Occult Primary
`(Cancer of Unknown Primary [CUP])
`Version 2.2025 — September 11, 2024
`NCCN.org
`NCCN recognizes the importance of clinical trials and encourages participation when applicable and available.
`Trials should be designed to maximize inclusiveness and broad representative enrollment.
`
`Continue
`Continue
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`Version 2.2025, 09/11/2024 © 2024 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
`
`NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)
`
`MERCK EX1276
`Merck Sharp & Dohme LLC v. The Johns Hopkins University
`IPR2024-00623
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`Printed by Elizabeth Moore on 4/30/2025 10:21:39 AM. For personal use only. Not approved for distribution. Copyright © 2025 National Comprehensive Cancer Network, Inc., All Rights Reserved.
`
`NCCN Guidelines Version 2.2025
`Occult Primary
`
`NCCN Guidelines Index
`Table of Contents
`Discussion
`
`*Marvaretta M. Stevenson, MD/Chair †
`Duke Cancer Institute
`*Daniel W. Bowles, MD/Vice Chair †
`University of Colorado Cancer Center
`Omar Abughanimeh, MBBS Þ † ‡
`Fred & Pamela Buffett Cancer Center
`Daniel Ahn, DO ‡
`Mayo Clinic Comprehensive Cancer Center
`Salwan Al Mutar, MD, MS †
`UT Southwestern Simmons
`Comprehensive Cancer Center
`David Bajor, MD †
`Case Comprehensive Cancer Center/
`University Hospitals Seidman Cancer Center
`and Cleveland Clinic Taussig Cancer Institute
`Sam Brondfield, MD, MA †
`UCSF Helen Diller Family
`Comprehensive Cancer Center
`Julie Bykowski, MD ф
`UC San Diego Moores Cancer Center
`Keith D. Eaton, MD, PhD † Þ
`Fred Hutchinson Cancer Center
`David Gierada, MD ф
`Siteman Cancer Center at Barnes-
`Jewish Hospital and Washington
`University School of Medicine
`Angela Jain, MD †
`Fox Chase Cancer Center
`Aparna Kalyan, MD †
`Robert H. Lurie Comprehensive Cancer
`Center of Northwestern University
`
`Zachary Kohutek, MD, PhD §
`Vanderbilt-Ingram Cancer Center
`Christina Kong, MD ≠
`Stanford Cancer Institute
`Jeremy Kortmansky, MD †
`Yale Cancer Center/Smilow Cancer Hospital
`John Kosteva, MD †
`Abramson Cancer Center
`at the University of Pennsylvania
`Anuradha Krishnamurthy, MD †
`Roswell Park Comprehensive Cancer Center
`Richard T. Lee, MD † £
`City of Hope National Medical Center
`Renato Lenzi, MD ‡
`The University of Texas
`MD Anderson Cancer Center
`Sam Lubner, MD †
`University of Wisconsin
`Carbone Cancer Center
`Alyssa Marr, MD †
`Fred & Pamela Buffett Cancer Center
`Nicholas McAndrew, MD, MSCE †
`UCLA Jonsson Comprehensive
`Cancer Center
`Mateusz Opyrchal, MD, PhD †
`Indiana University Melvin and Bren Simon
`Comprehensive Cancer Center
`Darryl Outlaw, MD ‡ †
`O'Neal Comprehensive Cancer Center at UAB
`Anuj Patel, MD †
`Dana-Farber/Brigham and Women's Cancer
`Center | Mass General Cancer Center
`Continue
`
`John Phay, MD ¶
`The Ohio State University Comprehensive
`Cancer Center - James Cancer Hospital
`and Solove Research Institute
`Asif Rashid, MD ≠
`The University of Texas
`MD Anderson Cancer Center
`Kerry Reynolds, MD ‡
`Mass General Cancer Center
`Stephen Rosenberg, MD, MS §
`Moffitt Cancer Center
`Jeffery Russell, MD, PhD, MBA †
`Huntsman Cancer Institute at the University of Utah
`Leonard Saltz, MD † Þ ‡
`Memorial Sloan Kettering Cancer Center
`Namrata Setia, MD ≠
`University of Chicago Medicine
`Comprehensive Cancer Center
`Jeffrey B. Smerage, MD, PhD ‡ †
`University of Michigan Rogel Cancer Center
`Siao-Yi Wang, MD, PhD †
`UC Davis Comprehensive Cancer Center
`NCCN
`Emily Kovach
`Megan Lyons, MS
`
`ф Diagnostic/Interventional
`radiology
`‡ Hematology/Hematology
`oncology
`Þ Internal medicine
`† Medical oncology
`≠ Pathology
`§ Radiotherapy/Radiation
`oncology
`
`£ Supportive care including
`palliative, pain management,
`pastoral care, and oncology
`social work
`¶ Surgery/Surgical oncology
`* Discussion section committee
`member
`
`NCCN Guidelines Panel Disclosures
`Version 2.2025, 09/11/2024 © 2024 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
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`Printed by Elizabeth Moore on 4/30/2025 10:21:39 AM. For personal use only. Not approved for distribution. Copyright © 2025 National Comprehensive Cancer Network, Inc., All Rights Reserved.
`
`NCCN Guidelines Version 2.2025
`Occult Primary
`
`NCCN Guidelines Index
`Table of Contents
`Discussion
`
`NCCN Occult Primary Panel Members
`Summary of the Guidelines Updates
`
`Initial Evaluation (OCC-1)
`Epithelial Occult Primaries (OCC-2)
`Adenocarcinoma or Carcinoma Not Otherwise Specified (OCC-3)
`Squamous Cell Carcinoma (OCC-11)
`Follow-up for All Occult Primaries (OCC-15)
`Immunohistochemistry/In Situ Hybridization Markers for Unknown Primary
`Cancers (OCC-A)
`Principles of Systemic Therapy (OCC-B)
`Principles of Radiation Therapy (OCC-C)
`Principles of Genetic/Familial Cancer Risk Assessment and Counseling (OCC-D)
`
`Abbreviations (ABBR-1)
`
`Find an NCCN Member Institution:
`https://www.nccn.org/home/member-
`institutions.
`NCCN Categories of Evidence and
`Consensus: All recommendations
`are category 2A unless otherwise
`indicated.
`See NCCN Categories of Evidence
`and Consensus.
`NCCN Categories of Preference:
`All recommendations are considered
`appropriate.
`See NCCN Categories of Preference.
`
`The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to
`treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual
`clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations
`or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN
`Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may
`not be reproduced in any form without the express written permission of NCCN. ©2024.
`
`Version 2.2025, 09/11/2024 © 2024 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
`
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`

