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TUMOUR IMMUNOLOGY, CLINICAL ASPECTS OF NEOPLASIA & Clinical Features of Tumors
1. NEOPLASIA - 8
TUMOUR IMMUNOLOGY,
CLINICAL ASPECTS OF NEOPLASIA,
Clinical Features of Tumors
Dr. Roopam Jain
Professor & Head, Pathology
2. HOST RESPONSE AGAINST TUMOUR
(TUMOUR IMMUNOLOGY)
Body’s immune system can recognise tumour
cells as ‘non-self’ and they attempt to destroy
them & limit the spread of cancer
1. Antitumour immune responses
2. Tumour antigens
3 Immunotherapy.
3. Host Defense Against Tumor
(Tumor Immunity)
Definition
coordinated biologic process designed to
recognize tumor cells and their products
and to kill or damage them
Cancer immuno-editing - effect of immune
system in preventing tumor formation &
select tumor cells that escape immune
elimination
4. Host Defense Against Tumor
Tumor Immunity
Tumor Specific Antigens (TSA)
Present only on tumor cells and not on any
normal cells and can be recognized by cytotoxic
T-lymphocytes.
Tumor Associated Antigens (TAA)
Not unique to tumors and are also present on
normal cells.
5. Tumor Antigens
Tumor Specific Antigens (TSA)
Present only on tumor cells and not on any normal
cells & can be recognized by cytotoxic T-lymphocytes.
Cancer testis antigen
Viral antigen
Mucin
Oncofetal antigens
Antigens resulting from mutational in protein
B catenin, RAS, P53,CDK4
6. Tumor Antigens
Tumor Associated Antigens(TAA)
present on tumour cells as well as on some normal
cells from where the tumour originated.
Over expressed Antigens
e.g HER-2 (neu) in 30 % Breast cancer
( present in normal breast & ovary)
Differentiation- Specific Antigens
e.g CD10& PSA
Expressed in normal B cells & Prostate
Used as a marker for tumors arise from these cells
7.
8. VARIOUS GROUPS OF
TUMOUR ANTIGENS
i) Oncoproteins from mutated oncogenes
ii) Protein products of tumour suppressor genes
iii) Overexpressed cellular proteins
iv) Abnormally expressed cellular proteins
v) Tumour antigens from viral oncoproteins
vi) Tumour antigens from randomly mutated genes
vii) Cell specific differentiation antigens
viii) Oncofoetal antigens
ix) Abnormal cell surface molecules
9. (1) Products of mutated oncogenes
(2) & tumor suppressor genes
-Synthesized in cytoplasm of tumor cells
-Recognized by CD+8 &CD4+ T cells
-p53,RAS, BCR-ABL
10. (3) Over expressed cellular proteins
- example : in melanoma the tumour antigen is
structurally normal melanocyte specific protein,
tyrosinase, which is over expressed compared
with normal cells.
- Similarly, HER2/ neu protein is over expressed
in many cases of breast cancer.
11. (4) Abnormally expressed cellular proteins
Sometimes, a cellular protein is present in some
normal cells but is abnormally expressed on the
surface of tumour cells of some cancers.
The classic example is - presence of MAGE gene
silent in normal adult tissues - but MAGE genes are
expressed on surface of many tumours such as
melanoma
Other examples - GAGE (G antigen), BAGE (B
melanoma antigen) and RAGE (renal tumour
antigen).
