Laboratory diagnosis of cancer section Robbins based md pathology exam answer
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NCI tumor markers laboratory tests cancer diagnosis biomarkers fact sheet
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Laboratory Diagnosis of Cancer
Laboratory diagnosis of cancer requires integration of clinical and radiologic findings with morphologic, immunophenotypic, cytogenetic, and molecular investigations. The diagnostic value depends greatly on an adequate, representative, and properly preserved specimen.
Robbins & Kumar Basic Pathology, pp. 227-229.
Robbins & Kumar Basic Pathology, pp. 227-229.
1. Morphologic methods
A. Histopathology
- Biopsy or excision followed by routine histologic examination is the diagnostic gold standard for most solid tumors.
- It establishes:
- Benign versus malignant nature
- Histologic type and tissue of origin
- Degree of differentiation
- Tumor grade
- Local invasion, lymphovascular invasion, surgical margins, and nodal metastasis
- Tissue is usually fixed in formalin, processed, and stained with hematoxylin and eosin (H&E).
B. Frozen section
- Fresh tissue is rapidly frozen, sectioned, stained, and examined during surgery.
- Main uses:
- Determine whether a lesion is malignant
- Assess resection margins
- Detect lymph-node metastasis
- Guide immediate operative decisions
- Limitation: permanent paraffin sections provide better morphologic detail; uncertain frozen-section diagnoses should await routine processing.
C. Cytology
Examination of exfoliated or aspirated cells for cytologic features of malignancy, especially:
- Pleomorphism
- Hyperchromatic enlarged nuclei
- Increased nuclear-cytoplasmic ratio
- Irregular nuclear membrane
- Prominent nucleoli
- Abnormal mitoses
Types:
-
Exfoliative cytology
- Papanicolaou smear for cervical precancer and carcinoma
- Cytology of sputum, urine, bronchial washings, body cavity fluids, and cerebrospinal fluid.
-
Fine-needle aspiration cytology (FNAC)
- A minimally invasive method for palpable masses in breast, thyroid, lymph nodes, salivary gland, etc.
- Image-guided FNAC can sample deep lesions in liver, pancreas, or pelvic nodes.
- Limitation: small sample size and sampling error; assessment of tissue architecture may be limited.
2. Immunohistochemistry (IHC)
IHC uses antibodies against cellular antigens to identify the lineage, differentiation, origin, and biologic properties of tumor cells.
Uses
- Distinguish poorly differentiated carcinoma from lymphoma, melanoma, or sarcoma.
- Determine primary site of a metastatic tumor.
- Classify lymphomas and leukemias.
- Identify prognostic and predictive markers.
Important examples
| Marker | Diagnostic significance |
|---|---|
| Cytokeratin | Epithelial origin, carcinoma |
| Vimentin | Mesenchymal tumors, though nonspecific |
| Desmin, myogenin | Muscle differentiation |
| LCA/CD45 | Leukocyte origin, lymphoma |
| CD3, CD20 | T-cell and B-cell lineage |
| S-100, SOX10, HMB-45, Melan-A | Melanoma |
| PSA, PSAP, NKX3.1 | Prostatic origin |
| TTF-1 | Lung adenocarcinoma or thyroid origin |
| ER, PR, HER2 | Prognosis and treatment selection in breast carcinoma |
| Ki-67 | Proliferative activity and grading support |
Thus, IHC is particularly useful in undifferentiated malignancies and metastatic tumors of unknown primary site.
Robbins & Kumar Basic Pathology, pp. 227-228.
Robbins & Kumar Basic Pathology, pp. 227-228.
3. Flow cytometry
Flow cytometry detects cell-surface and intracellular antigens in suspended cells using fluorescent antibodies.
Major applications
- Diagnosis and classification of acute leukemias
- Immunophenotyping of non-Hodgkin lymphomas
- Detection of clonality, such as light-chain restriction in B-cell neoplasms
- Detection of minimal residual disease after therapy
It rapidly identifies multiple antigens simultaneously, for example CD34, TdT, CD3, CD19, CD10, CD20, CD5, CD23, and myeloid markers.
4. Tumor markers
Tumor markers are substances produced by tumor cells or by host tissues in response to the tumor. They may be found in blood, urine, tissue, or other body fluids.
Uses of tumor markers
- Support diagnosis in an appropriate clinical setting
- Estimate tumor burden
- Assess prognosis
- Predict response to targeted therapy
- Monitor response to treatment
- Detect recurrence or residual tumor
Important serum tumor markers
| Tumor marker | Important association/use |
|---|---|
| PSA | Prostate carcinoma; monitoring treatment and recurrence |
| AFP | Hepatocellular carcinoma; nonseminomatous germ-cell tumors |
| β-hCG | Choriocarcinoma and testicular germ-cell tumors |
| CEA | Colorectal carcinoma and some other adenocarcinomas; mainly monitoring |
| CA-125 | Epithelial ovarian carcinoma; monitoring response/recurrence |
| CA 19-9 | Pancreatic and biliary tract carcinomas; monitoring |
| Calcitonin | Medullary thyroid carcinoma |
| Thyroglobulin | Follow-up of differentiated thyroid carcinoma |
| Monoclonal immunoglobulin | Multiple myeloma and other plasma-cell neoplasms |
| Chromogranin A | Neuroendocrine tumors, with important limitations |
Limitations
- Most tumor markers are neither sufficiently sensitive nor specific for population screening.
