Basic pathology

1. TUMOUR MARKERS AND
CLINICAL EFFECTS OF CANCER

2. Outline
Objectives
Introduction
Clinical uses of tumour markers
Ideal tumour markers
Classification of tumour markers
Local effects of tumours on host
Systemic effect of tumours on host
References

3. Objectives
At the end of the session, students will be able to:
Explain what are tumor markers
Describe the ideal characteristics of a tumor markers
Describe the Classification of tumor markers
Understand the role of tumor markers for therapeutic selection
(diagnosis and management of cancer)
Describe the clinical effects of cancer on the host

4. Introduction
• Tumor markers are biochemical substances produced by the tumor
itself or produced by the host in response to a tumor.
• They are biochemical indicators of a presence of a tumor .
• A molecule, a process or substance that can be altered quantitively or
qualitatively in precancerous or cancerous conditions, the alteration
being detectable by an assay.

5. Clinical uses of tumor markers
• Determine risk (PSA)
• Screen for early cancer (calcitonin, occult blood)
• Diagnose a type of cancer (hCG, catecholamines)
• Estimate prognosis (CA125)
• Predict response to therapy (CA15-3, CA125, PSA, hCG)
• Monitor for disease recurrence or progression (most widely used
function)
• Therapeutic selection (her2/neu, kras)

6. Ideal tumor marker
1. Be highly sensitive and specific to a tumor.
2. Level should change in response to tumor size.
3. An abnormal level should be obtained in presence of micro
metastasis.

7. Ideal tumor marker
4. The level should not have large fluctuations that are independent of
changes in tumor size.
5. Differentiate between neoplastic and non neoplastic diseases.
6. Cheap and simple so as to be applicable as a screening tool.

8. Ideal tumor marker
7. Levels in health individuals are at much lower concentrations than
those found in cancer patients.
8. Predict recurrences before they are clinically detectable.
9. Levels should be preceding the neoplastic process

9. Ideal tumor marker
10. Easily assayable and able to indicate all changes in cancer patients
receiving treatment
“In reality Ideal tumor marker does not exist!!!’’

10. Sensitivity and specificity of screening test
Sensitivity
The likelihood that given the presence of disease, an abnormal test result
predicts the disease. (the ability to identify the true cases of a particular
cancer type)
No/few false negatives
Specificity
The likelihood that given the absence of disease, a normal test result excludes
disease. (the ability not to identify people as having a particular cancer type
when they do not have it)
No/few false positives

11. CLASSIFICATION OF TUMOR
MARKERS

12. E
O
H
L
D
M
Hold Me
Hormones
Oncofetal antigens
Lineage specific proteins
DNA makers cell-free
Mucins & other glucoproteins
Enzymes
Tumor Makers

13. L Iineage specific proteins
H Hormones
O Oncofetal antigens
D DNA makers cell-free
E Enzymes
Tumor Marker Classification
M Mucins & other glucoproteins
In some cancers, hormone level or hormone
receptors can be used as diagnostic or prognostic
indicators.
Human Chorionic gonadotrophins
Trophoblastic tumors.
Calcitonin medullary carcinoma, Thyroid
Catecholamines, pheochromocytoma

14. A)Calcitonin:
Used as a marker in medullary thyroid tumors
High levels of calcitonin also reported in paraneoplastic syndromes like
bronchogenic carcinoma, small cell lung cancer, breast, liver, renal cancers
and in malignancies with skeletal metastases.
It is also useful for monitoring treatment and detecting the recurrence of
cancer.
H Hormones / Eg

15. b) Human Chorionic Gonadotropin (hCG):
Is a marker of germ cell tumors and trophoblastic disease
HCG shows 100 % sensitivity for choriocarcinoma irrespective of their
site and also to hydatidiform mole
In testicular tumors, the detection of HCG together with AFP correlates
with the histological findings
The reference values in serum of healthy men and non-pregnant women
are <5 IU/ml and post-menopausal women are <10 IU/ml
High levels indicate poor prognosis
H Hormones /Eg

16. C) Estrogen and Progesterone Receptors:
Marker for breast cancer
Cancer cells with estrogen or progesterone receptors depend on these
hormones to grow.
Helps in determining risk of occurrence and whether cancer can be treated
with hormonal therapy
Hormonal therapy blocks ER POSTIVE/PR POSITIVE from using estrogen and
progesterone respectively hence slow tumor growth.
H Hormones/RECEPTOR MARKERS

