Highlights & Basics
- Adenocarcinoma of unknown primary site is a common clinical entity, comprising 2% to 4% of all incident cancers worldwide.
- Untreated, prognosis is poor, with a median survival between 3 and 4 months.
- A key goal in the diagnostic workup is to identify subsets of patients with a more favorable clinicopathologic subtype and likely better outcome.
- Systemic chemotherapy is the mainstay of treatment for the overwhelming majority of patients.
- Rare subgroups may be candidates for targeted or immune therapies based on results of next-generation sequencing or other biomarkers predictive of response.
- Supportive therapies control pain and other symptoms.
Quick Reference
History & Exam
Key Factors
bone pain
family history of cancer
Other Factors
jaundice
ascites
personal history of previous cancer
history of smoking
pain
palpable mass
symptoms of postobstructive pneumonia
neurologic pain or weakness
headaches
seizures
cervical chain adenopathy
constitutional symptoms
depression
delirium
history of heavy alcohol consumption
hepatomegaly
hemoptysis
Diagnostics Tests
1st Tests to Order
CT chest/abdomen/pelvis
mammography
MRI of breast
transvaginal ultrasound
diagnostic paracentesis
direct laryngoscopy with or without esophagoscopy and bronchoscopy
Other Tests to consider
light microscopy, with hematoxylin and eosin (H&E) staining
positron emission tomography (PET)/CT
immunohistochemical (IHC) markers
estrogen and progesterone receptor status
serum tumor markers
next-generation sequencing (NGS)
Emerging Tests
gene expression profiling (GEP)
Treatment Options
presumptive
identification of primary site pending
identification of primary site pending
investigations complete and good performance status
acute
multiple metastases: favorable clinicopathologic subtype not identified
chemotherapy
Definition
Classifications
Cancer of unknown primary site
- Adenocarcinoma
- Undifferentiated carcinoma
- Squamous cell cancer
- Germ cell tumors
- Neuroendocrine carcinoma.
European Society for Medical Oncology: classification of favorable cancer of unknown primary (CUP)
- Single metastatic deposit or oligometastatic disease amenable to local ablative treatment (single-site or oligometastatic CUP)
- Women with isolated axillary lymph node metastases (breast-like CUP)
- Women with peritoneal carcinomatosis of a serous papillary adenocarcinoma (ovarian-like CUP)
- Squamous cell carcinoma involving nonsupraclavicular cervical lymph nodes (head and neck-like CUP)
- Men with blastic bone metastases and/or immunohistochemistry (IHC) or serum prostate-specific antigen (PSA) expression (prostate-like CUP)
- Adenocarcinoma with colorectal IHC (CK7-negative, CK20-positive, CDX2-positive) or molecular profile (colon-like CUP)
- Carcinoma with renal cell histologic and immunohistochemical profile (renal-like CUP).
Vignette
Common Vignette
Other Presentations
Epidemiology
Etiology
Pathophysiology
Images
CT abdomen with intravenous contrast, revealing numerous enhancing lesions in the right hepatic lobe, with associated ascites. Percutaneous biopsy of one of these hepatic lesions revealed adenocarcinoma, but no primary site was identified during routine workup. This is a typical presentation of AUP
CT abdomen with intravenous contrast, revealing numerous enhancing liver lesions in both hepatic lobes. Percutaneous biopsy of a right lobe lesion revealed adenocarcinoma
Diagnostic Approach
Identifying risk group
Clinical picture
- Pain from peritoneal or pleural irritation, or pathologic fracture with bony involvement
- Localized swelling, if superficial lymph nodes are involved (e.g., cervical chain adenopathy)
- Obstructive jaundice due to pancreaticobiliary lesions
- Symptoms of postobstructive pneumonia (pneumonia occurring distal to a bronchial mass) (e.g., cough, wheeze, dyspnea)
- Hemoptysis with parenchymal lung involvement
- Constitutional symptoms (e.g., weakness, anorexia, malaise, early satiety, and weight loss)
- Shortness of breath
- Neurologic pain or weakness
- Headaches and/or seizures
- Ascites
- Depression
- Delirium.
Pathologic analysis of tumor specimen
- Pan-keratin (AE1/AE3 and CAM5.2): can indicate a carcinoma lineage.
- Cytokeratin-7 (CK7): expression is generally limited to lung, breast, ovary, endometrium, and upper gastrointestinal/pancreaticobiliary cancers, and is not seen in lower gastrointestinal tract tumors.
