although different types of cancer are more likely to spread to certain areas than others. The most common sites where cancer spreads are bone, liver, and lung. The following list shows the most common sites of metastasis, not including the lymph nodes, for some common cancers:

Drawing that shows metastasis, when a primary cancer spreads from its first location to other parts of the body.

In metastasis, cancer cells break away from where they first formed and form new tumors in other parts of the body. 

Credit: © Terese Winslow

Enlarge Image

Common Sites Where Cancer Spreads
Cancer Type Main Sites of Metastasis
Bladder Bone, liver, lung
Breast Bone, brain, liver, lung
Colon Liver, lung, peritoneum
Kidney Adrenal gland, bone, brain, liver, lung
Lung Adrenal gland, bone, brain, liver, other lung
Melanoma Bone, brain, liver, lung, skin, muscle
Ovary Liver, lung, peritoneum
Pancreas Liver, lung, peritoneum
Prostate Adrenal gland, bone, liver, lung
Rectal Liver, lung, peritoneum
Stomach Liver, lung, peritoneum
Thyroid Bone, liver, lung
Uterus Bone, liver, lung, peritoneum, vagina

Symptoms of Metastatic Cancer

Metastatic cancer does not always cause symptoms. When symptoms do occur, what they are like and how often you have them will depend on the size and location of the metastatic tumors. Some common signs of metastatic cancer include:

  • pain and fractures, when cancer has spread to the bone
  • headache, seizures, or dizziness, when cancer has spread to the brain
  • shortness of breath, when cancer has spread to the lung
  • jaundice or swelling in the belly, when cancer has spread to the liver

Treatment for Metastatic Cancer

There are treatments for most types of metastatic cancer. Often, the goal of treating metastatic cancer is to control it by stopping or slowing its growth. Some people can live for years with metastatic cancer that is well controlled. Other treatments may improve the quality of life by relieving symptoms. This type of care is called palliative care. It can be given at any point during treatment for cancer.

The treatment that you may have depends on your type of primary cancer, where it has spread, treatments you’ve had in the past, and your general health. To learn about treatment options, including clinical trials, find your type of cancer in the treatment information for adult and childhood cancers.

When Metastatic Cancer Can No Longer Be Controlled

If you have been told your cancer can no longer be controlled, you and your loved ones may want to discuss end-of-life care. Whether or not you choose to continue treatment to shrink the cancer or control its growth, you can always receive palliative care to control the symptoms of cancer and the side effects of treatment. See Advanced Cancer for information on coping with and planning for end-of-life care.

Ongoing Research about Metastatic Cancer

Researchers are studying new ways to kill or stop the growth of primary and metastatic cancer cells. These ways include:

  • helping your immune system fight cancer
  • disrupting the steps in the process that allow the cancer cells to spread
  • targeting specific genetic changes in tumors

Visit the Metastatic Cancer Research page on this site to stay informed of ongoing research funded by NCI.

Bladder Cancer Stages

Bladder Cancer Stages

Cancer stage describes the extent of cancer in the body, such as the size of the tumor, whether it has spread, and how far it has spread from where it first formed. It’s important to know the stage of bladder cancer to plan treatment.

There are several different staging systems for cancer. Bladder cancer is usually staged using the TNM staging system. Your cancer may be described by this staging system in your pathology report. Based on the TNM results, a stage is assigned to your cancer, such as stage I, stage II, stage III, or stage IV (may also be written as stage 1, stage 2, stage 3, or stage 4). When talking with you about your cancer, your doctor may describe it as one of these stages.

Learn more about Cancer Staging.

Learn about the tests and procedures doctors use to stage bladder cancer.

Stage 0 (noninvasive papillary carcinoma and carcinoma in situ)

EnlargeStage 0 bladder cancer (noninvasive bladder cancer); drawing shows the bladder, lumen (the space where urine collects), ureter, prostate, and urethra. The first inset shows stage 0a (also called noninvasive papillary carcinoma) on the inner lining of the bladder. The second inset shows stage 0is (also called carcinoma in situ) on the inner lining of the bladder. Also shown are the connective tissue and muscle layers of the bladder and the layer of fat around the bladder.
Stage 0 bladder cancer (noninvasive bladder cancer). Cancer cells are found in tissue lining the inside of the bladder but have not invaded into the bladder wall. Stage 0a (also called noninvasive papillary carcinoma) may look like long, thin growths extending into the bladder lumen (the space where urine collects). Stage 0is (also called carcinoma in situ) is a flat tumor on the tissue lining the inside of the bladder.