17. D) HER-2/neu:
Is human epidermal growth factor receptor.
Is used to predict response of breast tumors in chemotherapy.
Herceptin (trastuzumab) is a humanized monoclonal antibody that binds to
Her2/neu and inhibits activation of the receptor.
Consequently breast tissue that is positive for Her2/neu are candidates for
Herceptin therapy
H Hormones/RECEPTOR MARKERS

18. L Iineage specific proteins
H Hormones
O Oncofetal antigens
D DNA makers cell-free
E Enzymes
Tumor Marker Classification
M Mucins & other glucoproteins
Normally expressed during fetal development but
absent/ low expression in health adult tissues.
Can be reactivate and expressed at higher level in
some cancers!
Alpha fetal Protein (AFP), Liver cancer
nonseminomatous germ
cell tumor of testis
Carcino embryonic antigen (CEA), Carcinoma of
colon,lungs, stomach,
pancreas and heart.

19. (a)α-Fetoprotein.
Detected in serum
Marker for Hepatocellular carcinoma and yolk sac tumor
Secreted by fetal liver, yolk sac and lesser extent in GI, crosses
placenta hence can be detected in maternal blood.
High from GA of 10-12th week and peaks at 30-32 weeks and sudden
drop noted soon before term.
O Oncofetal antigens

20. (a)α-Fetoprotein.
Normal levels in adults is usually <15 ng/mL.
In pregnant women, fetal AFP levels can be more than 500ng/ml.
AFP is relevant for prenatal diagnosis of spina bifida, anencephaly,
atresia of esophagus and multiple pregnancy not used in prenatal
diagnosis of genetic conditions.
O Oncofetal antigens

21. (b) Carcinoembryonic antigen (CEA)
It is a glycoprotein in nature
 a marker for colorectal carcinoma, also raised in gastric carcinoma,
pancreatic carcinoma, lung carcinoma, breast carcinoma and medullary
thyroid carcinoma
CEA also raised in heavy smokers, hepatitis, cirrhosis, pancreatitis and
gastritis.
is useful for staging and monitoring therapy and relapse after tumour
resection through periodic post operative analysis.
O Oncofetal antigens

22. L Iineage specific proteins
H Hormones
O Oncofetal antigens
D DNA makers cell-free
E Enzymes
Tumor Marker Classification
M Mucins & other glucoproteins
Also known as Lineage-specific antigens, are
proteins that are expressed in a cell lineage or
cell Type-specific manner.
Useful in identifying the tissue of origin for
metastatic cancers, where the primary site of
the tumor is unknown.
Eg: PSA, M Protein ( immunoglobilin)

23. L Iineage specific proteins
a) Prostate Specific Antigen (PSA) [serum]:
Glycoprotein secreted by prostatic acinar and ductal cells
It is essentially organ specific and not cancer specific.
Normal levels in the serum of men are 0 – 4 ng/ml
 Benign conditions: Can be elevated in BPH, prostatitis, colonoscopy
procedure, prostate massage, recent ejaculation.

24. L Lineage specific proteins
a) Prostate Specific Antigen (PSA) [serum]:
Malignancy: elevated in prostatic cancer
PSA is used to monitor treatment of Prostate CA
 PSA combined with digital rectal examination (DRE), Trans-rectal
ultrasound (TRUS) proves very useful in identifying early and curable
adenocarcinoma prostate. (Malati et. al. 2003).

25. L Iineage specific proteins
b) β2-microglobulin:
Globulin
Is a marker for multiple myeloma and Hodgkin lymphoma.
It also increases in chronic inflammation and viral hepatitis.
Prognostic indicator
Patients with higher levels of B2M usually have a poorer prognosis

26. L Iineage specific proteins
C) Ferritin
Is a marker for Hodgkin lymphoma, leukemia, liver, lung and
breast cancer.

27. L Iineage specific proteins
D) Thyroglubulin:
Tissue specific glycoprotein produced by thyroid follicular cells
Normal <60ug/L
Is a useful marker for detection of differentiated thyroid cancer.
Also increased in breast or lung cancer

