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    Sanyal chapter 59 Sanyal chapter 59 Document Transcript

    • 59 Tumour Markers Sabitri Sanyal 1. Write short note on the tumour markers (cancer markers). Any macromolecule (e.g. polypeptides, proteins, hormones, surface antigens, cytokines, oncogenes, gene products, etc.) when produced exclusively by cancer cells and sometimes non-exclusively by non-cancer cells but not in sufficient quantity is called the tumour marker. The tumour marker levels are directly related to the tumour mass and stage of the cancer, so baseline levels need to be measured prior to the therapeutic intervention and follow up; or follow up level by serial periodic measurements help to predict outcome of therapy. The rate of change of marker level is more important than its absolute value (50% change is considered clinically significant). The clinical application of marker study is screening, diagnosis, moni- toring treatment, detection of recurrence and prognosis of neoplastic disease process. 2. Enumerate some tumour markers with the associated malignancies. Markers Associated malignancies 1. Oncofoetal antigens (a) Alpha-fetoprotein (AFP) Hepatocellular carcinoma, non-seminomatous germ cell testicular tumour (b) Carcinoembryonic antigen (CEA) Carcinoma of colon, pancreas, lung, stomach and breast 2. Hormones (a) Human chorionic gonadotropin (HCG) Trophoblastic tumour and non-seminomatous testicular tumour (b) Calcitonin Medullary carcinoma thyroid (c) Catecholamine and metabolites Pheochromocytoma (d) Ectopic hormones (i) Adrenocorticotropin (ACTH) Small cell carcinoma of lung, pancreatic carcinoma and neural tumours (ii) Antidiuretic hormone/atrial Small cell carcinoma of lung and intracranial neoplasms natriuretic hormone (ADH/ANH) (iii) Parathyroid hormone-related Small cell carcinoma of lung, breast carcinoma, ovarian protein (PTHrp) carcinoma, renal cell carcinoma and adult T cell lymphoma (iv) Insulin Fibrosarcoma, mesenchymal sarcoma and hepatocellular carcinoma (v) Serotonin Bronchial adenoma, pancreatic and gastric carcinoma, renal cell (vi) Erythropoietin carcinoma, cerebellar haemangioma and hepatocellular carcinoma (vii) Ferritin Acute leukaemia, Hodgkin’s disease, multiple myeloma, malignant lymphoma, liver and prostatic carcinomaSanyal-Chapter 59.indd 484 4/11/2012 2:37:24 PM
    • CHAPTER 59 Tumour Markers 485 Markers Associated malignancies 3. Isoenzymes (a) Prostatic acid phosphatase (PAP) Prostate cancer (b) Neuron specific enolase Small cell carcinoma of lung and neuroblastoma 4. Specific proteins (a) Immunoglobulins Multiple myeloma and other gammopathies (b) β2 microglobulin Multiple myeloma (c) Prostate-specific Ag (PSA) Prostatic cancer (d) Thyroglobulin Differentiated thyroid cancer (e) Insulin-like growth factor binding Prostatic cancer protein 2 (IGFBP-2) 5. Mucins and glycoproteins (a) CA 125 Ovarian carcinoma (b) CA 19.9 Pancreatic and colonic carcinoma (c) CA 72.4 Gastric and colonic carcinoma (d) CA 15.3 Breast carcinoma (e) Cyfra 21.1 Lung carcinoma 6. Viruses (a) Human papilloma virus (HPV) Cervical carcinoma (b) Epstein–Barr virus (EBV) Burkitt’s lymphoma, nasopharyngeal carcinoma and some lymphoproliferative disorders 3. Enumerate the tumour markers for malignancies of the specific tissues. Cancer Marker Breast CA 15.3, CA 27.29, CEA, ER and PR, PS2, HER2/neu, P53, DNA ploidy, S phase and EGFr, BrCA gene Ovarian CA 125, CEA (for epithelial), urinary gonadotropin peptide (endometrioid), inhibin (granulosa cell T) Cervical HPV and squamous cell Ca-antigen (SCC-Ag) Trophoblastic Beta hCG Prostate PAP, PSA, DNA ploidy and IGFBP-2 Testicular AFP (yolk sac T), beta hCG, for trophoblastic cancer Urinary bladder DNA ploidy and S phase Colorectal CEA and P53 Gastric CA 72.4 and CEA Pancreatic CA 19.9, CEA, glucagon, insulin proinsulin, C-peptide, IGFBP-1 and pancreatic polypeptide Liver AFP, CEA and ferritin Lung Cyfra 21 or NSCLC and neuron specific enolase (SCLC) Thyroid Calcitonin (medullary and thyroglobulin [Differentiated thyroid Ca]) (Contd.)Sanyal-Chapter 59.indd 485 4/11/2012 2:37:24 PM