- Cytokeratin-20 (CK20): generally expressed on gastrointestinal epithelium, urothelium, and Merkel cells.
- CDX2 or SATB2: suggest colorectal or other gastrointestinal primary.
- TTF-1: suggestive of lung or thyroid primary.
- Napsin A: suggests lung primary.
- GATA3: suggests breast/urinary bladder/salivary gland primary.
Targeting search for primary site
- IHC markers, hormone receptor status, serum tumor markers, and dedicated imaging, including mammography, breast magnetic resonance imaging (MRI), and transvaginal ultrasound, should be undertaken.
- Women with isolated axillary adenopathy should undergo extensive workup for occult breast carcinoma, including mammography ± breast MRI/ultrasound, and estrogen/progesterone (ER/PR) hormone receptor status on tumor cells.
Further investigations
- PET/CT is not routinely recommended in evaluation of cancers of unknown primary. However, it may be considered in patients with isolated cervical lymphadenopathy with suspicion of head and neck primary tumor, and in those for whom contrast enhancement is contraindicated.[3] [22][36] [37] Randomized studies are needed to further establish the clinical utility of PET in patients with cancer of unknown primary.
- Mammography is mandatory in any woman with AUP.
- Transvaginal ultrasound is the preferred imaging modality for women presenting with ascites to assess for the presence of an ovarian mass. Color or power Doppler should be included in the examination.[38]
- Gastroesophageal or colorectal endoscopic examination is not uniformly necessary in asymptomatic patients with AUP. However, endoscopy should be considered in patients with IHC tests suggestive of an upper gastrointestinal or colorectal primary, or in selected patients premised upon clinical suspicion.
- Direct laryngoscopy with or without esophagoscopy and bronchoscopy is recommended for patients with cervical lymphadenopathy. The extent of examinations is dependent on the level of cervical nodes involved. Additional IHC testing can help to confirm an occult head and neck primary tumor.
- Prostate-specific antigen (PSA): men over the age of 40 with AUP, and all men with AUP and bone metastases, should have PSA checked to assess for potential prostate carcinoma.
- Serum alpha-fetoprotein (AFP)/beta-human chorionic gonadotropin (beta-hCG): may be indicative of germ cell tumors, and should be checked in patients with mediastinal tumors and in men under the age of 65 presenting with a retroperitoneal mass.
- CA 125: typically elevated in women with histology consistent with ovarian cancer.
- IHC markers for estrogen receptor (ER) and progesterone receptor (PR) should be performed in all women with adenocarcinoma, especially in those with isolated axillary lymphadenopathy.
Emerging investigations: gene expression profiling
Risk Factors
History & Exam
Tests
Differential Diagnosis
Differentiating Signs/Symptoms
- There may be no differences in signs and symptoms.
Differentiating Tests
- Pathologic evaluation reveals nonadenocarcinoma malignant cells.
- Workup and treatment strategies will now focus on the specific pathologic subtype identified.
Criteria
- Single metastatic deposit or oligometastatic disease amenable to local ablative treatment (single-site or oligometastatic CUP)
- Women with isolated axillary lymph node metastases (breast-like CUP)
- Women with peritoneal carcinomatosis of a serous papillary adenocarcinoma (ovarian-like CUP)
- Squamous cell carcinoma involving nonsupraclavicular cervical lymph nodes (head and neck-like CUP)
- Men with blastic bone metastases and/or immunohistochemistry (IHC) or serum prostate-specific antigen (PSA) expression (prostate-like CUP)
- Adenocarcinoma with colorectal IHC (CK7-negative, CK20-positive, CDX2-positive) or molecular profile (colon-like CUP)
- Carcinoma with renal cell histologic and immunohistochemical profile (renal-like CUP).
Screening
Treatment Approach
Chemotherapy: general considerations
Performance status
- 0: Fully active, able to carry on all predisease performance without restriction.
- 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work).
- 2: Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours.
- 3: Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
- 4: Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
- 5: Dead.
- Symptomatic with performance status of 1-2, or
- Asymptomatic with aggressive cancer and performance status 0.
Supportive care
- Bone pain: typically requires treatment with a nonsteroidal anti-inflammatory drug (NSAID), an opioid analgesic, or a corticosteroid, or a suitable combination of these agents. Zoledronic acid (a bisphosphonate) or denosumab can be given for pain due to bone metastases, and to decrease risk of skeletal-related events such as fractures. Palliative radiation therapy can also be considered.
