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Working Up a Positive Signal, by Cancer Signal Origin

Last checked September 5, 2026. Bracketed numbers open the source. GRAIL-authored sources are labeled in the source list.

This page is for informational purposes only and is not medical advice. The evaluation of any individual patient is the responsibility of the treating physician. If you are a patient with a positive result, please discuss it with your own clinician.

Of the multi-cancer tests sold in the US, Galleri and Caris Detect report a predicted origin for a positive result, and Cancerguard does not. GRAIL's guidance to clinicians is that "a Cancer Signal Detected result should be followed with a diagnostic assessment guided by the predicted Cancer Signal Origin" [1], and its website does not list specific tests. The first evaluation listed for each signal origin below is taken from a table in a 2026 paper whose authors include GRAIL employees [2]. Caris states that a positive Caris Detect report includes a suspected tissue of origin and recommendations for follow-up imaging, referrals, and diagnostic evaluation [3] [4]; I could not find those recommendations published anywhere outside the report itself. Cancerguard's report states there are no national guidelines for imaging after a positive result and points to a published workflow, written in part by Exact Sciences authors, of CT of the neck, chest, abdomen, and pelvis with IV contrast, then PET-CT if the CT is negative [5] [6].

Who obtains tissue generally depends on what the first evaluation shows: the endoscopist during an endoscopy, interventional radiology for an image-guided biopsy of a lesion the organ specialist cannot reach, or a surgeon when neither applies. When imaging shows disease at more than one site, biopsy of a distant site is often favored, since it can establish the diagnosis and the stage at the same time, provided the site can be sampled safely and is likely to yield a diagnosis.

As far as I can tell, no guideline assigns responsibility for the work-up after a positive result. GRAIL's position is that "diagnostic decisions are the responsibility of the treating physician" [7]. All three tests require a clinician's order, but each can be requested online, in which case the order is written by a telehealth clinician who is not the patient's own physician [8] [9] [4]. Early oncology involvement could be considered, particularly when the first evaluation is negative or imaging shows disease at more than one site.

Jump to a signal origin

Thoracic

Lung

First evaluation, as listed in the GRAIL-authored table
Chest CT [2]

Gastrointestinal

Stomach and esophagus

First evaluation, as listed in the GRAIL-authored table
Esophagoduodenoscopy (upper endoscopy) [2]

Colon and rectum

First evaluation, as listed in the GRAIL-authored table
Colonoscopy [2]

Anus

First evaluation, as listed in the GRAIL-authored table
Anoscopy or sigmoidoscopy [2]

Hepatobiliary and pancreas

Pancreas and gallbladder

First evaluation, as listed in the GRAIL-authored table
Pancreas-protocol CT and magnetic resonance cholangiopancreatography [2]

Liver and bile duct

First evaluation, as listed in the GRAIL-authored table
Triple-phase abdominal CT and alpha-fetoprotein [2]

Head and neck

Head and neck

First evaluation, as listed in the GRAIL-authored table
CT or MRI of the head and neck; laryngoscopy [2]

Thyroid

First evaluation, as listed in the GRAIL-authored table
Thyroid ultrasound [2]

Hematologic

Lymphoid lineage

First evaluation, as listed in the GRAIL-authored table
Complete blood count with differential and bone marrow biopsy; PET-CT [2]
Benign explanations reported
Monoclonal B-cell lymphocytosis: at one PATHFINDER site, 6 of 15 false-positive results were attributed to it [10]. GRAIL raised the specificity threshold for hematologic signals in the refined test to reduce false positives from monoclonal gammopathy of undetermined significance, monoclonal B-cell lymphocytosis, and clonal hematopoiesis of indeterminate potential [11].

Plasma cell lineage

First evaluation, as listed in the GRAIL-authored table
Complete blood count with differential and bone marrow biopsy [2]
Benign explanations reported
Monoclonal gammopathy of undetermined significance, which GRAIL names among the nonmalignant conditions behind hematologic false positives in the first test version [11].

Myeloid lineage

First evaluation, as listed in the GRAIL-authored table
Complete blood count with differential and bone marrow biopsy [2]
Benign explanations reported
Clonal hematopoiesis of indeterminate potential, which GRAIL names among the nonmalignant conditions behind hematologic false positives in the first test version [11].