    • 486 CLINICAL PATHOLOGY A Practical Manual (Contd.) Cancer Marker Head and neck Squamous cell carcinoma antigen (SCC-Ag) Neuroblastoma N-myc oncogene, neuron specific enolase and HVA Pheochromocytoma Chromogranine A, VMA, Catecholamines and metanephrines Paraneoplastic Neuronal nuclear (Hu) antibodies, Purkinje cell (Yo) antibodies and voltage-gated syndrome calcium channel antibodies 4. Write in brief about the clinical application and importance of the following tumour markers: CEA, AFP, CA 125, CA 19.9, EGFr (epidermal growth factor receptor), Cyfra 21.1, PSA (prostate-specific antigen), UGP/UGF (urinary gonadotropin peptide/fragment), NSE (neuron specific enolase), calcitonin, CA 72.4, CA 15.3, CA 27.29, HER-2/neu or C-erb B2, PAP (prostatic acid phosphatase), ferritin, SCC-Ag (squamous cell carcinoma antigen), Ki-67 antigen, VIP (vasoactive intestinal polypeptide), ER and PR (oestrogen receptor and progesterone receptor), HNPCC syndrome (genes involved in DNA mismatch repair). (a) CEA (carcinoembryonic antigen): CEA is a reliable tumour marker (TM) for prognostica- tion of the diagnosed cases of colorectal Ca and monitoring the treatment of metastatic breast carcinoma. The elevated level of this TM correlate well with the tumour mass and presence of elevated level of CEA at 6 weeks after therapy indicates residual mass. Recurrence is indicated by a rising CEA level. The elevated CEA levels have been reported in benign disorders like alcoholic cirrhosis, hepatitis, ulcerative colitis, Crohn’s disease and occasionally in healthy smokers. So, the elevated levels have little significance in diagnosis of unknown carcinoma. (b) AFP (alpha-fetoprotein): It is one of the best known and most used oncofoetal antigen and tumour marker. The elevated level is used in the diagnosis and monitoring of the treatment of primary hepatocellular CA and germ cell testicular tumour, e.g. yolk sac tumour. Seminomas are negative of AFP. AFP levels rapidly decline after surgical removal or treatment of liver CA or germ cell tumour. However, the elevated levels have been noticed in non-neoplastic conditions like cirrhosis, massive liver necrosis and chronic hepatitis. Also CA of colon, lung and pancreas may lead to elevated levels. AFP is also important in prenatal diagnosis of neural tube defect like spina bifida and Down’s syndrome showing pathological value during 15th to 20th week of pregnancy. (c) CA 125 (cancer antigen 125): The cell surface, glycoprotein is a reliable TM for already diagnosed ovarian carcinoma for prognostication and follow up. The CA 125 is elevated in cases of adenocarcinoma of cervix, endometrium, GI tract, breast, certain benign ovarian tumour, endometriosis, adenomyosis, fibroids and acute salpingitis. So, diagnostic value of this test is limited. (d) CA 19.9: This protein-bound carbohydrate antigen present on the cell surface of carci- noma cells or secreted by the CA cells is a helpful TM for already diagnosed pancreaticSanyal-Chapter 59.indd 486 4/11/2012 2:37:24 PM
    • CHAPTER 59 Tumour Markers 487 carcinoma for monitoring treatment by serial determinations of elevated levels. This is also elevated in adenocarcinoma of stomach, bile duct, colon, lungs and breast. The main application of this marker is to predict operability of pancreatic carcinoma, i.e. CA 19.9 values of < 1000 U/mL will have a tumour of < 5 cm in diameter is resect- able. Combined use of CA 19.9 and CEA increases the sensitivity, specificity and pre- dictability of monitoring pancreatic CA treatment. (e) EGFr (epidermal growth factor receptor): It is a transmembrane receptor which is respon- sible for regulation of the growth of breast tumour. This is located in the cytoplasm of breast tumour cells. This is used as a prognostic marker in breast carcinoma in patients with axiliary node negative breast cancer where EGFr positivity indicate shorter disease-free interval. (f) Cyfra 21.1: Cyfra 21.1 is a cytokeratin fragment 19 expressed by simple or pseudostrati- fied epithelial layer of bronchial tree. This test is useful in therapeutic monitoring and in detection of recurrences in lung carcinoma (non-small cell type, e.g. squamous