- Neuropathic pain: may respond to anticonvulsant therapy (e.g., gabapentin) or antidepressant therapy (e.g., duloxetine).
- Local pain: can be treated with regional nerve blocks or radiation therapy.
- Obstructive symptoms: are related to tumor mass or localized inflammation, and are common (e.g., bowel, biliary, and bronchial obstruction). Obstructive symptoms should be aggressively managed, using a multidisciplinary approach, with interventional radiology, endoscopic or surgical intervention, radiation therapy, and medications, as appropriate.
Patients with multiple metastases: unfavorable risk groups
Patients with multiple metastases: favorable subtypes
Patients with a single metastatic lesion
- Local ablative treatment of all lesions by surgery and/or radiation therapy is deemed feasible
- Oligometastatic state has been confirmed by imaging including positron emission tomography/computed tomography (PET/CT) and brain MRI
- Number of metastases does not exceed five
- No involvement of a diffuse organ, such as malignant pleural, peritoneal, or leptomeningeal carcinomatosis.
Treatment Options
identification of primary site pending
supportive care
Comments
- Initial treatment strategies are aimed at controlling symptoms attributable to the underlying process, such as pain or local obstruction, and the focus should be on palliation of symptoms. Specific treatment will depend upon the site involved. Expedited diagnostic workup allows initiation of appropriate chemotherapy in a timely fashion.[35]
- Typical symptoms requiring attention include fatigue, depression, anorexia, nausea, and delirium.
- Pain-control strategies can differ based upon the site and character of pain.
- Bone pain: typically requires treatment with a nonsteroidal anti-inflammatory drug (NSAID), an opioid analgesic, or a corticosteroid, or a suitable combination of these agents.
- Neuropathic pain: may respond to anticonvulsant therapy (e.g., gabapentin) or antidepressant therapy (e.g., duloxetine).
- Local pain: can be treated with regional nerve blocks or radiation therapy.
- Obstructive symptoms: are related to tumor mass or localized inflammation, and are common (e.g., bowel, biliary, and bronchial obstruction). Obstructive symptoms should be aggressively managed, using a multidisciplinary approach, with interventional radiology, endoscopic or surgical intervention, radiation therapy, and medications, as appropriate.
investigations complete and good performance status
commence chemotherapy
Comments
- The majority of patients with AUP are older adults, with some functional impairment related to the advanced disease. US guidelines recommend that systemic therapy for patients with disseminated disease should be reserved for the following patients: symptomatic with performance status of 1-2; or asymptomatic with aggressive cancer and performance status 0.[22]
- Supportive care should be initiated, ideally under the guidance of a palliative care physician or team.
multiple metastases: favorable clinicopathologic subtype not identified
chemotherapy
Primary Options
Comments
- For the majority of patients in whom a favorable clinicopathologic subtype is not identified, the recommended initial chemotherapeutic regimen is a combination of agents, either platinum-based (cisplatin or carboplatin) or taxane/platinum-containing (e.g., docetaxel or paclitaxel with cisplatin or carboplatin).[3]
- There is no agreement on appropriate second-line therapy for patients previously treated with platinum-containing regimens; no single agent or combination has proven beneficial (response rate or median survival). Decisions about second-line therapy are based on oncologist preference, or on other patient characteristics that may prevent the use of certain cytotoxic drug classes.
- See local specialist protocol for dosing guidelines.
multiple metastases: women with isolated axillary lymphadenopathy (likely primary: breast cancer)
primary breast cancer management protocol
Comments
- Female patients presenting with isolated axillary adenopathy and documented adenocarcinoma should undergo mammography and magnetic resonance imaging (MRI).
- Retrospective studies indicate that breast MRI can help to identify the primary cancer in approximately two-thirds of patients with negative clinical exam and negative mammography.[54] Immunohistochemical markers for estrogen receptor (ER) and progesterone receptor (PR) should be performed in all women with adenocarcinoma, especially in those with isolated axillary lymphadenopathy. Tumors exhibiting these receptors are sensitive to hormonal therapy.
supportive care
Comments
- Focus should be on palliation of symptoms. Typical symptoms requiring attention include fatigue, depression, anorexia, nausea, and delirium.
- Pain-control strategies can differ based upon the site and character of pain.
