Q5 LONG ANSWER 10M ★ High-yield

Describe the laboratory methods used in the diagnosis of cancer. Explain grading and staging and add a note on paraneoplastic syndromes.

Pathology · 2nd Professional — Para-Clinical

Laboratory Diagnosis of Cancer

Method	What it provides	Limitations
Histopathology (biopsy)	The gold standard — architecture, invasion, grade and margins	Invasive; needs adequate and representative tissue
Frozen section	Rapid answer during surgery — malignancy and margin status	Lower resolution; not for definitive typing
Cytology — exfoliative	Pap smear, sputum, urine, effusions; cheap and suitable for screening	Shows cells only, not invasion — cannot distinguish in situ from invasive disease
Fine needle aspiration cytology	Quick, cheap, minimally invasive; excellent for breast, thyroid, node and salivary lesions	Cannot assess capsular invasion — so it cannot separate follicular adenoma from carcinoma
Immunohistochemistry	Tissue of origin; receptor status; prognostic markers	Requires appropriate antibody panels
Flow cytometry	Immunophenotyping of leukaemias and lymphomas	Needs fresh cells in suspension
Molecular and cytogenetic	Translocations, mutations, gene amplification; guides targeted therapy	Cost and availability
Tumour markers	Monitoring response and detecting recurrence	Rarely diagnostic; poor specificity

Immunohistochemical markers of origin

Marker	Identifies
Cytokeratin	Epithelium — carcinoma
Vimentin	Mesenchyme — sarcoma
Desmin	Muscle
S-100 and HMB-45	Melanoma
Leucocyte common antigen (CD45)	Lymphoma
Chromogranin, synaptophysin	Neuroendocrine tumours
Glial fibrillary acidic protein	Glioma
Thyroglobulin, TTF-1	Thyroid; lung adenocarcinoma

Grading

Grade describes the degree of differentiation of the tumour cells, judged on histology.

Broders classification — grades I to IV, from well differentiated to anaplastic
Assessed from differentiation, nuclear pleomorphism and mitotic count
Modern systems are organ-specific — the Gleason score for prostate, the Nottingham (Bloom–Richardson) grade for breast
Grading is subjective and varies between observers, which limits its value compared with stage

Staging

Stage describes the extent of spread of the tumour, judged clinically, radiologically and pathologically.

Component	Meaning
T	Size and local extent of the primary tumour (T1–T4; Tis for carcinoma in situ)
N	Regional lymph node involvement (N0–N3)
M	Distant metastasis (M0 or M1)

The AJCC/UICC TNM system is the international standard; the Dukes classification for colorectal and FIGO for gynaecological cancers remain in use
"p" prefix (pTNM) indicates pathological staging after resection; "c" indicates clinical

CLINICAL PEARL

Stage matters far more than grade. For almost every solid tumour the extent of spread predicts survival better than how the cells look, and it determines whether treatment is curative or palliative. Stage is also more objective and more reproducible. When the two conflict, act on the stage.

Paraneoplastic Syndromes

Symptom complexes in a patient with cancer that cannot be explained by the local or metastatic spread of the tumour, nor by the hormones normally produced by its tissue of origin.

Syndrome	Mechanism	Commonest tumour
Hypercalcaemia	PTH-related peptide	Squamous cell carcinoma of lung; breast; renal; myeloma (by osteolysis)
Cushing syndrome	Ectopic ACTH	Small cell carcinoma of lung
SIADH	Ectopic ADH	Small cell carcinoma of lung
Polycythaemia	Ectopic erythropoietin	Renal cell carcinoma, hepatocellular carcinoma, cerebellar haemangioblastoma
Hypoglycaemia	Insulin-like growth factor 2	Hepatocellular carcinoma; large mesenchymal tumours
Lambert–EATON syndrome	Antibodies to presynaptic calcium channels	Small cell carcinoma of lung
Acanthosis nigricans	Growth factors	Gastric adenocarcinoma
Trousseau sign (migratory thrombophlebitis)	Mucin and tissue factor release	Pancreatic carcinoma
Hypertrophic osteoarthropathy and clubbing	Unknown	Bronchogenic carcinoma
Dermatomyositis	Autoimmune	Ovarian, lung, gastric

They occur in about 10–15% of patients with cancer, and may be the earliest manifestation of an occult tumour
They can be the cause of death in their own right — severe hypercalcaemia being the commonest

Cancer Cachexia

Progressive loss of body fat and lean muscle mass with profound weakness and anorexia
Not simply due to reduced intake or to tumour consumption of nutrients
Mediated by TNF (originally called cachectin), IL-1, IL-6 and proteolysis-inducing factor, which raise the basal metabolic rate and drive catabolism
Nutritional supplementation alone does not reverse it, which distinguishes it from simple starvation

Applied Aspects

Tumour markers are for monitoring, not diagnosis — a rising marker after treatment indicates recurrence, but a raised marker alone never establishes a diagnosis. The exceptions are AFP and hCG in germ cell tumours, where levels are used for diagnosis, staging and monitoring
Common markers — AFP (hepatocellular, germ cell), CEA (colorectal), CA-125 (ovarian), CA 19-9 (pancreatic), PSA (prostate), hCG (choriocarcinoma), calcitonin (medullary thyroid)
Screening is justified only where the disease is common, detectable early, and treatable — cervical, breast and colorectal cancer meet these criteria; cervical screening is the most important in India and remains badly underused
The multidisciplinary team meeting combines pathology, radiology, surgery and oncology, and is now the standard means of deciding treatment
An unexplained paraneoplastic syndrome should prompt a search for a primary — recognising it early can lead to a curable diagnosis

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