cell cancer, large cell cancer and adenoma). Cyfra 21.1 levels correlate with the stages of the disease and thus help in tumour staging. It is a better prognostic marker for lung cancers as compared with marker like CEA and SCC. (g) PSA (prostate-specific antigen): It is a cytoplasmic glycoprotein specific to prostate epi- thelial cells; thus a reliable TM for already diagnosed prostatic cancer. This test is mainly useful to monitor post-operative recurrences, after prostatectomy following carcinoma. False positive cases have been recorded in BHP, after prostatic massage, following cystoscopy, needle biopsy or transurethral resection. PSA may be lowered after or during therapy for BHP. Three major fractions of PSA have been identified: (i) Free PSA: This is about 5–50% of total PSA in serum; this is used to differentiate cases of prostate cancer from BHP. Free PSA to total PSA ratio is > 25% in BHP and when < 16% then it is cancer. (ii) PSA bound antichymotrypsin (PSA-ACT): It is about 50–95% of the total PSA in serum. The total PSA is being measured by commercial assays. (iii) PSA bound to alpha-2-macroglobulin (PSA-MG): The test is not yet available. (h) UGP/UGF (urinary gonadotropin peptide/fragment): Human chorionic gonadotropin (hCG) has two subunits—alpha and beta. Beta subunit is unique and its degradation product urinary gonadotropin peptide (UGP) is a tumour marker for endometrioid type of ovarian cancer. This test is useful as an adjunct to CA 125 for monitoring recurrences of ovarian carcinoma after operative removal. It is also positive in some cases of bronchogenic carcinoma, oesophageal carcinoma and lymphoma. False positive cases have been reported in cases with endometriosis and leiomyoma of uteri. (i) NSE (neuron specific enolase): The estimation of NSE is done as marker of small cell lung cancer (SCLC) and neuroblastoma and thus useful in differentiating SCLC from NSCLC and for follow up of neuroblastoma cases. In all organic neurologic pathologies elevated levels of NSE have been seen. However, to a lesser extent NSE elevation has been noted in medullary carcinoma of thyroid, pancreatic islet cell tumour, pheochromocytoma and carcinoid.Sanyal-Chapter 59.indd 487 4/11/2012 2:37:24 PM
    • 488 CLINICAL PATHOLOGY A Practical Manual (j) Calcitonin: This is a marker of choice for early diagnosis of medullary carcinoma of thyroid as well as in follow up of such cases; high concentration, post-surgery, indi- cates incomplete removal or metastasis. This is also used for screening the high-risk group with family history of medullary carcinoma and multiple endocrine neoplasias. Non-specific increases have been noted in SCLC, Apudomas, chronic renal failure, hyperparathyroidism and Paget’s disease of bone. (k) CA 72.4: The elevated levels of this tumour marker together with CEA are recom- mended for follow up of patients with already diagnosed gastric carcinoma. Together with CA 125, this test helps in management of ovarian carcinoma. To a lesser extent, elevated levels are also seen in other lower GI malignancies, some non-malignant conditions, e.g. ulcerative colitis, Crohn’s disease, gastric dyspla- sia and intestinal metaplasia. (l) CA 15.3: This protein-bound carbohydrate antigen is present on the cell surface or secreted by the carcinoma cells; is used as a valuable marker for already diagnosed breast carcinoma. Combined use of CA 15.3 and CEA increases the sensitivity, specific- ity of the follow up cases of breast carcinoma. Since genetic predisposition of breast carcinoma is a proven entity, CA 15.3 screening is recommended in all women with family history of breast carcinoma. Elevation of the level of CA 15.3 to a lesser extent is noted in carcinoma of ovary, stomach and pancreas. (m) CA 27.29: This is a newer marker for the breast carcinoma, but exact clinical signifi- cance is yet to be established. (n) HER-2/neu or C-erbB2: This is an oncogene encoding growth factor receptor related to epidermal growth factor/receptor. HER-2/neu over expression is a phenotypic marker of comedo carcinoma of breast and also is associated with higher proliferative rate, early local