- They can be elevated in benign conditions, inflammation, pregnancy, smoking, or organ dysfunction.
- A normal marker level does not exclude malignancy.
- Therefore, markers generally do not establish a diagnosis alone and are most useful for serial monitoring after the tumor type is already known.
Robbins emphasizes that serum proteins such as PSA are valuable in post-treatment surveillance but problematic screening tests because of limited sensitivity and specificity. Robbins & Kumar Basic Pathology, p. 228. This is consistent with the NCI tumor-marker guidance, which describes their main roles in diagnosis support, treatment selection, response assessment, and recurrence monitoring.
5. Molecular diagnosis of cancer
Molecular tests identify genetic and epigenetic abnormalities in tumors. Methods include:
- Conventional cytogenetics or karyotyping
- Fluorescence in situ hybridization (FISH)
- Polymerase chain reaction (PCR), including RT-PCR
- DNA sequencing, including next-generation sequencing
- Gene-expression profiling
- DNA copy-number analysis
- Methylation studies
Applications
A. Diagnosis and classification
Certain genetic abnormalities define particular tumors.
Examples:
- BCR::ABL1 fusion: chronic myeloid leukemia
- PML::RARA fusion: acute promyelocytic leukemia
- MYC translocation: Burkitt lymphoma
- EWSR1 rearrangement: Ewing sarcoma
- IDH mutations and 1p/19q codeletion: classification of diffuse gliomas
B. Prognosis
Genetic changes can predict outcome:
- MYCN amplification in neuroblastoma indicates poor prognosis.
- Specific cytogenetic and molecular abnormalities stratify acute leukemias.
- Gene-expression signatures can stratify breast cancers.
C. Selection of targeted therapy
Identification of actionable molecular alterations permits personalized treatment.
Examples:
- ERBB2/HER2 amplification: anti-HER2 therapy in breast and gastric carcinoma
- EGFR mutations, ALK and ROS1 rearrangements: targeted therapy in lung adenocarcinoma
- BCR::ABL1: tyrosine kinase inhibitors in CML
- BRAF mutation: melanoma and selected other tumors
- KRAS/NRAS mutation testing: predicts lack of response to anti-EGFR therapy in colorectal carcinoma
- BRCA1/BRCA2 defects: PARP inhibitor sensitivity in selected cancers
D. Detection of minimal residual disease
Highly sensitive PCR or sequencing-based tests can detect small numbers of residual malignant cells after therapy, especially in leukemias and lymphomas.
E. Identification of inherited cancer predisposition
Testing may detect germline mutations in:
- BRCA1 and BRCA2
- APC
- TP53
- Mismatch-repair genes: MLH1, MSH2, MSH6, PMS2
- RET
This permits surveillance, genetic counseling, and preventive strategies for patients and families.
6. Molecular profiling and liquid biopsy
Molecular profiling assesses multiple mutations, copy-number changes, gene-expression patterns, or mutational signatures in a tumor. It can:
- Refine tumor classification
- Predict prognosis
- Identify therapeutic targets
- Recognize tumors of different origin that share targetable mutations
Liquid biopsy detects tumor-derived material in blood or other body fluids, particularly:
- Circulating tumor cells
- Circulating cell-free tumor DNA
- Tumor DNA in stool, sputum, or urine
Potential roles include detecting actionable mutations, monitoring response, identifying emerging resistance, and detecting minimal residual disease. These methods are useful adjuncts but do not replace conventional tissue diagnosis in many settings. Biomarker results also represent only a time-specific sample of a genetically heterogeneous tumor, as noted in NCI biomarker testing information.
Conclusion
The laboratory diagnosis of cancer begins with adequate tissue sampling and morphology. Histopathology, cytology, IHC, and flow cytometry establish the diagnosis and classify tumors. Tumor markers are chiefly useful for monitoring rather than screening. Molecular testing and tumor profiling increasingly guide diagnosis, prognostication, detection of residual disease, recognition of hereditary predisposition, and targeted therapy selection.
Robbins key concept: IHC and flow cytometry classify tumors by protein-expression patterns, while molecular analysis assists diagnosis, prognosis, minimal-residual-disease detection, hereditary cancer assessment, and targeted therapy selection.
Robbins & Kumar Basic Pathology, pp. 227-229.
Robbins & Kumar Basic Pathology, pp. 227-229.
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