`Printed by Elizabeth Moore on 4/30/2025 10:21:39 AM. For personal use only. Not approved for distribution. Copyright © 2025 National Comprehensive Cancer Network, Inc., All Rights Reserved.
`
`NCCN Guidelines Version 2.2025
`Occult Primary
`
`NCCN Guidelines Index
`Table of Contents
`Discussion
`
`Updates in Version 2.2025 of the NCCN Guidelines for Occult Primary from Version 1.2025 include:
`MS-1
`• The discussion section has been updated to reflect the changes in the algorithm.
`Updates in Version 1.2025 of the NCCN Guidelines for Occult Primary from Version 2.2024 include:
`Global
`• References updated throughout document.
`OCC-1
`• Initial evaluation, bullet 1: Complete H&P, including breast, genitourinary, pelvic, and rectal, skin, and/or oral cavity exam as appropriate, with attention
`to...
`• Workup:
`Bullet removed: Gene sequencing to predict tissue of origin is not recommended.
`Bullet added: Tissue of origin studies are not recommended.
`OCC-1A
`• Footnote d, references added.
`OCC-3
`• Header added: Histologic Diagnosis. (also for OCC-4, OCC-5, OCC-6, OCC-8, OCC-9, OCC-10, OCC-11, OCC-13, and OCC-14)
`• Footnote k modified: Symptom-directed endoscopy, such as endoscopy, can be considered... (also for OCC-4, OCC-5, OCC-6, and OCC-11)
`OCC-8
`• Mediastinum algorithm text removed:
`Consider additional consultation with pathologist to determine if further analysis would be helpful.
`OCC-11
`• Supraclavicular nodes, additional workup, bullet added: Endoscopy as indicated.
`OCC-A (1 of 5)
`• Header modified: Potential Immunohistochemistry/In Situ Hybridization Markers for Unknown Primary Cancers
`• Subheading modified: Communication between the clinician and the pathologist is essential for the workup to direct the staining pattern to the clinical
`differential diagnosis. The pathologist should select a focused panel of IHC or ISH markers, and avoid a large series of markers. IHC and ISH markers
`for unknown primary cancers are provided as a resource to assist in localizing a primary but are not uniformly specific or sensitive. Avoid a large series
`of immunohistochemistry markers. Communication with the pathologist is essential to workup.
`OCC-A (4 of 5)
`• Neuroendocrine carcinoma, other positive markers: CD56 removed.
`OCC-B (all)
`• Pages extensively revised.
`OCC-B (2 of 14)
`• Repotrectinib added as a Useful in Certain Circumstances regimen for NTRK gene fusion-positive tumors. (Also for OCC-B [8 of 14])
`OCC-C
`• General principles, dosing regimen modified: (48-60 Gy / in 4–5 fractions).
`
`Version 2.2025, 09/11/2024 © 2024 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
`
`UPDATES
`
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`Printed by Elizabeth Moore on 4/30/2025 10:21:39 AM. For personal use only. Not approved for distribution. Copyright © 2025 National Comprehensive Cancer Network, Inc., All Rights Reserved.
`
`NCCN Guidelines Version 2.2025
`Occult Primary
`
`NCCN Guidelines Index
`Table of Contents
`Discussion
`
`INITIAL EVALUATIONb
`
`WORKUP
`
`PATHOLOGIC DIAGNOSIS
`
`Suspected
`metastatic
`malignancya
`
`• Complete history and
`physical (H&P), including
`breast, genitourinary, pelvic,
`rectal, skin, and/or oral
`cavity exam as appropriate,
`with attention to and review
`of:
`• Past biopsies or
`malignancies
`• Removed lesions
`• Spontaneously regressing
`lesions
`• Existing imaging studies
`• Calcium
`• Complete blood count (CBC)
`• Creatinine
`• Electrolytes
`• Hemoccult test as indicated
`• Lactate dehydrogenase
`(LDH) as indicated
`• Liver function tests (LFTs)
`• Urinalysis as indicated
`• Chest/abdomen/pelvis CTc
`scan
`• Clinically directed
`endoscopy, as indicated
`
`Biopsyd:
`• Core needle biopsy (preferred)
`and/or fine-needle aspiration
`(FNA) with cell block of most
`accessible site
`• Consult pathologist for
`adequacy of specimen and
`additional studies including
`immunohistochemical (IHC)
`stainse
`• Tumor mutational burden
`(TMB) determination by
`a validated and/or FDA-
`approved assay (category 2B)f
`• Microsatellite instability
`(MSI)/mismatch repair (MMR)
`testingg
`• Molecular profiling of tumor
`tissue using next-generation
`sequencing (NGS) (or other
`technique to identify gene
`fusions) can be considered
`after an initial determination of
`histology has been madeh
`• Tissue of origin studies are
`not recommendedi
`
`Epithelial; not site
`specific or poorly
`differentiated
`neoplasm
`
`Lymphoma and
`other hematologic
`malignancies
`
`Thyroid carcinoma
`
`Melanoma
`
`Sarcoma
`
`Clinical Presentation
`(OCC-2)
`
`See NCCN Guidelines
`Treatment by Cancer Type
`
`See NCCN Guidelines for
`Thyroid Carcinoma
`See NCCN Guidelines for
`Melanoma: Cutaneous
`
`See NCCN Guidelines for
`Soft Tissue Sarcoma
`
`Germ cell tumor
`
`See NCCN Guidelines
`for Testicular Cancer
`
`Nonmalignant
`diagnosis
`
`Further evaluation
`and
`Appropriate follow-up
`
`Version 2.2025, 09/11/2024 © 2024 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
`
`Footnotes on OCC-1A
`
`OCC-1
`
`Note: All recommendations are category 2A unless otherwise indicated.
`
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`