Stage 0 refers to noninvasive bladder cancer. This means that cancer cells are found in tissue lining the inside of the bladder but have not invaded the bladder wall. Stage 0 is divided into stages 0a and 0is, depending on the type of tumor:

  • Stage 0a is also called noninvasive papillary carcinoma, which may look like long, thin growths extending into the bladder lumen (the space where urine collects). Stage 0a can be low grade or high grade, depending on how abnormal the cells look under the microscope (see the section on Bladder cancer grade).
  • Stage 0is is also called carcinoma in situ, which is a flat tumor on the tissue lining the inside of the bladder. Stage 0is is always high grade (see the section on Bladder cancer grade).

Learn about treatment for stage 0 bladder cancer.

Stage I bladder cancer

Stage I is a form of non-muscle-invasive bladder cancer that has spread into the connective tissue but has not reached the muscle layers of the bladder.

EnlargeStage I bladder cancer (non-muscle-invasive bladder cancer); drawing shows the bladder, ureter, prostate, and urethra. An inset shows cancer in the inner lining of the bladder and in the layer of connective tissue next to it. Also shown are the muscle layers of the bladder and the layer of fat around the bladder.
Stage I bladder cancer (non-muscle-invasive bladder cancer). Cancer has spread into the connective tissue but has not reached the muscle layers of the bladder.

Learn about treatment for stage I bladder cancer.

Stage II bladder cancer

Stage II may also be described as muscle-invasive bladder cancer. In stage II, cancer has spread through the connective tissue into the muscle layers of the bladder.

EnlargeStage II bladder cancer (muscle-invasive bladder cancer); drawing shows the bladder, ureter, prostate, and urethra. An inset shows cancer in the inner lining of the bladder and in the layer of connective tissue and the muscle layers of the bladder. Also shown is the layer of fat around the bladder.
Stage II bladder cancer (muscle-invasive bladder cancer). Cancer has spread through the connective tissue into the muscle layers of the bladder.

Learn about treatment for stage II bladder cancer.

Stage III bladder cancer

Stage III may also be described as locally advanced bladder cancer. Stage III is divided into stages IIIA and IIIB.

  • In stage IIIA
    • cancer has grown all the way through the bladder muscles and bladder wall into the layer of fat surrounding the bladder and may have spread to the reproductive organs (prostate, seminal vesicles, uterus, or vagina) but has not spread to lymph nodes; or
    • cancer has spread to one lymph node in the pelvis that is not near the major arteries in the pelvis, called the common iliac arteries.
      EnlargeTwo-panel drawing showing stage IIIA bladder cancer in a male (left panel) and a female (right panel); both panels show cancer in the bladder and in (a) the layer of fat around the bladder and (b) one lymph node in the pelvis. Also shown are the right and left common iliac arteries, the prostate (left panel), and the uterus (right panel).
      Stage IIIA bladder cancer. Cancer (a) has grown all the way through the bladder muscles and bladder wall into the layer of fat around the bladder and may have spread to the prostate and/or seminal vesicles in men or the uterus and/or vagina in women but has not spread to lymph nodes; or (b) has spread to one lymph node in the pelvis that is not near the common iliac arteries.
  • In stage IIIB, cancer has spread to more than one lymph node in the pelvis that is not near the common iliac arteries or to at least one lymph node that is near the common iliac arteries.
    EnlargeTwo-panel drawing showing stage IIIB bladder cancer in a male (left panel) and a female (right panel); both panels show cancer in the bladder and in (a) more than one lymph node in the pelvis that is not near the common iliac artery and (b) one lymph node near the common iliac artery. Also shown are the right and left common iliac arteries, the prostate (left panel), and the uterus (the right panel).
    Stage IIIB bladder cancer. Cancer has spread to (a) more than one lymph node in the pelvis that is not near the common iliac arteries; or (b) at least one lymph node that is near the common iliac arteries.

Learn about treatment for stage III bladder cancer.

Stage IV bladder cancer

Stage IV is divided into stages IVA and IVB.