28. L Iineage specific proteins
H Hormones
O Oncofetal antigens
D DNA makers cell-free
E Enzymes
Tumor Marker Classification
M Mucins & other glucoproteins
Also Known as Circulating Tumor DNA Makers,
Specific genetic alterations or mutation found in cell
free DNA fragments that circulate in the bloodstream.
Represent in promising field in cancer research.
Eg: EGFR mutations: Non-small Cell lung cancer
(Epidermal Growth Factors Receptors) .
KRAS mutation: Colorectal cancer and
pancreatic cancer
BRAF V600E mutations: melanoma and
papillary thyroid cancer

29. L Iineage specific proteins
H Hormones
O Oncofetal antigens
D DNA makers cell-free
E Enzymes
Tumor Marker Classification
M Mucins & other glucoproteins
Gycoproteins are involved in several cellular
functions, and play a role in cellular adhesions ,
signaling and immune response.
Altered expression or modification of those
glycoproteins can occur in cancer cells.
CA-125 Ovarian cancer
CA19-9 colorectal cancer and
pancreatic cancer
CA15-3 Breast cancer

30. L Iineage specific proteins
H Hormones
O Oncofetal antigens
D DNA makers cell-free
E Enzymes
Tumor Marker Classification
M Mucins & other glucoproteins
Enzymes are proteins that catalyze the chemical
reaction in the body.
Elevation of certain enzymes can serve as tumor
makers.
Lactate Dehydrogenase ( LDH), Lymphoma,
leukemia and Germ cell tumors.
Alkaline phosphatase ( ALP), Liver cancer and
bone metastasis

31. Table showing tumor markers & ass. benign conditions
TUMOR MAKERS BENIGN CONDITIONS
AFP ( alfa feto protein) Viral hepatitis, liver injury, IBD, pregnancy
β-hCG ( beta Human chorionic gonadotrophin) Testicular failure, marijuana smokers, pregnancy
CEA(Carcinoembryonic antigen) Smokers, IBD, hepatitis, cirrhosis, pancreatitis,gastritis
CA 125(Carbohydrate antigen) Peritoneal irritation, endometriosis, pelvic inflammatory disease,
hepatitis, pregnancy
PAP(Prostatic acid phosphatase Peritoneal irritation, endometriosis, pelvic inflammatory disease,
hepatitis, pregnancy
PSA( Prostatic specific antigen) Prostatitis, benign prostatic hyperplasia
31

32. LOCAL EFFECTS OF CANCER

33. Introduction
• Both benign and malignant tumors cause local effects on the host due
to their size or location.
• Benign tumors are well circumscribed masses causing mass effect by
pushing aside surrounding normal tissue without invading or
infiltrating.
• Malignant tumors due to rapid and invasive growth potential may
invade ,infiltrate and destroy surrounding tissues and therefore cause
more serious effects.

34. Cont…
• The local effects of tumors include:
Compression
Mechanical obstruction
Tissue destruction
Infarction, ulceration and hemorrhage

35. Compression
• Many benign tumors pose only a cosmetic problem. Some benign
tumors, however, due to their critical location, have more serious
consequences.
Examples.
Pituitary adenoma may lead to serious endocrinopathy (can
compress and destroy the surrounding normal gland, giving rise to
hypopituitarism)
Pituitary macroadenomas may also compress the optic chiasma
causing progressive loss of outer peripheral vision (bitemporal
hemianopsia), blurred vision and headache.

36. Compression
• Biliary obstruction due to a small benign tumor in ampulla of Vater.
• Adrenal adenomas : Patient may develop abdominal or lower back
pain due to abnormal enlargement of the gland which put pressure
on surrounding nerve.

37. Compression
• Oncological emergencies may occur due to compression of vital
structures:
Compression of SVC by mediastinal tumors can cause SVC syndrome
as a result of incomplete or complete hindrance of blood flow from
external compression or intrinsic obstruction of SVC or related greater
veins. Example in Small Cell Lung Cancer.
Compression of lumbar plexus in metastatic Prostate Cancer that
leads to Spinal cord compression leading to loss of sphincter control,
sensory loss and paralysis.

38. Mechanical obstruction
• Benign and malignant tumors in the gut may produce intestinal
obstruction.
• Cancer of esophagus: Growing tumor can obstruct the esophageal
lumen causing dysphagia and heartburn.
• Cancer of head of pancreas: Can obstruct the bile duct leading to
signs and symptoms of obstructive jaundice.