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`Printed by Elizabeth Moore on 4/30/2025 10:21:39 AM. For personal use only. Not approved for distribution. Copyright © 2025 National Comprehensive Cancer Network, Inc., All Rights Reserved.
`
`NCCN Guidelines Version 2.2025
`Occult Primary
`
`NCCN Guidelines Index
`Table of Contents
`Discussion
`
`FOOTNOTES
`a For many patients the apparent uncertainties surrounding the diagnosis of an unknown primary cancer may result in significant psychosocial distress and increased
`difficulty in accepting treatment options. Empathetic discussion about the natural history of these types of cancer and their prognosis, and the provision of support and
`counseling both by the primary oncology team and specialized services may help to alleviate this distress. See NCCN Guidelines for Distress Management.
`b Testing for some tumor markers such as serum CA-125, CA 19-9, and CA 15-3 may be useful in certain circumstances, but are not diagnostic and caution must be
`exercised in their interpretation.
`c CT should be performed with contrast and MRI should be performed with and without IV contrast unless contraindicated. FDG-PET/CT is an alternative in patients with
`a contraindication to contrast enhancement.
`d If available, the pathologist should be involved with the biopsy to provide rapid on-site evaluation (ROSE) to confirm adequate sampling of the lesion and to perform
`specimen triage including cell block with immediate formalin fixation, flow cytometry, and other ancillary studies as needed. Sauter JL, et al. J Am Soc Cytopathol
`2020;9:570-578; VanderLaan PA, et al. J Am Soc Cytopathol 2019;8:333-341.
`e Immunohistochemistry/In Situ Hybridization Markers for Unknown Primary Cancers (OCC-A).
`f Merino DM, et al. J Immunother Cancer 2020;8:e000147.
`g The population of patients with MSI-high/MMR-deficient (MSI-H/dMMR) occult primary tumors is low. Use IHC for MMR or polymerase chain reaction (PCR) for MSI,
`which are different assays measuring the same biological effect.
`h Consider tumor/somatic molecular profiling for patients who are candidates for anti-cancer therapy to identify uncommon mutations (ie, RET fusions). Testing on tumor
`tissue is preferred; however, cell-free DNA testing can be considered if tumor tissue testing is not feasible.
`i Hayashi H, et al. J Clin Oncol 2019;37:570-579.
`
`Version 2.2025, 09/11/2024 © 2024 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
`
`OCC-1A
`
`Note: All recommendations are category 2A unless otherwise indicated.
`
`Page 6 of 80
`
`

