Tumor Markers

Slide 1 · Tumor markers

Principles, major marker families, interpretation, and liquid biopsy

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Explain why a positive circulating marker cannot by itself establish malignancy.

Relate major tumor-marker classes to their associated neoplasms.

Interpret marker persistence or recurrence after treatment without assuming specificity.

Describe the rationale and limitations of cell-free DNA and RNA testing.

Slide 3 · What a tumor marker measures

Tumor-associated biological product

Measured in blood or another body fluid

An assay result requiring clinical interpretation

Association with cancer does not imply exclusive production by cancer.

Slide 4 · The scope extends beyond serum proteins

Biochemical analytes

Hormones, enzymes, antigens, immunoglobulins

Glycoproteins

Mucins and related circulating markers

Molecular analytes

Tumor-associated cell-free DNA and circulating RNA

The sampled molecule and specimen determine the assay—not its diagnostic certainty.

Slide 5 · Tumor-associated is not tumor-specific

Association

Marker may be elevated in malignancy

Some tumor cells release measurable material

Limitation

Non-neoplastic conditions may also elevate markers

A marker alone does not prove the tissue contains cancer

Slide 6 · Three distinct clinical questions

Detection

Does the result raise suspicion?

Treatment response

Does the level change after intervention?

Recurrence

Does a previously reduced marker reappear?

Follow-up more than stand-alone diagnosis.

Slide 7 · Why a single assay does not diagnose cancer

Abnormal biochemical result

Consider sensitivity and specificity limits

Integrate findings with other tests

Establish diagnosis from the complete evaluation

A single positive result is a clinical clue, not a definitive diagnosis.

Slide 8 · Sensitivity: Cancer may escape detection

General principle

Cancer can be present without a sufficient measurable signal

A negative result cannot universally exclude malignancy

Textbook example

PSA is the explicit textbook example

No PSA concentration guarantees freedom from prostate cancer

Slide 9 · Specificity: Benign disease can mimic cancer

Benign condition affects marker

Circulating concentration may rise

Positive result is not cancer-specific

PSA and benign prostatic hyperplasia illustrate this problem.

Slide 10 · Why population screening is difficult

Cancer-associated analytes may occur in people without cancer.

Some cancers fail to produce a detectable marker signal.

A test aimed at one analyte may lack the specificity needed for broad screening.

Accurate, sensitive, specific early-detection tests as an active research goal.

Slide 11 · Context determines the interpretation

Before diagnosis

An abnormal marker prompts correlation, not a final label

With known cancer

A relevant marker can supplement the tumor assessment

After treatment

A longitudinal result may inform response or recurrence evaluation

The same analyte can have different clinical utility at different time points.

Slide 12 · Tumor markers complement tissue evaluation

Clinical information

Histology / cytology and ancillary testing

Marker assay in context

Integrated cancer assessment

The adjacent Robbins laboratory-diagnosis section identifies morphology as the diagnostic foundation.

Slide 13 · Serial monitoring is a principal use

A marker secreted by an established tumor may provide a trackable biochemical signal.

Successful therapy can be accompanied by loss of detectable circulating marker.

Persistence or reappearance raises concern for residual or recurrent tumor.

The interpretation must remain tied to the tumor type and other clinical evidence.

Slide 14 · A falling marker is evidence, not a verdict

Tumor-directed intervention

Reduced marker signal

Compatible with response to therapy

Correlate with overall tumor evaluation

A conceptual sequence; No patient-level measurement or response magnitude is assumed.

Slide 15 · Marker persistence after resection

CLINICAL APPLICATION

After resection of a marker-producing malignancy, the tumor-associated analyte remains measurable.

What is the main teaching implication?

Persistent marker may indicate tumor remaining; Confirm using the complete clinical assessment.

The marker cannot localize or independently characterize the residual lesion.

Slide 16 · Reappearance after initial decline

CLINICAL APPLICATION

A circulating marker decreases after treatment and is later detected again in follow-up.

Why does this result matter?

Reappearance as a signal that can suggest tumor recurrence.

Do not equate a biochemical signal alone with confirmed anatomic recurrence.

Slide 17 · Marker families

Hormones

HCG; Calcitonin; Catecholamines

Oncofetal antigens

AFP; CEA

Proteins / glycoproteins

Immunoglobulins; PSA/PSMA; CA-series markers

Molecular markers

Cell-free mutant DNA; Circulating RNA

The biomarker classes reflect different biological sources and assay targets.