39. Tissue destruction
• Malignant tumors, both primary and metastatic, can infiltrate and
destroy the vital structures.
• Carcinoma of cervix – May invade surrounding tissue to cause Vesico-
Vaginal Fistula and Recto-vaginal Fistula - ( urine or fecal
incontinence)

40. Infarction, ulceration, hemorrhage
• A tumor may ulcerate through a surface e.g mucosa, epidermis, with
consequent bleeding e.g melena, hematuria. This may lead to
necrosis and secondary infection, more predominant with malignant
tumors than benign tumors.
• Large tumors in mobile organs (e.g. an ovarian tumor) may undergo
torsion and produce infarction and hemorrhage.
• A leiomyoma in the wall of the renal artery may encroach on the
blood supply, leading to renal ischemia and hypertension.

41. SYSTEMIC EFFECT OF CANCER

42. 1. Cancer cachexia
• Accelerated loss of body fat and lean
body mass accompanied by weakness
and anorexia among cancer patients.
• However, cachexia is not caused by
the nutritional demands of the tumor.
• The exact mechanism of cachexia is
not clear, but there are several
postulates trying to explain the
phenomena.
Source: Up To Date

43. a. Cytokines, inflammation and hyper
metabolic state
• In cancer patients there is increased
resting energy expenditure leading
to catabolic activities.
• Several cytokines including TNF – α,
IL- 6, IL-1β play a major role
• TNF – α suppresses appetite leading
to anorexia.
Source: https://www.mdpi.com/1422-0067/19/8/2225

44. b. ATP-Ubiquitin – proteasome pathway
• Proteolysis inducing factor causes
breakdown of skeletal muscles
protein via ATP dependent
ubiquitin – proteasome pathway

45. c. Lipolysis and lipid mobilizing factor
• Lipid mobilizing factor is
produced by cancer cells and
causes degradation of
adipocytes.
• TNF – α, CIF , IL-6 also inhibit
the release of free fatty acids
from lipoproteins which then
causes excess lipolysis.

46. Adipose triglyceride lipase (ATGL) catalyzes the rate-
limiting first step, converting TAG into diacylglycerol
(DAG) and a free FA. DAG is then acted upon by hormone
sensitive lipase (HSL) to remove the second FA to form
monoacylglycerol (MAG). The third and final enzyme,
monoglyceride lipase (MGL) converts MAG into glycerol
and a third free FA.

48. 2. Neoplastic Fever
• Fever of unexplained origin may be presenting feature in some
malignancies.
• Such malignancies includes Hodgkin’s disease, adenocarcinoma
kidney, osteogenic sarcoma and many other tumors.
• The exact mechanism of tumor associated fever is not known but
probably the tumor cells themselves elaborate pyrogens.

49. 3. Paraneoplastic syndrome
• Defined as symptom complexes that occur in patients with cancer and
that cannot be readily explained by local or distant spread of the
tumor or by the elaboration of hormones not indigenous to the tissue
of origin of the tumor.
The most common syndromes are hypercalcemia, cushing syndrome
and nonbacterial thrombotic endocarditis (NBTE)
The neoplasm most associated with these syndrome are Lung ,
Breast CA and Hematological malignancy.

50. Significance of paraneoplastic syndrome
• Such syndromes may represent the earliest manifestation of an occult
neoplasm.
• In affected patients, the pathologic changes may be associated with
significant clinical illness and may even be lethal.
• The symptom complex may mimic metastatic disease, thereby
confounding treatment.

51. a. Hypercalcemia
• Hypercalcemia in cancer patients is multifactorial, but the most important
mechanism is the synthesis of a parathyroid hormone–related protein
(PTHrP) by tumor cells.
• Some tumors associated with hypercalcemia is Lung (sq. cell Ca), kidney,
breast, Adult T-cell leukaemia-lymphoma
• Hypercalcemia resulting from skeletal metastases is not a paraneoplastic
syndrome.

52. b. Cushing syndrome
• Caused by ectopic production of ACTH or ACTH like polypeptides by
cancer cells.
• It is mostly observed in Lung (small cell carcinoma), ACTH or ACTH-
like pancreas and neural tumors.

53. c. Non bacterial thrombotic endocarditis
• Paraneoplastic syndromes also may manifest as hypercoagulability,
leading to venous thrombosis and nonbacterial thrombotic
endocarditis.
• Most common in (cancer, autoimmune disorders, HIV).
• In contrast to infective endocarditis valvular lesion of NBTE are sterile
and non destructive.