`

`Printed by Elizabeth Moore on 4/30/2025 10:21:39 AM. For personal use only. Not approved for distribution. Copyright © 2025 National Comprehensive Cancer Network, Inc., All Rights Reserved.
`
`NCCN Guidelines Version 2.2025
`Occult Primary
`
`NCCN Guidelines Index
`Table of Contents
`Discussion
`
`PATHOLOGIC DIAGNOSIS
`
`CLINICAL PRESENTATIONj
`
`Epithelial;
`not site
`specific
`
`Adenocarcinoma
`or
`carcinoma not
`otherwise specified
`
`Molecular profiling of tumor
`tissue using NGS (or other
`technique to identify gene
`fusions) can be considered
`after initial determination of
`histology has been madeh
`
`Squamous cell carcinoma
`
`Neuroendocrine tumor
`
`• Predominant and isolated cervical nodes
`• Supraclavicular nodes
`• Axillary nodes
`
`• Mediastinum
`• Chest (multiple nodules) or pleural effusions
`• Peritoneal
`
`• Retroperitoneal mass
`• Inguinal nodes
`• Liver
`
`• Bone
`• Brain
`• Multiple sites of involvement
`
`OCC-3
`
`OCC-4
`
`OCC-5
`
`OCC-6
`
`OCC-11
`
`See NCCN Guidelines
`for Neuroendocrine
`and Adrenal Tumors
`
`h Consider tumor/somatic molecular profiling for patients who are candidates for anti-cancer therapy to identify uncommon mutations (ie, RET fusions). Testing on tumor
`tissue is preferred; however, cell-free DNA testing can be considered if tumor tissue testing is not feasible.
`j If carcinoma is present in more than one of these anatomic distributions, follow the workup indicated for the predominately involved anatomic site.
`
`Version 2.2025, 09/11/2024 © 2024 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
`
`OCC-2
`
`Note: All recommendations are category 2A unless otherwise indicated.
`
`Page 7 of 80
`
`

