Adenocarcinoma of unknown primary site

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Last reviewed: 6 Aug 2025

Last updated: 30 Jul 2025

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.

Definition

Adenocarcinoma of unknown primary site (ACUP) is the major subgroup in the common clinical entity of cancer of unknown primary site (CUP). It is defined as metastatic adenocarcinoma for which the primary site is undetectable at presentation, despite thorough physical exam, and laboratory and radiographic investigation.[1]

History and exam

Key diagnostic factors

pain (e.g., abdomen, chest, bone)
family history of cancer
constitutional symptoms

Full details

Other diagnostic factors

jaundice
symptoms of postobstructive pneumonia
hemoptysis
ascites
cervical chain adenopathy
personal history of previous cancer
history of smoking
palpable mass
neuropathic pain or weakness
headaches
seizures
delirium
history of heavy alcohol consumption
hepatomegaly

Full details

Risk factors

age >60 years

Full details

Diagnostic tests

1st tests to order

complete blood count
comprehensive metabolic panel
CT chest/abdomen/pelvis
MRI
biopsy (pathologic assessment)
immunohistochemistry (IHC) tests

Full details

Tests to consider

fecal occult blood test
lactate dehydrogenase
urinalysis
18F-fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT
breast imaging (mammography, MRI, ultrasound)
transvaginal ultrasound
paracentesis
endoscopy
direct laryngoscopy with or without esophagoscopy and bronchoscopy
serum tumor markers
genetic biomarker testing

Full details

Emerging tests

tissue of origin testing

Treatment algorithm

INITIAL

identification of primary site pending

ACUTE

unfavorable subtype: multiple metastases and/or without a likely primary site

favorable subtype: women with isolated axillary lymphadenopathy (likely breast primary)

favorable subtype: women with peritoneal carcinomatosis of a serous papillary adenocarcinoma (likely ovarian primary)

favorable subtype: poorly differentiated carcinoma with neuroendocrine features (likely small cell lung cancer primary)

favorable subtype: well-differentiated neuroendocrine tumors (likely neuroendocrine primary)

favorable subtype: adenocarcinoma with colorectal immunohistochemistry (likely colorectal primary)

favorable subtype: poorly differentiated carcinoma of the mediastinum or retroperitoneum in males <40 years (likely testicular primary)

favorable subtype: blastic bone metastases with immunohistochemistry/serum prostate-specific antigen (likely prostate primary)

favorable subtype: single metastatic lesion

favorable subtype: oligometastatic disease

Contributors

Authors

Michael S. Lee, MD

Associate Professor

Department of Gastrointestinal Medical Oncology

Division of Cancer Medicine

University of Texas MD Anderson Cancer Center

Houston

Disclosures

MSL has consulted for Pfizer, Bayer, Delcath, and Imvax. His institution has received research funding from Amgen, Exelixis, Bristol-Myers Squibb, Pfizer, Rafael Pharmaceuticals, EMD Serono, Genentech/Roche, Merck, Arcus, and Shanghai EpiMab Biotherapeutics. MSL is the author of a number of papers cited in this topic.

Acknowledgements

Dr Michael S. Lee would like to gratefully acknowledge Dr Ross C. Donehower, Dr David Cosgrove, and Dr Hatim Hussain, previous contributors to this topic.

Disclosures

RCD, DC, and HH declare that they have no competing interests.

Peer reviewers

Nikhil Khushalani, MD

Assistant Professor

Department of Medicine

Roswell Park Cancer Institute

Buffalo

Disclosures

NK declares that he has no competing interests.

Zelig Tochner, MD

Associate Professor

Radiation Oncology

Children's Hospital of Philadelphia

Philadelphia

Disclosures

ZT declares that he has no competing interests.

Justin Stebbing, MA, MRCP, MRCPath, PhD

Consultant Medical Oncologist/Senior Lecturer

Department of Medical Oncology

Imperial College/Imperial Healthcare NHS Trust

Charing Cross Hospital

London

Disclosures

JS declares that he has no competing interests.

Peer reviewer acknowledgements

BMJ Best Practice topics are updated on a rolling basis in line with developments in evidence and guidance. The peer reviewers listed here have reviewed the content at least once during the history of the topic.

Disclosures

Peer reviewer affiliations and disclosures pertain to the time of the review.

References

Our in-house evidence and editorial teams collaborate with international expert contributors and peer reviewers to ensure that we provide access to the most clinically relevant information possible.

Key articles

National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: occult primary [internet publication].Full text

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.Full text Abstract

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

Reference articles

A full list of sources referenced in this topic is available to users with access to all of BMJ Best Practice.

Differentials
- Squamous or neuroendocrine carcinoma of unknown primary
More Differentials
Guidelines
- NCCN clinical practice guidelines in oncology: head and neck cancers
- NCCN clinical practice guidelines in oncology: occult primary
More Guidelines
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Adenocarcinoma of unknown primary site

Summary

Definition

History and exam

Key diagnostic factors

Other diagnostic factors

Risk factors

Diagnostic tests

1st tests to order

Tests to consider

Emerging tests

Treatment algorithm

identification of primary site pending

unfavorable subtype: multiple metastases and/or without a likely primary site

favorable subtype: women with isolated axillary lymphadenopathy (likely breast primary)

favorable subtype: women with peritoneal carcinomatosis of a serous papillary adenocarcinoma (likely ovarian primary)

favorable subtype: poorly differentiated carcinoma with neuroendocrine features (likely small cell lung cancer primary)

favorable subtype: well-differentiated neuroendocrine tumors (likely neuroendocrine primary)

favorable subtype: adenocarcinoma with colorectal immunohistochemistry (likely colorectal primary)

favorable subtype: poorly differentiated carcinoma of the mediastinum or retroperitoneum in males <40 years (likely testicular primary)

favorable subtype: blastic bone metastases with immunohistochemistry/serum prostate-specific antigen (likely prostate primary)

favorable subtype: single metastatic lesion

favorable subtype: oligometastatic disease

Contributors

Authors

Michael S. Lee, MD

Disclosures

Acknowledgements

Disclosures

Peer reviewers

Nikhil Khushalani, MD

Disclosures

Zelig Tochner, MD

Disclosures

Justin Stebbing, MA, MRCP, MRCPath, PhD

Disclosures

Peer reviewer acknowledgements

Disclosures

References

Key articles

Reference articles

A full list of sources referenced in this topic is available to users with access to all of BMJ Best Practice.

Differentials

Guidelines

Log in or subscribe to access all of BMJ Best Practice

Log in or subscribe to access all of BMJ Best Practice

Log in to access all of BMJ Best Practice