54. Classification of Paraneoplastic syndrome
1. Endocrinopathy
2. hematological and vascular disorders,
3. dermatological,
4. nervous and muscular disorders,
5. renal,
6. gastrointestinal and
7. miscellaneous (nonspecific)

55. Clinical Syndrome Major Forms of Neoplasia Causal Mechanism(s)/Agent(s)
ENDOCRINOPATHIES
Cushing syndrome Small cell carcinoma of lung ACTH or
ACTH-like substance
Pancreatic carcinoma
Neural tumors
ACTH or ACTH-like substance
Syndrome of inappropriate
antidiuretic hormone secretion
Small cell carcinoma of lung; intracranial
neoplasms
Antidiuretic hormone or atrial natriuretic
hormones
Hypercalcemia SCC of lung
Breast carcinoma
Renal carcinoma
Adult T cell leukemia/lymphoma
Ovarian carcinoma
Parathyroid hormone–related protein, TGF-α,
TNF, IL-1
Hypoglycemia Fibrosarcoma
Other mesenchymal sarcomas
Hepatocellular carcinoma
Insulin or insulin-like substance

56. Clinical Syndrome Major Forms of Neoplasia Causal Mechanism(s)/Agent(s)
Carcinoid syndrome Bronchial adenoma (carcinoid)
Pancreatic carcinoma
Gastric carcinoma
Serotonin, bradykinin
Polycythemia Renal carcinoma
Cerebellar hemangioma
Hepatocellular carcinoma
Erythropoietin
NERVE AND MUSCLE SYNDROME
Myasthenia Bronchogenic carcinoma, thymoma Immunologic
Disorders of the central and PNS Breast carcinoma, teratoma
DERMATOLOGIC DISORDERS
Acanthosis nigricans Gastric carcinoma
Lung carcinoma
Uterine carcinoma
Immunologic; secretion of epidermal growth
factor
Dermatomyositis Bronchogenic and breast carcinoma Immunologic

57. Clinical Syndrome Major Forms of Neoplasia Causal Mechanism(s)/Agent(s)
OSSEOUS, ARTICULAR AND SOFT TISSUE CHANGES
Hypertrophic osteoarthropathy and
clubbing of the fingers
Bronchogenic carcinoma Unknown
VASCULAR AND HEMATOLOGIC CHANGES
Venous thrombosis (Trousseau
phenomenon)
Pancreatic carcinoma
Bronchogenic carcinoma
Other cancers
Tumor products (mucins that activate clotting)
Nonbacterial thrombotic endocarditis Advanced cancers Hypercoagulability
Anemia Thymoma Immunologic
OTHERS
Nephrotic syndrome Tumor antigens, immune complexes Various cancers

58. 4. Hormonal effect
• Endocrine tumor may retain the secretory hormonal function of their
benign ancestors Eg. Insulinoma of the endocrine pancrease may
cause hypoglycaemia through excessive insulin production.
• A thyroid adenoma may produce thyroxine ,leading to
hyperthyroidism.
• A parathyroid adenoma may produce parathyroid hormone, leading
to hypercalcaemia and osteoporosis.

59. 5. Tumour lysis syndrome
• This is a condition caused by extensive destruction of a large number of
rapidly proliferating tumor cells such as lymphomas and leukemia than
solid tumors.
• May be due to large tumor burden (e.g. in Burkitt’s lymphoma),
chemotherapy, administration of glucocorticoids or certain hormonal
agents (e.g. tamoxifen).
• It is characterized by hyperuricaemia, hyperkalaemia, hyperphosphataemia
and hypocalcaemia, all of which may result in acidosis and renal failure.

60. Reference
• https://www.uptodate.com/contents/image?csi=db3ad63c-060e-484d-
9ca7-53a2976b862c&source=contentShare&imageKey=ONC%2F90162
• Robbins Basic Pathology, 9TH Edition, Chapter 5, pg 207-2014
• Text Book of Pathology by Harshmohan, 6TH Edition, Chapter 8, pg 192-
255.
• https://www.ejcancer.com/article/S0959-8049(05)00845-2/fulltext
• https://www.sciencedirect.com/science/article/abs/pii/S104084281400
1838?via%3Dihub
• https://login.research4life.org/tacsgr1onlinelibrary_wiley_com/doi/epdf
/10.1002/cam4.6388