  • In stage IVA
    • cancer has spread to the abdominal wall or pelvic wall; or
    • cancer has spread to lymph nodes that are above the major arteries in the pelvis, called the common iliac arteries.
  • In stage IVB, cancer has spread to other parts of the body, such as the lung, bone, or liver.
    EnlargeStage IVA and IVB bladder cancer; drawing shows cancer that has spread from the bladder to (a) the abdominal or pelvic wall and (b) lymph nodes above the common iliac arteries. Also shown is cancer that has spread to (c) other parts of the body, including the lung, liver, and bone.
    Stage IVA and IVB bladder cancer. In stage IVA, cancer has spread to (a) the abdominal or pelvic wall; or (b) lymph nodes above the common iliac arteries. In stage IVB, cancer has spread to (c) other parts of the body, such as the lung, liver, or bone.

Stage IV bladder cancer is also called metastatic bladder cancer. Metastatic cancer happens when cancer cells travel through the lymphatic system or blood and form tumors in other parts of the body. The metastatic tumor is the same type of cancer as the primary tumor. For example, if bladder cancer spreads to the lung, the cancer cells in the lung are actually bladder cancer cells. The disease is called metastatic bladder cancer, not lung cancer. Learn more in Metastatic Cancer: When Cancer Spreads.

Learn about treatment for stage IV bladder cancer.

Bladder cancer grade

Cancer grade describes how abnormal the bladder cancer cells look under a microscope and how quickly the cancer cells are likely to grow and spread. Your doctor uses grade and other factors about your cancer, such as its stage, to form a treatment plan and in some cases, to estimate your prognosis.

  • Low-grade bladder cancer cells look more like normal cells and tend to grow and spread more slowly than high-grade cancer cells.
  • High-grade bladder cancer tends to grow and spread more quickly than low-grade bladder cancer. High-grade cancers usually have a worse prognosis than low-grade cancers and may need treatment right away or treatment that is more aggressive.

To learn more, see Tumor Grade.

Recurrent bladder cancer

Recurrent bladder cancer is cancer that has recurred (come back) after it has been treated. Bladder cancer tends to recur after treatment, even when it is noninvasive at the time of diagnosis. Low-grade bladder cancer mainly recurs in the bladder lining. High-grade bladder cancer is more likely to have spread to the muscle layers or other parts of the body when it recurs. Tests will be done to help determine where the cancer has returned in your body, if it has spread, and how far. The type of treatment that you have for recurrent bladder cancer will depend on where it has come back.

Learn more in Recurrent Cancer: When Cancer Comes Back.

Learn about treatment for recurrent bladder cancer.

What Is Bladder Cancer?

What Is Bladder Cancer?

Bladder cancer occurs when cells in the bladder start to grow without control. The bladder is a hollow, balloon-shaped organ in the lower part of the abdomen that stores urine.

The bladder has a muscular wall that allows it to get larger to store urine made by the kidneys and to shrink to squeeze urine out of the body. There are two kidneys, one on each side of the backbone, above the waist. The bladder and kidneys work together to remove toxins and wastes from your body through urine:

  • Tiny tubules in the kidneys filter and clean the blood.
  • These tubules take out waste products and make urine.
  • The urine passes from each kidney through a long tube called a ureter into the bladder.
  • The bladder holds the urine until it passes through a tube called the urethra and leaves the body.
EnlargeAnatomy of the male urinary system (left panel) and female urinary system (right panel); two-panel drawing showing the right and left kidneys, the ureters, the bladder filled with urine, and the urethra. The inside of the left kidney shows the renal pelvis. An inset shows the renal tubules and urine. Also shown are the prostate and penis (left panel) and the uterus (right panel).
Anatomy of the male urinary system (left panel) and female urinary system (right panel) showing the kidneys, ureters, bladder, and urethra. The inside of the left kidney shows the renal pelvis. An inset shows the renal tubules and urine. Also shown are the prostate and penis (left panel) and the uterus (right panel). Urine is made in the renal tubules and collects in the renal pelvis of each kidney. The urine flows from the kidneys through the ureters to the bladder. The urine is stored in the bladder until it leaves the body through the urethra.

Types of bladder cancer

Urothelial carcinoma (also called transitional cell carcinoma) is cancer that begins in the urothelial cells, which line the urethra, bladder, ureters, renal pelvis, and some other organs. Almost all bladder cancers are urothelial carcinomas.

Urothelial cells are also called transitional cells because they change shape. These cells are able to stretch when the bladder is full of urine and shrink when it is emptied.

Other types of bladder cancer are rare:

  • Squamous cell carcinoma is cancer that begins in squamous cells (thin, flat cells lining the inside of the bladder). This type of cancer may form after long-term irritation or infection with a tropical parasite called schistosomiasis, which is common in Africa and the Middle East but rare in the United States. When chronic irritation occurs, transitional cells that line the bladder can gradually change to squamous cells.
  • Adenocarcinoma is cancer that begins in glandular cells that are found in the lining of the bladder. Glandular cells in the bladder make mucus and other substances.
  • Small cell carcinoma of the bladder is cancer that begins in neuroendocrine cells (nerve-like cells that release hormones into the blood in response to a signal from the nervous system).