Slide 18 · Hormonal markers reflect tumor production

Neoplasm with hormone-related product

Secretion or release into circulation

Targeted biochemical assay

Association with a particular tumor group

A hormonal marker is not automatically specific to a single diagnosis.

Slide 19 · Human chorionic gonadotropin (hCG)

Hormone

HCG

Trophoblastic tumors

Nonseminomatous testicular tumors

HCG among tumor-associated hormonal markers.

Slide 20 · HCG links two different tumor settings

Trophoblastic

Trophoblastic neoplasia

Tumor group explicitly associated with hCG

Germ cell

Nonseminomatous testicular tumors

HCG included among relevant marker associations

Slide 21 · Calcitonin: Thyroid lineage association

Hormone

Calcitonin

Medullary carcinoma of the thyroid

The marker association is specific to the named tumor type in Table 7.12.

Slide 22 · Catecholamines and metabolites

Hormonal analytes

Catecholamines

Pheochromocytoma

Related tumors

The measurable target can include biochemical metabolites, not only a secreted hormone.

Slide 23 · Ectopic hormone production differs in purpose

Assay association

Tumor-associated hormonal product

May serve as a circulating marker

Clinical consequence

Ectopic hormonal action

May produce a clinical paraneoplastic syndrome

Slide 24 · Paraneoplastic endocrine examples

ACTH / ACTH-like

Cushing syndrome in associated tumors

Antidiuretic hormone

Syndrome of inappropriate ADH secretion

PTH-related protein

One mechanism of malignancy-associated hypercalcemia

Examples Table 7.11; A hormone-mediated syndrome is not interchangeable with a tumor-specific test.

Slide 25 · Oncofetal antigens as circulating markers

Tumor-associated antigen expression

Release into blood

Biochemical detection

Limited by non-neoplastic elevations

AFP and CEA are the central examples in this family.

Slide 26 · Alpha-fetoprotein: Hepatocellular tumors

Oncofetal antigen

AFP

Hepatocellular carcinoma

Elevated AFP is an association; The textbook does not support using it as a stand-alone diagnosis.

Slide 27 · AFP: Nonseminomatous germ cell tumors

Oncofetal antigen

AFP

Yolk sac tumors

Some teratocarcinomas

Some embryonal carcinomas

The associations in the source do not imply expression in every germ cell tumor.

Slide 28 · AFP joins distinct tumor lineages

Hepatic

Liver cell cancer

Hepatocellular carcinoma

Germ cell

Germ cell neoplasia

Yolk sac and selected nonseminomatous types

Slide 29 · AFP is not a universal screening result

AFP is produced by several tumor types in the Robbins discussion.

Non-neoplastic conditions can also increase serum AFP.

An elevated AFP therefore does not, by itself, establish cancer.

Its useful role can include assessment of treatment response in an appropriate patient.

Slide 30 · Carcinoembryonic antigen: Tumor spectrum

Digestive tract

Colon, pancreas, stomach

Other epithelial tumors

Lung and breast carcinomas

These are associated tumor sites, not proof of tissue of origin from a serum result.

Slide 31 · CEA is not restricted to colorectal cancer

Common association

Colorectal carcinoma is a major association

CEA can contribute to serial monitoring

Why it matters

Other carcinomas can also produce CEA

A serum value alone does not localize the primary tumor

Slide 32 · CEA elevations may be non-neoplastic

Robbins explicitly cautions that CEA may increase in non-neoplastic conditions.

This undermines the value of an isolated result as a screening test.

Interpretation requires context, including whether a CEA-producing tumor is already known.

Slide 33 · CEA after successful tumor resection

Known CEA-producing tumor

Surgical removal

Circulating CEA may become undetectable

Persisting or returning CEA merits recurrence evaluation

Clearance and reappearance as longitudinal surveillance concepts.

Slide 34 · CEA and AFP: Shared interpretation rule

Property

CEA

AFP

Marker family

Oncofetal antigen

Oncofetal antigen

Tumor associations

Several carcinomas

Hepatocellular and selected germ cell tumors

Non-neoplastic elevation

Possible

Possible

Useful context

Response / recurrence monitoring

Response / recurrence monitoring

Slide 35 · Immunoglobulins: Lineage-associated markers

Lineage-specific proteins

Immunoglobulins

Multiple myeloma

Other secretory plasma cell tumors

Other gammopathies (Table 7.12)

The measured protein reflects a secretory cellular lineage.

Slide 36 · An immunoglobulin result requires context

Detectable immunoglobulin-related analyte

Determine the clinical / laboratory context

Consider plasma cell–associated processes

Correlate with diagnostic evaluation

Table 7.12 lists immunoglobulins in myeloma and other gammopathies; It does not make a standalone diagnostic rule.