recurrences and micro- invasion; can also be used to identify patients for administration of adjuvant chemotherapy. (o) PAP (prostatic acid phosphatase): The estimation of this PAP is usually used with PSA level estimation. This is less sensitive in early stages of prostatic cancer. However, this is highly specific for prostatic carcinoma because it is seldom posi- tive with pure BHP. (p) Ferritin: Elevated ferritin levels have been detected in haemopoietic malignancies, car- cinomas of breast, liver, colorectum and prostate. The causes of elevated levels in these malignancies may be due to cell necrosis, blocked erythropoiesis, inflammation or production by tumour tissue. But the use of this a tumour marker is limited. The clinical importance of ferritin detection in blood lies in diagnosis of iron metab- olism disorders, to detect iron overload, in thalassaemia to regulate chelatin therapy; in differentiating true iron deficiency from various anaemias of chronic diseases, also to monitor oral iron therapy for iron deficiency anaemia and therapeutic phlebotomy for iron overload patients.Sanyal-Chapter 59.indd 488 4/11/2012 2:37:24 PM
    • CHAPTER 59 Tumour Markers 489 (q) SCC-Ag (squamous cell carcinoma antigen): SCC antigen has been extracted from squa- mous cell carcinoma tissue of cervix. This is localised in the cytoplasm of squamous cells. Squamous cells of head neck and uterus also show positivity. The detection of elevated level and its serial determination is useful in patients with cervical carcinoma during therapy and for monitoring the treatment of squamous cell carcinoma of head and neck, lung, oesophagous, anal canal, etc. The serum concentration of SCC is high- est in cases with metastasis. (r) Ki-67 antigen: This is an S-phase fraction-related antigen which is a proliferative marker. This can be detected by monoclonal antibodies and do not require flow cytom- etry technique as is required for S-phase related antigen. This is used to establish growth fraction of the tumour cells determined by the number of the positive tumour cells among the total number of cells and calculated as index. The index correlates well with the histological grading of the neoplasms. Low-grade lymphomas will show Ki-67 index of > 20–25%, will have a more aggressive course and among intermediate and high grade lymphomas Ki-67 index of > 60% indicates poorer survival. (s) VIP (vasoactive intestinal polypeptide): Neural stimulation produces a peptide known as VIP, which has biological effect on cardiovascular, gastrointestinal and respiratory system. The effects include increased secretion of bicarbonate and electrolytes and decreased absorption of electrolytes and water. The increased levels of VIP is seen in VIPomas and watery diarrhoea syndrome. VIPomas are part of multiple endocrine neoplasia (MEN) syndrome Type I and secrete VIP. Watery diarrhoea syndrome with elevated VIP level has been associated with neurogenic tumours like ganglioneuroma, neuroblastoma and pheochromocytoma as well as certain bronchogenic tumour and islet cell hyperplasia. (t) ER and PR (oestrogen receptor and progesterone receptor): Measurements of ER and PR in breast carcinoma tissue by immunochemistry or flow cytometry are important in patient management. The presence of significant levels predict responsiveness to hor- mone therapy. Oestrogen receptors (ER) are distributed in the breast and throughout the female genital tract cell and nucleus. ER is mostly distributed in the epithelial cells of breast and female genital tract and to a lesser extent in the stromal cells, lamina propria and muscularis mucosae. The distribution of ER is independent of menopausal status and stage of menstrual cycle. The presence of ER is of good prognostic significance in breast cases because this indicates responsiveness to hormone therapy. Progesterone receptor (PR) is also located in the nucleus. PR regulates cell prolif- eration and differentiation. The expression of PR is regulated by ER. Like ER, PR is also distributed in the normal tissues of breast and female genital tract. Differential expression of ER and PR is seen in cycling endometrium. Stromal cells stain intensely for PR and not for ER during late secretory phase; in post-menopausal endometrium PR is restricted to epithelial cells but ER is expressed by both stromal and epithelial cells.Sanyal-Chapter 59.indd 489 4/11/2012 2:37:24 PM