`

`Printed by Elizabeth Moore on 4/30/2025 10:21:39 AM. For personal use only. Not approved for distribution. Copyright © 2025 National Comprehensive Cancer Network, Inc., All Rights Reserved.
`
`NCCN Guidelines Version 2.2025
`Occult Primary
`
`NCCN Guidelines Index
`Table of Contents
`Discussion
`
`HISTOLOGIC DIAGNOSIS
`
`CLINICAL PRESENTATION
`
`ADDITIONAL WORKUPk
`
`Predominant and
`isolated cervical nodes
`
`See NCCN Guidelines for Head and Neck Cancers
`
`Adenocarcinoma
`or
`carcinoma not
`otherwise specified
`
`Supraclavicular nodes
`
`Axillary nodes
`
`• Neck/chest/abdomen/pelvis CTc (if not done)
`• Endoscopy, if clinically indicated
`• Appropriate IHCl
`• Mammogram (in those with intact breast tissue
`including gynecomastia); if nondiagnostic and
`histopathologic evidence for breast cancer,
`breast MRIc and/or breast ultrasound indicated
`• >40 y: Prostate-specific antigen (PSA) (in those
`with a prostate or post-prostatectomy)
`
`• Neck/chest/abdomen/pelvis CTc (if not done)
`• Appropriate IHCl
`• Mammogram (in those with intact breast tissue
`including gynecomastia); if nondiagnostic and
`histopathologic evidence for breast cancer,
`breast MRIc and/or breast ultrasound indicated
`• >40 y: PSA (in those with a prostate or post-
`prostatectomy)
`
`Management
`Based on Workup
`Findings (OCC-7)
`
`c CT should be performed with contrast and MRI should be performed with and without IV contrast unless contraindicated. FDG-PET/CT is an alternative in patients with
`a contraindication to contrast enhancement.
`k Symptom-directed endoscopy can be considered for individual patients based on clinical findings and IHC markers.
`l An expanded panel of IHC markers may be used as appropriate. See Immunohistochemistry/In Situ Hybridization Markers for Unknown Primary Cancers (OCC-A).
`
`Version 2.2025, 09/11/2024 © 2024 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
`
`OCC-3
`
`Note: All recommendations are category 2A unless otherwise indicated.
`
`Page 8 of 80
`
`

`

`Printed by Elizabeth Moore on 4/30/2025 10:21:39 AM. For personal use only. Not approved for distribution. Copyright © 2025 National Comprehensive Cancer Network, Inc., All Rights Reserved.
`
`NCCN Guidelines Version 2.2025
`Occult Primary
`
`NCCN Guidelines Index
`Table of Contents
`Discussion
`
`HISTOLOGIC
`DIAGNOSIS
`
`CLINICAL
`PRESENTATION
`
`Mediastinum
`
`ADDITIONAL WORKUPk
`
`• Chest/abdomen/pelvis CTc (if not done)
`• Beta-human chorionic gonadotropin (hCG), alpha-fetoprotein
`• Appropriate IHCl
`• Mammogram (in those with intact breast tissue including gynecomastia);
`if nondiagnostic and histopathologic evidence for breast cancer, breast
`MRIc and/or breast ultrasound indicated
`• >40 y: PSA (in those with a prostate or post-prostatectomy)
`• Testicular ultrasound, if beta-hCG or alpha-fetoprotein markers elevated
`(in those with testes)
`
`Adenocarcinoma
`or
`carcinoma not
`otherwise specified
`
`Chest
`(multiple nodules)
`or
`Pleural effusion
`
`• Chest/abdomen/pelvis CTc (if not done)
`• Appropriate IHCl
`• Consider gynecologic oncologist consult if CA-125 is elevated or
`clinically indicated (in those with a uterus and/or ovaries present)
`• Mammogram (in those with intact breast tissue including gynecomastia);
`if nondiagnostic and histopathologic evidence for breast cancer, breast
`MRIc and/or breast ultrasound indicated
`• >40 y: PSA (in those with a prostate or post-prostatectomy)
`
`Management
`Based on
`Workup
`Findings
`(OCC-7)
`
`Peritoneal/
`Ascites
`
`• Chest/abdomen/pelvis CTc (if not done)
`• Urine cytology; cystoscopy if suspicious
`• Appropriate IHCl
`• CA-125 (in those with a uterus and/or ovaries present)
`• Gynecologic oncologist consult (in those with a uterus and/or ovaries
`present)
`• Mammogram (in those with intact breast tissue including gynecomastia);
`if nondiagnostic and histopathologic evidence for breast cancer, breast
`MRIc and/or breast ultrasound indicated
`• >40 y: PSA (in those with a prostate or post-prostatectomy)
`
`c CT should be performed with contrast and MRI should be performed with and without IV contrast unless contraindicated. FDG-PET/CT is an alternative in patients with
`a contraindication to contrast enhancement.
`k Symptom-directed endoscopy can be considered for individual patients based on clinical findings and IHC markers.
`l An expanded panel of IHC markers may be used as appropriate. See Immunohistochemistry/In Situ HybridizationMarkers for Unknown Primary Cancers (OCC-A).
`
`Version 2.2025, 09/11/2024 © 2024 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
`
`OCC-4
`
`Note: All recommendations are category 2A unless otherwise indicated.
`
`Page 9 of 80
`
`