There are other ways to describe bladder cancer:

  • Non-muscle-invasive bladder cancer is cancer that has not reached the muscle wall of the bladder. Most bladder cancers are non-muscle-invasive.
  • Muscle-invasive bladder cancer is cancer that has spread through the lining of the bladder and into the muscle wall of the bladder or beyond it.

Learn more about bladder cancer

Symptoms

Many bladder cancer symptoms are also seen with other less serious conditions. These are the warning signs you shouldn’t ignore.

Causes and Risk Factors

Using tobacco, especially smoking cigarettes, is a major risk factor for bladder cancer. Learn about tobacco use and other risk factors for bladder cancer and what you can do to lower your risk.

Screening

Learn about bladder cancer screening tests for people at high risk.

Diagnosis

Learn about the tests that are used to diagnose and stage bladder cancer.

Prognosis and Survival Rates

Learn about bladder cancer survival rates and why this statistic doesn’t predict exactly what will happen to you.

Stages

Stage refers to the extent of your cancer, such as how large the tumor is and if it has spread. Learn about bladder cancer stages, an important factor in deciding your treatment plan.

Treatment

Learn about the different ways bladder cancer can be treated.

Coping and Support

Coping with bladder cancer and the side effects of treatment can feel overwhelming. Learn about resources to help you cope and gain a sense of control.

Childhood Bladder Cancer

Childhood bladder cancer is a very rare type of cancer that forms in the tissues of the bladder. Learn about the symptoms of bladder cancer in children, and how it is diagnosed and treated.

Bladder Cancer Diagnosis

Bladder Cancer Diagnosis

If you have symptoms or lab test results that suggest bladder cancer, your doctor will need to find out if they’re due to cancer or another condition. Your doctor may

  • ask about your personal and family medical history to learn more about your symptoms and possible risk factors for bladder cancer
  • ask for a sample of your urine so it can be checked in the lab for blood, abnormal cells, or infection
  • do a physical exam, which for women, may include a pelvic exam, to check for signs of cancer

Depending on your symptoms, medical history, and results of your urine lab tests and physical exam, your doctor may recommend more tests to find out if you have bladder cancer, and if so, its extent (stage).

Tests to diagnose bladder cancer

The following tests and procedures are used to diagnose bladder cancer. The results will also help you and your doctor plan treatment.

Cystoscopy

Cystoscopy is a procedure in which the doctor looks inside the bladder and urethra (the tube that carries urine out of your body) to check for abnormal areas. A cystoscope is slowly inserted through the urethra into the bladder to allow the doctor to see inside. A cystoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove very small bladder tumors or tissue samples for biopsy. Cystoscopy helps to diagnose, and sometimes treat, bladder cancer and other conditions.

EnlargeCystoscopy; drawing shows a side view of the lower pelvis containing the bladder, uterus, vagina, rectum, and anus. A cystoscope (a thin, tube-like instrument with a light and a lens for viewing) is shown passing through the urethra and into the bladder. Fluid is used to fill the bladder. An inset shows a woman lying on an examination table with her knees bent and legs apart. She is covered by a drape. The doctor is looking at an image of the inner wall of the bladder on a computer monitor to check for abnormal areas.
Cystoscopy. A cystoscope (a thin, tube-like instrument with a light and a lens for viewing) is inserted through the urethra into the bladder. Fluid is used to fill the bladder. The doctor looks at an image of the inner wall of the bladder on a computer monitor to check for abnormal areas.

Biopsy

A biopsy is usually done during a cystoscopy procedure. Biopsy is a procedure in which a sample of cells or tissue is removed from the bladder so that a pathologist can view it under a microscope to check for signs of cancer. It may be possible to remove the entire tumor at the time of the biopsy.

Talk with your doctor to learn what to expect during and after your cystoscopy and biopsy. Some people have blood in the urine or discomfort and a burning sensation while urinating for a day or two.

To learn about the type of information that can be found in a pathologist’s report about the cells or tissue removed during a biopsy, see Pathology Reports.