- Bone pain: typically requires treatment with a nonsteroidal anti-inflammatory drug (NSAID), an opioid analgesic, or a corticosteroid, or a suitable combination of these agents. Zoledronic acid (a bisphosphonate) or denosumab can be given for pain due to bone metastases and to decrease risk of skeletal-related events such as fractures. Palliative radiation can also be considered.
- Neuropathic pain: may respond to anticonvulsant therapy (e.g., gabapentin) or antidepressant therapy (e.g., duloxetine).
- Local pain: can be treated with regional nerve blocks or radiation therapy.
- Obstructive symptoms: are related to tumor mass or localized inflammation, and are common (e.g., bowel, biliary, and bronchial obstruction). Obstructive symptoms should be aggressively managed, using a multidisciplinary approach, with interventional radiology, endoscopic or surgical intervention, radiation therapy, and medications as appropriate.
multiple metastases: women with papillary adenocarcinoma of the peritoneal cavity (likely primary: ovarian cancer)
ovarian cancer management protocol
Comments
- Histologically analogous to stage III ovarian cancer.
- BRCA1/2 germline mutations may be present and CA 125 is typically elevated, consistent with an ovarian cancer profile. First-line therapy includes optimal surgical debulking and systemic chemotherapy, generally a taxane/platinum doublet.[2] There is some evidence, although not consistent, to support the use of intraperitoneal chemotherapy for advanced-stage ovarian cancer; its potential role in the management of papillary adenocarcinoma of the peritoneal cavity has not yet been evaluated.[55] [56] [57]
supportive care
Comments
- Focus should be on palliation of symptoms. Typical symptoms requiring attention include fatigue, depression, anorexia, nausea, and delirium.
- Pain-control strategies can differ based upon the site and character of pain.
- Bone pain: typically requires treatment with a nonsteroidal anti-inflammatory drug (NSAID), an opioid analgesic, or a corticosteroid, or a suitable combination of these agents. Zoledronic acid (a bisphosphonate) or denosumab can be given for pain due to bone metastases and to decrease risk of skeletal-related events such as fractures. Palliative radiation can also be considered.
- Neuropathic pain: may respond to anticonvulsant therapy (e.g., gabapentin) or antidepressant therapy (e.g., duloxetine).
- Local pain: can be treated with regional nerve blocks or radiation therapy.
- Obstructive symptoms: are related to tumor mass or localized inflammation, and are common (e.g., bowel, biliary, and bronchial obstruction). Obstructive symptoms should be aggressively managed, using a multidisciplinary approach, with interventional radiology, endoscopic or surgical intervention, radiation therapy, and medications as appropriate.
multiple metastases: poorly differentiated carcinoma with neuroendocrine features (likely primary: small cell lung cancer)
small cell lung cancer management protocol
Comments
- A significant minority of poorly differentiated or undifferentiated carcinomas have neuroendocrine features identified by histologic assessment. Favorable neuroendocrine carcinoma subtypes are not considered in European guidelines because an elusive primary cancer is a common finding.[2]
- Combination chemotherapy with paclitaxel, carboplatin, and etoposide was associated with a major response rate of 53% (median survival 14.5 months; 2- and 3-year survival rates of 33% and 24%, respectively) in one phase 2 clinical trial of treatment-naive patients with metastatic poorly differentiated neuroendocrine carcinoma.[58] In a subsequent phase 2 study, irinotecan and cisplatin was not inferior to etoposide and cisplatin in patients with poorly differentiated gastroenteropancreatic neuroendocrine carcinoma.[59] Enrollment to the study was terminated early (n=66 patients) because initial analyses reported similar response rates.[59]
supportive care
Comments
- Focus should be on palliation of symptoms. Typical symptoms requiring attention include fatigue, depression, anorexia, nausea, and delirium.
- Pain-control strategies can differ based upon the site and character of pain.
- Bone pain: typically requires treatment with a nonsteroidal anti-inflammatory drug (NSAID), an opioid analgesic, or a corticosteroid, or a suitable combination of these agents. Zoledronic acid (a bisphosphonate) or denosumab can be given for pain due to bone metastases and to decrease risk of skeletal-related events such as fractures. Palliative radiation can also be considered.
- Neuropathic pain: may respond to anticonvulsant therapy (e.g., gabapentin) or antidepressant therapy (e.g., duloxetine).
- Local pain: can be treated with regional nerve blocks or radiation therapy.