12. (5) Tumor antigens produced by
oncogenic viruses
-produced by DNA viruses- HPV & EBV
-Immune system recognize and kill virus infected
cells
e.g. viral oncoproteins of HPV (E6, E7) in
cervical cancer and EBNA proteins of EBV
in Burkitt’s lymphoma
13. (6) Products of other mutated genes
-Various other carcinogens such as chemicals
and radiation induce random mutations in
the target cells
14. (7) Cell specific differentiation
antigens
-normally present on cells of origin
-CD10(CALLA) & CD20- B cell derived tumors
15. (8) Onco-fetal antigens
expressed high levels in cancer cells & in fetus
but not adult tissue
Alpha fetoprotein(AFP) in hepatocellular carcinoma
& nonseminomatous testicular tumors
Carcinoembryonic antigen(CEA) in carcinomas of
colon, pancreas, lung, stomach & heart
16. (9) Abnormal cell surface molecules
In some cancers, there is - Altered cell-surface Glycolipids
and Glycoproteins, Gangliosides, blood group antigens
& mucins
-as diagnostic markers & targets for therapy
-Glycolipids- e.g. Gangliosides Gm2,GD2 & GD3 in
melanoma
-Mucins –high mol. wt. Glycoproteins
e.g. CA-125 & CA-19 in ovarian carcinoma
MUC-1 in breast carcinoma
18. Mechanisms of Immunity to
Tumors
Cytotoxic T lymphocytes (CTL) - that are
sensitized to tumor specific antigens and kill tumor
cells. Play a role in virus induced malignancy
Natural Killer (NK) cells - can attack tumor
cells directly without antibody coating or by
Antibody Dependent Cell Cytotoxicity (ADCC)
utilizing the Fc receptor on the NK cells, effective
against cells with reduced MHC expression
19. Mechanisms of Immunity
to Tumors
Killer Macrophages - activated by IFN-g
elaborated by Helper T lymphocytes. Participate
in ADCC and can kill tumor cells through
release of TNF-Alpha.
20.
21. Evidence for Immune Response to Tumors
1) Infiltrate of lymphocytes and macrophages associated
with better prognosis in many tumors.
2) Peripheral blood NK activity correlates with survival.
3) Peripheral blood lymphocytes counts fall as cancer
overwhelms host; patients develop anergy to skin tests.
4) Non-specific vaccines can stimulate macrophages and
improve prognosis. IFN-g and IL-2 can stimulate NK
cells and improve outcome.
5) High incidence of some tumors in immunosuppressed
individuals.
24. Clinical Features of Tumors
Tumors are essentially parasites with some
only causing mischief while others are
catastrophic
ALL tumors, even benign ones, can cause
morbidity and mortality
25. Clinical Features of Tumors
The following will be discussed under this
heading:
1) the effects of a tumor on the host
2) the grading and clinical staging of cancer
3) the laboratory diagnosis of tumors
27. Effects of Tumor on Host
Certainly cancers are far more threatening than
benign tumors but both types can cause problems
because of:
1) location and impingement on adjacent structures
2) functional activity such as hormone synthesis
3) bleeding and secondary infections when they
ulcerate
28. Effects of Tumor on Host (Conti……)
4) initiation of acute symptoms caused by either
rupture or infarction
5) Neoplasms arising in endocrine glands may
produce manifestations by elaboration of hormones
6) The erosive destructive growth of cancers or the
expansile pressure of a benign tumor on any
surface may cause ulcerations, secondary infections
and bleeding
29. A. LOCAL EFFECTS
i) Compression - e.g. pituitary adenoma may lead to
serious endocrinopathy; a small benign tumour in ampulla of
Vater may lead to biliary obstruction.
ii) Mechanical obstruction - Benign and malignant
tumours in the gut may produce intestinal obstruction.
iii) Tissue destruction Malignant tumours, both
primary and metastatic, infiltrate and destroy the vital
structures.
iv) Infarction, ulceration, haemorrhage -
infarction, surface ulceration, haemorrhage , torsion and
produce infarction and haemorrhage.
30. B. SYSTEMIC MANIFESTATIONS
1. CANCER CACHEXIA
2. FEVER
3. TUMOUR LYSIS SYNDROME
4. PARANEOPLASTIC SYNDROMES
31. 31
Clinical manifestations of Cancer
Cachexia – wasting
anorexia
early satiety
weight loss
anemia
marked weakness
taste alterations
altered metabolism
32. 32
Clinical manifestations of Cancer
Anemia
chronic bleeding
malnutrition
medical therapies
malignancy in blood forming organs
Administer erythropoietin
33. Effects of Tumor on Host:
Cancer Cachexia .