`

`Printed by Elizabeth Moore on 4/30/2025 10:21:39 AM. For personal use only. Not approved for distribution. Copyright © 2025 National Comprehensive Cancer Network, Inc., All Rights Reserved.
`
`NCCN Guidelines Version 2.2025
`Occult Primary
`
`NCCN Guidelines Index
`Table of Contents
`Discussion
`
`HISTOLOGIC
`DIAGNOSIS
`
`CLINICAL
`PRESENTATION
`
`ADDITIONAL WORKUPk
`
`Retroperitoneal mass
`
`Adenocarcinoma
`or
`carcinoma not
`otherwise specified
`
`Inguinal nodes
`
`Liver
`
`• Chest/abdomen/pelvis CTc (if not done)
`• Urine cytology; consider cystoscopy if suspicious
`• Appropriate IHCl
`• Gynecologic oncologist consult if CA-125 is elevated or clinically
`indicated (in those with a uterus and/or ovaries present)
`• Mammogram (in those with intact breast tissue including
`gynecomastia); if nondiagnostic and histopathologic evidence
`for breast cancer, breast MRIc and/or breast ultrasound indicated
`• >40 y: PSA (in those with a prostate or post-prostatectomy)
`• <65 y: Beta-hCG, alpha-fetoprotein, testicular ultrasound (in those
`with testes)
`
`• Chest/abdomen/pelvis CTc (if not done)
`• Proctoscopy if clinically indicated
`• CA-125 (in those with a uterus and/or ovaries present)
`• Gynecologic oncologist consult (in those with a uterus and/or
`ovaries present)
`• >40 y: PSA (in those with a prostate or post-prostatectomy)
`
`• Chest/abdomen/pelvis CTc (if not done)
`• Endoscopic evaluation
`• Alpha-fetoprotein
`• Appropriate IHCl
`• Mammogram (in those with intact breast tissue including
`gynecomastia); if nondiagnostic and histopathologic evidence for
`breast cancer, breast MRIc and/or breast ultrasound indicated
`• Consider further liver-directed imaging (see NCCN Guidelines for
`Hepatocellular Carcinoma and NCCN Guidelines for Biliary Tract
`Cancers)
`
`Management
`Based on Workup
`Findings (OCC-7)
`
`c CT should be performed with contrast and MRI should be performed with and without IV contrast unless contraindicated. FDG-PET/CT is an alternative in patients with
`a contraindication to contrast enhancement.
`k Symptom-directed endoscopy can be considered for individual patients based on clinical findings and IHC markers.
`l An expanded panel of IHC markers may be used as appropriate. See Immunohistochemistry/In Situ Hybridization Markers for Unknown Primary Cancers (OCC-A).
`
`Version 2.2025, 09/11/2024 © 2024 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
`
`OCC-5
`
`Note: All recommendations are category 2A unless otherwise indicated.
`
`Page 10 of 80
`
`

`

`Printed by Elizabeth Moore on 4/30/2025 10:21:39 AM. For personal use only. Not approved for distribution. Copyright © 2025 National Comprehensive Cancer Network, Inc., All Rights Reserved.
`
`NCCN Guidelines Version 2.2025
`Occult Primary
`
`CLINICAL PRESENTATION
`
`ADDITIONAL WORKUPk
`
`HISTOLOGIC
`DIAGNOSIS
`
`NCCN Guidelines Index
`Table of Contents
`Discussion
`
`Adenocarcinoma
`or
`carcinoma not
`otherwise specified
`
`Bone
`
`Brain
`
`Multiple sites
`of involvement
`
`• Chest/abdomen/pelvis CTc with bone scan
`• Appropriate IHCl
`• Mammogram (in those with intact breast tissue including
`gynecomastia); if nondiagnostic and histopathologic
`evidence for breast cancer, breast MRIc and/or breast
`ultrasound indicated
`• PSA (in those with a prostate or post-prostatectomy)
`
`• See NCCN Guidelines for Central Nervous System Cancers
`for primary treatment of central nervous system (CNS)
`metastatic lesions
`• Chest/abdomen/pelvis CTc (if not done)
`• Appropriate IHCl
`• Mammogram (in those with intact breast tissue including
`gynecomastia); if nondiagnostic and histopathologic
`evidence for breast cancer, breast MRIc and/or breast
`ultrasound indicated
`
`• Chest/abdomen/pelvis CTc (if not done)
`• Appropriate IHCl
`• Mammogram (in those with intact breast tissue including
`gynecomastia); if nondiagnostic and histopathologic
`evidence for breast cancer, breast MRIc and/or breast
`ultrasound indicated
`• PSA (in those with a prostate or post-prostatectomy)
`
`Management
`Based on Workup
`Findings (OCC-7)
`
`c CT should be performed with contrast and MRI should be performed with and without IV contrast unless contraindicated. FDG-PET/CT is an alternative in patients with
`a contraindication to contrast enhancement.
`k Symptom-directed endoscopy can be considered for individual patients based on clinical findings and IHC markers.
`l An expanded panel of IHC markers may be used as appropriate. See Immunohistochemistry/In Situ Hybridization Markers for Unknown Primary Cancers (OCC-A).
`
`Version 2.2025, 09/11/2024 © 2024 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
`
`OCC-6
`
`Note: All recommendations are category 2A unless otherwise indicated.
`
`Page 11 of 80
`
`