Breast and gynecologic

Breast

First evaluation, as listed in the GRAIL-authored table
Diagnostic mammogram (MRI if a recent mammogram was negative) [2]

Ovary

First evaluation, as listed in the GRAIL-authored table
Transvaginal ultrasound and CA-125 [2]

Uterus

First evaluation, as listed in the GRAIL-authored table
Transvaginal ultrasound [2]

Cervix

First evaluation, as listed in the GRAIL-authored table
Colposcopy and cytology with HPV testing [2]

Genitourinary

Prostate

First evaluation, as listed in the GRAIL-authored table
Prostate-specific antigen and prostate MRI [2]

Bladder and urothelial tract

First evaluation, as listed in the GRAIL-authored table
CT urogram and cystoscopy [2]

Kidney

First evaluation, as listed in the GRAIL-authored table
Triple-phase renal CT [2]

Skin, sarcoma, neuroendocrine

Melanoma (melanocytic lineage)

First evaluation, as listed in the GRAIL-authored table
Full-body skin exam [2]

Bone and soft tissue (sarcoma)

First evaluation, as listed in the GRAIL-authored table
MRI, or CT of the chest, abdomen, and pelvis [2]

Neuroendocrine tumor of the lung or other organs

First evaluation, as listed in the GRAIL-authored table
CT of the chest, abdomen, and pelvis [2]

Sources

Each bracketed number opens one of these. Statements were checked against the linked page on September 5, 2026.

  1. [1] Implementing Galleri in your practice (galleri.com HCP page) manufacturer HCP page
  2. [2] Massart M, Raoof S, Hubbell E, Klein EA. Molecular cancer signal localization in MCED testing minimizes radiation and imaging burden compared with whole-body imaging approaches. Cancer Prev Res 2026;19:353-60. Table 3: recommended initial diagnostic evaluation for each of 21 signal origin predictions peer-reviewed paper; two authors are GRAIL employees
  3. [3] Caris Detect (Caris Life Sciences product page): positive report includes suspected tissue of origin; provider may recommend targeted evaluations manufacturer page
  4. [4] Caris Detect on Everlywell: results include a suspected tissue of origin and recommendations to guide follow-up imaging, referrals and diagnostic evaluations retail partner page
  5. [5] Cancerguard sample positive patient report (Exact Sciences) manufacturer sample report
  6. [6] Kisiel JB, Ebbert JO, Taylor WR, Marinac CR, Choudhry OA, Rego SP, Beer TM, Beidelschies MA. Shifting the cancer screening paradigm: developing a multi-biomarker class approach to multi-cancer early detection testing. Life 2024;14(8):925. Proposes CT neck/chest/abdomen/pelvis with IV contrast, then FDG-PET/CT if negative peer-reviewed review; several authors are Exact Sciences employees
  7. [7] Galleri FAQs for providers manufacturer HCP page
  8. [8] Galleri: how to get the test (galleri.com): through your healthcare provider, or requested online through an independent telemedicine provider manufacturer page
  9. [9] Cancerguard: request the test online (cancerguard.com): a licensed provider from Recuro Health reviews the request and writes the prescription manufacturer page
  10. [10] Khare S et al. Multi-cancer early detection utilizing blood-based genomics: single-institution case series (Oregon Health & Science University, a PATHFINDER site). Front Oncol 2025;15:1637999 peer-reviewed case series
  11. [11] Marinac CR, McDonnell CH, Nadauld LD, et al. Clinical evaluation of cancer signal origin prediction and diagnostic resolution following multicancer early detection testing in the PATHFINDER study. Cancer Prev Res 2025;18:475 peer-reviewed PATHFINDER sub-analysis, GRAIL co-authored
Disclosures. Before Stage One is written by Michael LaPelusa, MD in his personal capacity. Views expressed are his own and do not represent the views of any institution. Content is provided for informational purposes only and should not be relied upon as medical, legal, business, investment, or tax advice. Nothing here is a recommendation to undergo, avoid, prescribe, or order any medical test or treatment, nor a recommendation to buy or sell any security. Readers should consult their own physicians and advisers regarding clinical, financial, and legal decisions. The author does not hold positions in any company discussed unless explicitly disclosed in the post. See full disclosures.