Slide 37 · Prostate-specific antigen: A useful model

Lineage-specific protein

PSA

Prostatic adenocarcinoma

PSA is common in clinical practice but sharply illustrates specificity and sensitivity limitations.

Slide 38 · Benign prostatic hyperplasia can raise PSA

Malignant cause

Prostate carcinoma may elevate PSA

Cancer remains a possible explanation

Benign cause

Benign prostatic hyperplasia may elevate PSA

An elevated value does not establish malignancy

Slide 39 · No PSA value excludes all prostate cancer

The textbook explicitly states that no serum PSA level ensures absence of cancer.

An apparently reassuring result is therefore not an absolute exclusion test.

The finding must be interpreted with the rest of the prostate evaluation.

Slide 40 · How to interpret an elevated PSA

PSA concentration above expectation

Cancer is one possibility

Benign prostatic hyperplasia is another

Further clinical assessment determines significance

Do not invent an absolute PSA cutoff: None is specified in the topic excerpt.

Slide 41 · PSA and PSMA are grouped in the table

Protein

Robbins association

Teaching distinction

PSA

Prostate cancer

Serum marker discussed in main text

PSMA

Prostate cancer

Listed as a lineage-specific marker in Table 7.12

Slide 42 · Mucins and related glycoproteins

Tumor-associated glycoprotein / mucin

Measurable antigen family

Named CA-series marker

Use limited by context and specificity

Table 7.12 lists CA-125, CA-19-9, and CA-15-3.

Slide 43 · CA-125: Ovarian cancer association

Mucin / glycoprotein

CA-125

Ovarian cancer

A tumor-marker association is not, by itself, a screening or diagnostic guarantee.

Slide 44 · CA-19-9: Gastrointestinal associations

Mucin / glycoprotein

CA-19-9

Pancreatic cancer

Colon cancer

The Robbins table associates this marker with more than one tumor site.

Slide 45 · CA-15-3: Breast cancer association

Mucin / glycoprotein

CA-15-3

Breast cancer

The source identifies association, without providing a standalone diagnostic cutoff.

Slide 46 · Compare the CA-series associations

Marker

Associated tumor(s) in Table 7.12

Interpretive limit

CA-125

Ovarian

Association ≠ diagnosis

CA-19-9

Pancreatic and colon

More than one tumor type

CA-15-3

Breast

Not a universal screening test

Slide 47 · Marker selection follows the clinical problem

Identify suspected or established tumor context

Select biologically relevant analyte

Interpret the result within that context

Assess course with corroborating findings

Conceptual workflow synthesized marker roles; Not a formal clinical guideline.

Slide 48 · Markers do not supply tumor morphology

Circulating marker

Biochemical result

Suggests production of an associated analyte

Tissue / cytology

Pathology assessment

Characterizes cells, architecture and tumor type

Slide 49 · A blood marker rarely resolves tumor origin

CLINICAL APPLICATION

A patient has an increased CEA concentration, but the primary lesion has not been characterized.

Can the source of the tumor be assigned from CEA alone?

No. Several tumor types and non-neoplastic conditions are associated with CEA.

Use morphologic and clinical correlation rather than reverse-diagnosing from one marker.

Slide 50 · Cell-free DNA expands the marker concept

Tumor-associated DNA released into body fluid

Isolation from serum, urine or stool

Detection of selected mutant sequences

Molecular information to interpret in context

The source discusses mutation detection across several body fluids.

Slide 51 · Why mutation-based assays attract interest

Cancer is associated with genetic driver alterations.

Highly sensitive methods can detect selected mutant sequences in cell-free DNA.

Blood and other accessible fluids offer opportunities for molecular assessment.

Robbins still cautions against assuming population-screening performance from a single marker.

Slide 52 · EGFR mutants in serum: Lung cancer

Cell-free DNA marker

EGFR mutation

Lung cancer

Serum specimen listed in Table 7.12

This is a tumor-associated sequence example; Performance estimates are not given in the source.

Slide 53 · Colon cancer: Several DNA targets

TP53

Mutant sequences may be assayed

APC

Mutant sequences may be assayed

RAS

Mutant sequences may be assayed

The table links these targets to stool and serum specimens in colon cancer.

Slide 54 · Pancreatic cancer: Stool and serum DNA

Cell-free DNA marker

TP53 / RAS

Pancreatic cancer

Stool and serum samples

Marker candidates are not equivalent to a validated population screening program.