`

`Printed by Elizabeth Moore on 4/30/2025 10:21:39 AM. For personal use only. Not approved for distribution. Copyright © 2025 National Comprehensive Cancer Network, Inc., All Rights Reserved.
`
`NCCN Guidelines Version 2.2025
`Occult Primary
`
`NCCN Guidelines Index
`Table of Contents
`Discussion
`
`WORKUP FINDINGS
`
`Primary found
`
`Adenocarcinoma
`or carcinoma not
`otherwise specifieda
`
`Disseminated
`metastasesa
`
`MANAGEMENT BASED ON WORKUP FINDINGS
`
`Treat per NCCN disease-specific guidelines
`NCCN Guidelines Treatment by Cancer Type
`
`• Head and neck
`• Supraclavicular
`• Axillary
`• Mediastinum
`
`• Lung nodules
`• Pleural effusion
`• Peritoneal
`• Retroperitoneal
`mass
`
`• Inguinal node
`• Liver
`• Bone
`• Brain
`
`OCC-8
`
`OCC-9
`
`OCC-10
`
`• Symptom control
`• Clinical trial preferred
`• Consider systemic therapy on an individual basism
`• Specialized approachesn
`
`a For many patients the apparent uncertainties surrounding the diagnosis of an unknown primary cancer may result in significant psychosocial distress and increased
`difficulty in accepting treatment options. Empathetic discussion about the natural history of these types of cancer and their prognosis, and the provision of support and
`counseling both by the primary oncology team and specialized services may help to alleviate this distress. See NCCN Guidelines for Distress Management.
`m Principles of Systemic Therapy (OCC-B).
`n For specialized approaches that are therapeutic in nature, see Discussion.
`
`Follow-up (OCC-15)
`
`Version 2.2025, 09/11/2024 © 2024 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
`
`OCC-7
`
`Note: All recommendations are category 2A unless otherwise indicated.
`
`Page 12 of 80
`
`

`

`Printed by Elizabeth Moore on 4/30/2025 10:21:39 AM. For personal use only. Not approved for distribution. Copyright © 2025 National Comprehensive Cancer Network, Inc., All Rights Reserved.
`
`NCCN Guidelines Version 2.2025
`Occult Primary
`
`NCCN Guidelines Index
`Table of Contents
`Discussion
`
`HISTOLOGIC
`DIAGNOSIS
`
`CLINICAL PRESENTATION
`
`MANAGEMENT BASED ON WORKUP FINDINGS
`
`Head and neck
`
`Supraclavicular
`
`Adenocarcinoma
`or
`carcinoma
`not otherwise specifieda
`
`Axillary
`
`Treat per NCCN Guidelines for Head and Neck Cancers
`
`• Treat per NCCN Guidelines for Breast Cancer
`Screening and Diagnosis (in those with intact
`breast tissue including gynecomastia)
`• Axillary node dissection (in those with a prostate
`or post-prostatectomy), consider radiation therapy
`(RT)o if clinically indicated, consider systemic
`therapym if clinically indicated
`
`<40 y
`
`Treat as poor-risk germ cell tumor per NCCN
`Guidelines for Testicular Cancer or germ cell tumor
`per NCCN Guidelines for Ovarian Cancer
`
`Mediastinum
`
`40 to <50 y
`
`Treat as poor-risk germ cell tumor per NCCN
`Guidelines for Testicular Cancer or germ cell tumor
`per NCCN Guidelines for Ovarian Cancer or treat per
`NCCN Guidelines for Non-Small Cell Lung Cancer
`
`≥50 y
`
`Treat per NCCN Guidelines for Non-Small Cell
`Lung Cancer
`
`a For many patients the apparent uncertainties surrounding the diagnosis of an unknown primary cancer may result in significant psychosocial distress and increased
`difficulty in accepting treatment options. Empathetic discussion about the natural history of these types of cancer and their prognosis, and the provision of support
`and counseling both by the primary oncology team and specialized services may help to alleviate this distress. See NCCN Guidelines for Distress Management.
`m Principles of Systemic Therapy (OCC-B).
`o Principles of Radiation Therapy (OCC-C).
`
`Follow-up (OCC-15)
`
`Version 2.2025, 09/11/2024 © 2024 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
`
`OCC-8
`
`Note: All recommendations are category 2A unless otherwise indicated.
`
`Page 13 of 80
`
`