- Obstructive symptoms: are related to tumor mass or localized inflammation, and are common (e.g., bowel, biliary, and bronchial obstruction). Obstructive symptoms should be aggressively managed, using a multidisciplinary approach, with interventional radiology, endoscopic or surgical intervention, radiation therapy, and medications as appropriate.
multiple metastases: well-differentiated neuroendocrine tumors
neuroendocrine tumor management protocols
Comments
- Neuroendocrine tumors include islet cell tumors, carcinoid tumors, and gastrinomas, among others. Favorable neuroendocrine carcinoma subtypes are not considered in European guidelines because an elusive primary cancer is a common finding.[2]
- If feasible, surgical debulking or chemoembolization is preferred as an initial therapy, as control of tumor bulk appears to delay progression of systemic disease. Chemotherapy is variably effective, depending on the underlying tumor type, with pancreatic neuroendocrine tumors exhibiting much better response rates than carcinoid tumors derived from other primary sites. Treatments appropriate for well-differentiated metastatic neuroendocrine tumors should be considered, including somatostatin analogs (e.g., octreotide, lanreotide), everolimus, sunitinib, or peptide receptor radiation therapy.[3]
- Well-differentiated neuroendocrine tumors should be treated as carcinoid tumors.[22] See VIPoma .
supportive care
Comments
- Focus should be on palliation of symptoms. Typical symptoms requiring attention include fatigue, depression, anorexia, nausea, and delirium.
- Pain-control strategies can differ based upon the site and character of pain.
- Bone pain: typically requires treatment with a nonsteroidal anti-inflammatory drug (NSAID), an opioid analgesic, or a corticosteroid, or a suitable combination of these agents. Zoledronic acid (a bisphosphonate) or denosumab can be given for pain due to bone metastases and to decrease risk of skeletal-related events such as fractures. Palliative radiation can also be considered.
- Neuropathic pain: may respond to anticonvulsant therapy (e.g., gabapentin) or antidepressant therapy (e.g., duloxetine).
- Local pain: can be treated with regional nerve blocks or radiation therapy.
- Obstructive symptoms: are related to tumor mass or localized inflammation, and are common (e.g., bowel, biliary, and bronchial obstruction). Obstructive symptoms should be aggressively managed, using a multidisciplinary approach, with interventional radiology, endoscopic or surgical intervention, radiation therapy, and medications as appropriate.
multiple metastases: adenocarcinoma with colorectal immunohistochemistry (likely primary: colorectal cancer)
colorectal cancer management protocol
Comments
- Patients with immunohistochemistry suggestive of colorectal primary site (CDX2-positive, CK20-positive, CK7-negative) may benefit from chemotherapy regimens used for treatment of metastatic colorectal cancer (e.g., fluorouracil/leucovorin with oxaliplatin [FOLFOX or FLOX] or irinotecan [FOLFIRI], with or without bevacizumab).[2] [22] [61] See Colorectal cancer .
supportive care
Comments
- Focus should be on palliation of symptoms. Typical symptoms requiring attention include fatigue, depression, anorexia, nausea, and delirium.
- Pain-control strategies can differ based upon the site and character of pain.
- Bone pain: typically requires treatment with a nonsteroidal anti-inflammatory drug (NSAID), an opioid analgesic, or a corticosteroid, or a suitable combination of these agents. Zoledronic acid (a bisphosphonate) or denosumab can be given for pain due to bone metastases and to decrease risk of skeletal-related events such as fractures. Palliative radiation can also be considered.
- Neuropathic pain: may respond to anticonvulsant therapy (e.g., gabapentin) or antidepressant therapy (e.g., duloxetine).
- Local pain: can be treated with regional nerve blocks or radiation therapy.
- Obstructive symptoms: are related to tumor mass or localized inflammation, and are common (e.g., bowel, biliary, and bronchial obstruction). Obstructive symptoms should be aggressively managed, using a multidisciplinary approach, with interventional radiology, endoscopic or surgical intervention, radiation therapy, and medications as appropriate.
multiple metastases: poorly differentiated carcinoma of the mediastinum or retroperitoneum in males <40 years
testicular cancer management protocol
Comments
- These patients should be assessed for germ cell tumors (using alpha-fetoprotein [AFP] and beta-human chorionic gonadotropin [hCG] serum tumor markers).[3] [22] Male patients should be considered for testicular ultrasound, particularly if tumor markers are elevated, and primarily treated with curative intent with a cisplatin-based regimen (e.g., bleomycin, etoposide, cisplatin [BEP]).[22] See Testicular cancer .