Slide 55 · Lung cancer: Sputum and serum DNA

Cell-free DNA marker

TP53 / RAS

Lung cancer

Sputum and serum samples

Tumor-associated variants may be sought in different fluid matrices.

Slide 56 · Bladder cancer: Urine-based DNA example

Cell-free DNA marker

TP53 mutation

Bladder cancer

Urine specimen

Urine illustrates that a liquid biopsy need not use blood.

Slide 57 · Body fluids used for mutant DNA assays

Specimen

Source-listed tumor examples

DNA targets mentioned

Serum

Lung, colon, pancreas

EGFR; TP53/APC/RAS

Stool

Colon, pancreas

TP53/APC/RAS

Sputum

Lung

TP53/RAS

Urine

Bladder

TP53

Slide 58 · One molecular target may not be enough

Cancer develops via multiple events

Different tumors need not share one alteration

Single-target test misses part of the spectrum

Multi-marker strategies merit study

Robbins explicitly argues single-marker population screening may lack adequate specificity.

Slide 59 · Multi-analyte liquid biopsy rationale

Multiple DNA variants

Look for several driver mutations

Additional analytes

Potentially combine different cancer-associated markers

Interpretation

Screening utility still requires validation

Conceptual research strategy; Not a claim of established clinical accuracy.

Slide 60 · Circulating tumor-associated RNA

Tumor cells release RNA-containing material

RNA becomes detectable in blood

Molecular profiling may be possible

Evidence that circulating RNA can be profiled.

Slide 61 · Exosomes as carriers of circulating RNA

Some tumors release membrane vesicles

Exosomes occur in blood and other fluids

Circulating RNA is enriched in exosomes

An original native schematic of the relationship described on page 301.

Slide 62 · Liquid biopsy: Promise versus evidence gap

Technical opportunity

Accessible bodily fluid

Molecular mutations and RNA can be assayed

Multiple markers may broaden information

Clinical restraint

Early detection remains a research challenge

One analyte may not screen populations adequately

Assay detectability ≠ demonstrated clinical benefit

Slide 63 · Case: An abnormal PSA in isolation

CLINICAL APPLICATION

A person without a confirmed cancer diagnosis has an elevated serum PSA.

What can be concluded?

Prostate malignancy is possible; Benign prostatic hyperplasia is also a recognized cause.

Do not convert one result into a definitive cancer diagnosis.

Slide 64 · Case: An unremarkable PSA result

CLINICAL APPLICATION

A clinical evaluation raises concern for prostate malignancy, but PSA is not elevated.

Does the marker rule out the tumor?

No. There is no PSA value that guarantees absence of prostate cancer.

The remainder of the assessment still matters.

Slide 65 · Case: CEA returns after resection

CLINICAL APPLICATION

CEA fell after surgery for a known CEA-producing carcinoma; A later sample detects it again.

What hypothesis should be investigated?

Recurrence or persistent tumor becomes an important concern.

A serum marker is not sufficient to determine the location or extent of tumor.

Slide 66 · Case: An AFP elevation

CLINICAL APPLICATION

A serum AFP result is elevated in a patient with an undiagnosed lesion.

Why is a single-test diagnosis inappropriate?

AFP is associated with more than one tumor type and may rise in non-neoplastic conditions.

Correlate the laboratory result with the broader evaluation.

Slide 67 · Case: A mutant sequence in body fluid

CLINICAL APPLICATION

A molecular assay detects a tumor-associated variant in a fluid sample.

Is this proof that population screening is solved?

No. Detecting a mutation and demonstrating sufficient screening specificity are separate claims.

Broad early-detection deployment as an active research challenge.

Slide 68 · A practical interpretive checklist

Biological source

Which tumor(s) or benign conditions can produce it?

Intended role

Detection, response assessment, or recurrence monitoring?

Time context

Single sample or a serial post-treatment observation?

Corroboration

What independent clinical / pathologic evidence exists?

A disciplined checklist reduces overinterpretation of tumor-associated analytes.

Slide 69 · Core teaching conclusions

No circulating tumor marker discussed here independently establishes cancer.

Some conventional markers are valuable when followed after treatment in known tumors.

Associations are marker- and tumor-dependent, and benign elevations matter.

Cell-free DNA, circulating RNA and multi-marker assays are promising, but screening validity remains a separate requirement.

Slide 70 · Principal reference

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th edition (2026). Chapter 7, “Clinical Aspects of Neoplasia,” section “Tumor Markers,” pp. 300–301; Table 7.12.

Related context: “Laboratory Diagnosis of Cancer” (pp. 296–300) and Table 7.11 (paraneoplastic endocrine syndromes).