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Adenocarcinoma of unknown primary site

Last reviewed: 30 Oct 2023
Last updated: 02 Jun 2023



History and exam

Key diagnostic factors

  • bone pain
  • family history of cancer
More key diagnostic factors

Other diagnostic 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
Other diagnostic factors

Risk factors

  • age >60 years
More risk factors

Diagnostic investigations

1st investigations to order

  • CT chest/abdomen/pelvis
  • mammography
  • MRI of breast
  • transvaginal ultrasound
  • diagnostic paracentesis
  • direct laryngoscopy with or without esophagoscopy and bronchoscopy
More 1st investigations to order

Investigations 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)
More investigations to consider

Emerging tests

  • gene expression profiling (GEP)

Treatment algorithm


identification of primary site pending


multiple metastases: favorable clinicopathologic subtype not identified

multiple metastases: women with isolated axillary lymphadenopathy (likely primary: breast cancer)

multiple metastases: women with papillary adenocarcinoma of the peritoneal cavity (likely primary: ovarian cancer)

multiple metastases: poorly differentiated carcinoma with neuroendocrine features (likely primary: small cell lung cancer)

multiple metastases: well-differentiated neuroendocrine tumors

multiple metastases: adenocarcinoma with colorectal immunohistochemistry (likely primary: colorectal cancer)

multiple metastases: poorly differentiated carcinoma of the mediastinum or retroperitoneum in males <40 years

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

single metastatic lesion

oligometastatic disease



Michael S. Lee, MD

Associate Professor

Department of Gastrointestinal Medical Oncology

Division of Cancer Medicine

University of Texas MD Anderson Cancer Center




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.


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.


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




NK declares that he has no competing interests.

Zelig Tochner, MD

Associate Professor

Radiation Oncology

Children's Hospital of Philadelphia




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




JS declares that he has no competing interests.

  • Adenocarcinoma of unknown primary site images
  • Differentials

    • Squamous or neuroendocrine carcinoma of unknown primary
    More Differentials
  • Guidelines

    • Cancer of unknown primary: ESMO clinical practice guideline for diagnosis, treatment and follow-up
    • NCCN clinical practice guidelines in oncology: occult primary
    More Guidelines
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