- Historically, many patients with poorly differentiated carcinoma with midline distribution actually had extragonadal germ cell tumors. European guidelines, therefore, suggest that the poorly differentiated carcinoma with midline distribution subtype should no longer be used.[2]
supportive care
Comments
- Focus should be on palliation of symptoms. Typical symptoms requiring attention include fatigue, depression, anorexia, nausea, and delirium.
- Pain-control strategies can differ based upon the site and character of pain.
- Bone pain: typically requires treatment with a nonsteroidal anti-inflammatory drug (NSAID), an opioid analgesic, or a corticosteroid, or a suitable combination of these agents. Zoledronic acid (a bisphosphonate) or denosumab can be given for pain due to bone metastases and to decrease risk of skeletal-related events such as fractures. Palliative radiation can also be considered.
- Neuropathic pain: may respond to anticonvulsant therapy (e.g., gabapentin) or antidepressant therapy (e.g., duloxetine).
- Local pain: can be treated with regional nerve blocks or radiation therapy.
- Obstructive symptoms: are related to tumor mass or localized inflammation, and are common (e.g., bowel, biliary, and bronchial obstruction). Obstructive symptoms should be aggressively managed, using a multidisciplinary approach, with interventional radiology, endoscopic or surgical intervention, radiation therapy, and medications as appropriate.
blastic bone metastases with immunohistochemistry/serum prostate-specific antigen (likely primary: prostate cancer)
prostate cancer management protocol
Comments
- Blastic bone metastases in older men (ages ≥40 years) with elevated prostate-specific antigen (PSA) are most likely to be prostate carcinoma. Treatment with androgen deprivation therapy (with or without radiation therapy), or other treatments appropriate for newly diagnosed prostate cancer, should be administered.[3] See Prostate cancer .
supportive care
Comments
- Focus should be on palliation of symptoms. Typical symptoms requiring attention include fatigue, depression, anorexia, nausea, and delirium.
- Pain-control strategies can differ based upon the site and character of pain.
- Bone pain: typically requires treatment with a nonsteroidal anti-inflammatory drug (NSAID), an opioid analgesic, or a corticosteroid, or a suitable combination of these agents. Zoledronic acid (a bisphosphonate) or denosumab can be given for pain due to bone metastases and to decrease risk of skeletal-related events such as fractures. Palliative radiation can also be considered.
- Neuropathic pain: may respond to anticonvulsant therapy (e.g., gabapentin) or antidepressant therapy (e.g., duloxetine).
- Local pain: can be treated with regional nerve blocks or radiation therapy.
- Obstructive symptoms: are related to tumor mass or localized inflammation, and are common (e.g., bowel, biliary, and bronchial obstruction). Obstructive symptoms should be aggressively managed, using a multidisciplinary approach, with interventional radiology, endoscopic or surgical intervention, radiation therapy, and medications as appropriate.
single metastatic lesion
definitive local therapy
Comments
- Patients presenting with a single metastatic lesion of unknown primary site are rare, and treatment should be individualized. However, the general consensus is to consider definitive local therapy, usually surgical; definitive radiation therapy may be appropriate depending on anatomic location.[2] [22] Adjuvant chemotherapy may be considered to control metastatic foci that are not yet evident.[3]
- Common sites of solitary lesions include the liver, adrenal gland, brain, and bone. Treatment varies depending on suspected primary. Cytokeratin staining and other immunohistochemical markers assist in determining the likely primary site of the tumor and thus the best treatment option. A chemotherapeutic regimen with broad activity across tumor types (encompassing most likely sites of disease, such as occult lung carcinoma, or gastrointestinal tumors) is often preferred.
supportive care
Comments
- Focus should be on palliation of symptoms. Typical symptoms requiring attention include fatigue, depression, anorexia, nausea, and delirium.
- Pain-control strategies can differ based upon the site and character of pain.
- Bone pain: typically requires treatment with a nonsteroidal anti-inflammatory drug (NSAID), an opioid analgesic, or a corticosteroid, or a suitable combination of these agents. Zoledronic acid (a bisphosphonate) or denosumab can be given for pain due to bone metastases and to decrease risk of skeletal-related events such as fractures. Palliative radiation can also be considered.
- Neuropathic pain: may respond to anticonvulsant therapy (e.g., gabapentin) or antidepressant therapy (e.g., duloxetine).