Computed tomography (CT) urogram or intravenous pyelogram (IVP)

CT urogram is a test that takes a CT scan of the urinary tract using a contrast dye injected into a vein. To begin the procedure, a CT machine takes a series of detailed pictures of the kidneys. The contrast dye is then injected, and another CT scan of the kidneys, bladder, and ureters is done. About 10 minutes later, a final scan is taken as the contrast dye drains from the kidneys into the bladder. CT urogram also captures detailed pictures of nearby bones, soft tissues, and blood vessels. This allows the doctor to see how well your urinary tract is working and to check for signs of disease.

IVP is an x-ray imaging test of your urinary tract. After a contrast dye is injected into a vein, a series of x-ray pictures of the kidneys, ureters, and bladder are taken to find out if cancer is present in these organs. As the contrast dye moves through the kidneys, ureters, and bladder, more x-ray pictures are taken at specific times. This allows your doctor to see how well your urinary tract is working and to check for signs of disease.

Urine tumor marker test

Urinary tumor markers are substances found in the urine that are either made by bladder cancer cells or that the body makes in response to bladder cancer. For this test, a sample of urine is checked in the lab to detect the presence of these substances. Urine tumor marker tests may be used to help diagnose some types of bladder cancer.

Tests to stage bladder cancer

If you’re diagnosed with bladder cancer, you will be referred to a urologic oncologist. This is a doctor who specializes in diagnosing and treating cancers of the male and female urinary tract and the male reproductive organs. They will recommend tests to determine the extent of cancer. Sometimes the cancer is only in the bladder. Or, it may have spread from the bladder to other parts of the body. The process of learning the extent of cancer in the body is called staging. It is important to know the stage of the bladder cancer to plan treatment.

For information about a specific stage of bladder cancer, see Bladder Cancer Stages.

The following imaging tests may be used to determine the bladder cancer stage.

Computed tomography (CT) scan

A CT scan uses a computer linked to an x-ray machine to make a series of detailed x-ray pictures of areas inside the body from different angles. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly.

Magnetic resonance imaging (MRI)

MRI uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body, such as the bladder. This procedure is also called nuclear magnetic resonance imaging. Images may be taken at three different times after the dye is injected, to get the best picture of abnormal areas in the bladder. This is called triple-phase MRI.

Chest x-ray

A chest x-ray is an x-ray of the organs and bones inside the chest. An x-ray is a type of high-energy radiation that can go through the body and onto film, making a picture of areas inside the chest.

Bone scan

A bone scan is a procedure that checks to see if there are rapidly dividing cells, such as cancer cells, in the bone. A very small amount of radioactive material is injected into a vein and travels through the bloodstream. The radioactive material collects in the bones with cancer and is detected by a scanner.

Getting a second opinion

Some people may want to get a second opinion to confirm their bladder cancer diagnosis and treatment plan. If you choose to seek a second opinion, you will need to get important medical test results and reports from the first doctor to share with the second doctor. The second doctor will review the pathology report, slides, and scans before giving a recommendation. The doctor who gives the second opinion may agree with your first doctor, suggest changes or another approach, or provide more information about your cancer.

To learn more about choosing a doctor and getting a second opinion, see Finding Cancer Care. You can contact NCI’s Cancer Information Service via chat, email, or phone (both in English and Spanish) for help finding a doctor, hospital, or getting a second opinion. For questions you might want to ask at your appointments, see Questions to Ask Your Doctor.

Bladder Cancer Symptoms

Bladder Cancer Symptoms

The symptoms of bladder cancer can vary from person to person. The most common symptom is blood in the urine, called hematuria. It’s often slightly rusty to bright red in color. You may see blood in your urine at one point, then not see it again for a while. Sometimes there are very small amounts of blood in the urine that can only be found by having a test done.

Other common symptoms of bladder cancer include

  • frequent urination
  • pain or burning during urination
  • feeling as if you need to urinate even if your bladder isn’t full
  • urinating often during the night

When the cancer has grown large or spread beyond the bladder to other parts of the body, symptoms may include

  • being unable to urinate
  • lower back pain on one side of the body
  • pain in the abdomen
  • bone pain or tenderness
  • unintended weight loss and loss of appetite
  • swelling in the feet
  • feeling tired

It’s important to check with your doctor if you have any of these symptoms. Keep in mind that urinary tract infections, kidney or bladder stones, or other problems related to the kidney could be the cause, not cancer. Your doctor will ask you when your symptoms started and how often you’re having them. They will most likely ask you to give a urine sample as a first step in diagnosing what is causing your symptoms. To learn more, see Bladder Cancer Diagnosis.