    • 490 CLINICAL PATHOLOGY A Practical Manual (u) Intermediate filaments: Certain normal constituent of the cell cytoplasm may be identi- fied by immunochemistry and thus utilising this technique on those particular specific antigens, tumours of uncertain origin or undifferentiated tumours can be identified. These are intermediate filaments, e.g. keratin expression in epithelial cells, desmin expression in mesenchymal myogenic cells, vimentin expression in mesenchymal non-myogenic cells, neurofilament expression in neural cells and glial fibrillary acidic protein expression in glial cells. Thus, the following tumours are known to have the expression of the following intermediate filaments: Intermediate filament Neoplasia Keratin All carcinomas, mesotheliomas, chordoma, non-seminomatous germ cell tumours, synovial sarcoma and epithelioid sarcoma Vimentin Mesenchymal non-myogenic neoplasms, malignant melanoma, malignant lymphoma and malignant fibrous histiocytoma Desmin Leiomyosarcoma and rhabdomyosarcoma Glial acidic fibrillary protein (GAFP) Astrocytoma, ependymoma and medulloblastoma Neurofilament Neuroblastoma, ganglioneuroma, ganglioneuroblastoma, pheochromocytoma, paraganglioma, pulmonary small cell carcinoma and Markel cell tumour Leucocyte common antigen Malignancies originated from bone marrow progenitor cells, (not intermediate filament) lymphocytes, monocytes, granulocytes, erythroid precursors, (LCA, CD 45) megakaryocytes, mast cells, etc. Also differentiates reactive hyperplasia of lymph node and malignant lymphoma, differentiates undifferentiated carcinoma and melanoma from lymphoma (v) BrCA gene: BrCA tumour suppressor genes are used as tumour markers for screening and identification of high-risk families with hereditary breast cancer. Two genes have been identified, mainly BrCA1 and BrCA2. Mutation in BrCA1 is responsible for 50% of all inherited breast cancer cases. BrCA2 mutations accounts for 70% of those cases of breast cancers which are not caused by BrCA1 gene. This BrCA gene is also respon- sible for increased risk of breast cancers in men. Thus, the genetic testing for the pres- ence of BrCA gene can identify the population at high risk for breast cancer. With germ line mutation of BrCA1 gene, there is additional risk of epithelial cancer of ovary, pros- tate and colon cancer. Mutation of BrCA2 gene increases the risk of developing cancer of male breast, ovary, pancreas and larynx. BrCA1 gene is located on chromosome 12 and BrCA2 gene on chromosome 13; functions of these two genes are transcription regulation. (w) HNPCC (hereditary non-polyposis colon cancer syndrome genes): This hereditary non- polyposis cancer syndrome disorder is characterised by familial carcinomas of colon affecting predominantly the caecum and proximal colon. HNPCC results from defects in genes involved in DNA mismatch repair. Cells with defects in DNA repair haveSanyal-Chapter 59.indd 490 4/11/2012 2:37:24 PM
    • CHAPTER 59 Tumour Markers 491 error (RER) phenotype which can be detected by examining microsatellites sequences in the tumour cell DNA. Microsatellite instability is a hallmark of defective mismatch repair. Germline mutation in alpha MSH2 (2p16) gene account for tumour development in 50% of the sufferer with HNPCC. In 30% HNPCC cases, the mutation affects the alpha MLHI gene on chromosome 3p21. The remaining 20% of HNPCC cases have mutation in alpha PMS1 and alpha PMS2 and other mutation repair gene. Each affected individual inherit one defective copy of one of several DNA mismatch repair gene and acquires the second hit in the colonic epithelial cells. As mutations occur more rapidly in the patients with HNPCC, the evolution of tumour occurs more rapidly and cancers developing at a much younger age group (< 50 years) than those who have no defect in DNA repair genes.Sanyal-Chapter 59.indd 491 4/11/2012 2:37:24 PM