`

`Printed by Elizabeth Moore on 4/30/2025 10:21:39 AM. For personal use only. Not approved for distribution. Copyright © 2025 National Comprehensive Cancer Network, Inc., All Rights Reserved.
`
`NCCN Guidelines Version 2.2025
`Occult Primary
`
`NCCN Guidelines Index
`Table of Contents
`Discussion
`
`HISTOLOGIC
`DIAGNOSIS
`
`CLINICAL PRESENTATION
`
`MANAGEMENT BASED ON WORKUP FINDINGS
`
`Lung nodules
`
`Pleural effusion
`
`Adenocarcinoma
`or
`carcinoma not
`otherwise specifieda
`
`Peritoneal/
`Ascites
`
`Breast marker positive
`
`Other
`
`Histology consistent
`with ovary
`
`Other
`
`• If completely resectable, consider surgery
`• Clinical trial preferred
`• Consider systemic therapym
`• Symptom control
`• Stereotactic body RT (SBRT)/stereotactic
`ablative radiotherapy (SABR)o
`Treat per NCCN Guidelines for Breast Cancer
`
`• Clinical trial preferred
`• Consider systemic therapym
`• Symptom control
`• Consider treating as lung primary (stage IVA) per
`NCCN Guidelines for Non-Small Cell Lung Cancer
`
`Treat per NCCN Guidelines for Ovarian Cancer
`
`• Clinical trial preferred
`• Consider systemic therapym
`• Symptom control
`
`Retroperitoneal
`mass
`
`Histology consistent
`with germ cell tumor
`
`Treat as poor-risk germ cell tumor per NCCN
`Guidelines for Testicular Cancer or germ cell tumor
`per NCCN Guidelines for Ovarian Cancer
`
`Non-germ cell histology
`
`• Surgery and/or RTo
`• Consider systemic therapy for selected patientsm
`
`a For many patients the apparent uncertainties surrounding the diagnosis of an unknown primary cancer may result in significant psychosocial distress and increased
`difficulty in accepting treatment options. Empathetic discussion about the natural history of these types of cancer and their prognosis, and the provision of support and
`counseling both by the primary oncology team and specialized services may help to alleviate this distress. See NCCN Guidelines for Distress Management.
`m Principles of Systemic Therapy (OCC-B).
`o Principles of Radiation Therapy (OCC-C).
`
`Follow-up (OCC-15)
`
`Version 2.2025, 09/11/2024 © 2024 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
`
`OCC-9
`
`Note: All recommendations are category 2A unless otherwise indicated.
`
`Page 14 of 80
`
`

`

`Printed by Elizabeth Moore on 4/30/2025 10:21:39 AM. For personal use only. Not approved for distribution. Copyright © 2025 National Comprehensive Cancer Network, Inc., All Rights Reserved.
`
`NCCN Guidelines Version 2.2025
`Occult Primary
`
`NCCN Guidelines Index
`Table of Contents
`Discussion
`
`HISTOLOGIC
`DIAGNOSIS
`
`CLINICAL PRESENTATION
`
`MANAGEMENT BASED ON WORKUP FINDINGS
`
`Adenocarcinoma
`or
`carcinoma not
`otherwise specifieda
`
`Unilateral
`
`Bilateral
`
`Unresectable
`
`Resectable
`
`Isolated lesion
`or
`painful lesion
`or
`lesion with potential
`for fracture in weight-
`bearing area
`
`Inguinal node
`
`Liver
`
`Bone
`
`Brain
`
`Lymph node dissection, consider RTo if
`clinically indicated ± systemic therapym
`
`Bilateral l