- Local pain: can be treated with regional nerve blocks or radiation therapy.
- Obstructive symptoms: are related to tumor mass or localized inflammation, and are common (e.g., bowel, biliary, and bronchial obstruction). Obstructive symptoms should be aggressively managed, using a multidisciplinary approach, with interventional radiology, endoscopic or surgical intervention, radiation therapy, and medications as appropriate.
oligometastatic disease
ablative surgery and/or radiation therapy
Comments
- European guidelines suggest that selected patients with oligometastatic disease may be managed using local ablative surgery and/or radiation therapy.[2] [62] Candidate patients should satisfy the following criteria: local ablative treatment of all lesions by surgery and/or radiation therapy is deemed feasible; oligometastatic state has been confirmed by imaging including positron emission tomography/computed tomography and brain magnetic resonance imaging; number of metastases does not exceed five; no involvement of a diffuse organ, such as malignant pleural, peritoneal, or leptomeningeal carcinomatosis.[2]
- Median event-free and overall survival of 15.6 months and 52.5 months, respectively, has been reported following local ablative treatment of single-site and oligometastatic carcinoma of unknown primary.[62]
supportive care
Comments
- Focus should be on palliation of symptoms. Typical symptoms requiring attention include fatigue, depression, anorexia, nausea, and delirium.
- Pain-control strategies can differ based upon the site and character of pain.
- Bone pain: typically requires treatment with a nonsteroidal anti-inflammatory drug (NSAID), an opioid analgesic, or a corticosteroid, or a suitable combination of these agents. Zoledronic acid (a bisphosphonate) or denosumab can be given for pain due to bone metastases and to decrease risk of skeletal-related events such as fractures. Palliative radiation can also be considered.
- Neuropathic pain: may respond to anticonvulsant therapy (e.g., gabapentin) or antidepressant therapy (e.g., duloxetine).
- Local pain: can be treated with regional nerve blocks or radiation therapy.
- Obstructive symptoms: are related to tumor mass or localized inflammation, and are common (e.g., bowel, biliary, and bronchial obstruction). Obstructive symptoms should be aggressively managed, using a multidisciplinary approach, with interventional radiology, endoscopic or surgical intervention, radiation therapy, and medications as appropriate.
Emerging Tx
Targeted therapy and immunotherapy for biomarker-specified subgroups
Prevention
Primary Prevention
Secondary Prevention
Follow-Up Overview
Prognosis
Specific prognostic features
- Unfavorable CUP subtype
- Adenocarcinoma histology
- Male sex
- Older age (≥65 years)
- History of smoking (more than 10 pack-years)
- Poor performance status
- Multiple comorbidities
- Metastases involving multiple organs (eg, liver, lung, bone), peritoneal metastases, multiple cerebral metastases
- Nonpapillary malignant ascites (adenocarcinoma)
- Adenocarcinoma with multiple lung/pleural or bone lesions.
- Elevated alkaline phosphatase
- Elevated lactate dehydrogenase (LDH)
- Low serum albumin and lymphopenia
- Elevated neutrophil versus lymphocyte ratio (indicative of an inflammatory state).
Monitoring
Complications
Citations
Krämer A, Bochtler T, Pauli C, et al. Cancer of unknown primary: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023 Mar;34(3):228-46.[Abstract][Full Text]
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: occult primary (cancer of unknown primary).[Full Text]
National Institute for Health and Care Excellence. Metastatic malignant disease of unknown primary origin in adults: diagnosis and management. Apr 2023 [internet publication].[Full Text]
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Key Articles
Other Online Resources
Referenced Articles
Guidelines
Diagnostic
Summary
This guideline provides a comprehensive overview of the diagnostic approach for this cancer.Published by
National Comprehensive Cancer Network
Published
2022
Summary
Recommendations regarding the diagnosis of cancer of unknown primary.Published by
European Society for Medical Oncology
Published
2023
Summary
Includes diagnostic workup.Published by
Spanish Society of Medical Oncology (SEOM)
Published
2021
Treatment
Summary
This guideline provides a comprehensive overview of the management of this cancer.Published by
National Comprehensive Cancer Network (NCCN)
Published
2022
Summary
Recommendations regarding classification and management of favorable and unfavorable cancer of unknown primary.Published by
European Society for Medical Oncology
Published
2023
Summary
Treatment guidance based upon suggested primary cancer profile.Published by
Spanish Society of Medical Oncology (SEOM)
Published
2021