Cancer patients commonly suffer progressive
loss of body fat and lean body mass
accompanied by profound weakness,
anorexia and anemia. This wasting
syndrome is termed CACHEXIA
The causes of cachexia are obscure but
cachexia is NOT caused by the nutritional
demands of the neoplasm
34. Cancer Cachexia .
Current evidence indicates that cachexia results from the
action of soluble factors such as cytokines (TNF-alpha
and IL-1) either produced by the tumor or the host
Reduced food intake alone is not sufficient to explain the
cachexia of malignancy
Various other causes of cancer cachexia include
necrosis, ulceration, haemorrhage, infection,
malabsorption, anxiety, pain, insomnia,
hypermetabolism and pyrexia.
36. 3. TUMOUR LYSIS SYNDROME .
caused by extensive destruction of a large number of
rapidly proliferating tumour cells.
lymphomas and leukaemias, 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.
37. 4. Paraneoplastic Syndromes .
group of conditions developing in patients with
advanced cancer,
either by the local or distant spread of the tumor
or by the elaboration of hormones indigenous to
the tissue from which the tumor arose, are known
as PARANEOPLASTIC SYNDROMES
About 10 to 15% of the patients with advanced
cancer develop
38. Paraneoplastic Syndromes
Paraneoplastic syndromes are important for three
reasons:
1) they may represent the earliest manifestation of
an occult tumor
2) they may represent significant clinical
problems and may even be lethal
3) they may mimic metastatic disease and
therefore confound treatment
39. Paraneoplastic Syndromes
(Endocrinopathies)
Cushing Syndrome Small cell
carcinoma-lung;
pancreatic
carcinoma; neural
tumors
ACTH or ACTH-
like substance
Syndrome of
inappropriate ADH
secretion
Small cell
carcinoma-lung;
intracranial
neoplasms
ADH or Atrial
natriuretic
hormones
42. Paraneoplastic Syndromes
(Nerve and Muscle Syndromes)
Myasthenia Bronchogenic
carcinoma,
Thymoma
Immunologic
Disorders of the
central and
peripheral nervous
systems
Breast,
Carcinoma Lung
(small cell Ca),
Immunologic
49. 32 A 49-year-old man experiences an episode of hemoptysis.
On physical examination, he has puffiness of the face, pedal
edema, and systolic hypertension. A chest radiograph shows a
5-cm mass of the right upper lobe of the lung. A fine-needle
aspiration biopsy of this mass yields cells consistent with
small-cell anaplastic carcinoma. A bone scan shows no
metastases. Immunohistochemical staining of the tumor cells
is most likely to be positive for which of the following?
□ (A) Parathyroid hormone–related peptide
□ (B) Erythropoietin
□ (C) Corticotropin
□ (D) Insulin
□ (E) Gastrin
50. 33 During a routine health maintenance
examination of a 40-year-old man, a stool guaiac
test result was positive. A followup
sigmoidoscopy showed a 1.5-cm, circumscribed,
pedunculated mass on a short stalk, located in
the upper rectum. Which of the following terms
best describes this lesion?
□ (A) Adenoma
□ (B) Hamartoma
□ (C) Sarcoma
□ (D) Choristoma
□ (E) Nevus
51. 36 A 23-year-old woman has noted a nodule on the skin
of her upper chest. She reports that the nodule has
been present for many years and has not changed in
size. On physical examination, there is a 0.5-cm, dark
red, nontender, raised nodule with a smooth surface.
Which of the following is the most likely diagnosis?
□ (A) Adenoma
□ (B) Fibroadenoma
□ (C) Hamartoma
□ (D) Hemangioma
□ (E) Leiomyoma
□ (F) Lipoma
□ (G) Melanoma
□ (H) Nevus
52. 37 A 63-year-old man sees the physician because of cough
and hemoptysis. He has a 65-pack-year history of smoking. A
chest CT scan shows a 5-cm right hilar mass. Bronchoscopy
is performed, and lung biopsy specimens show small-cell
anaplastic lung carcinoma. His family history shows three
first-degree maternal relatives who developed leukemia,
sarcoma, and carcinoma before age 40 years. Which of the
following genes is most likely to have undergone mutation to
produce these findings?
□ (A) APC (tumor suppressor gene)
□ (B) BCL2 (anti-apoptosis gene)
□ (C) ERBB2 (growth factor receptor gene)
□ (D) K-RAS (GTP-binding protein gene)
□ (E) NF1 (GTPase-activating protein)
□ (F) p53 (DNA damage response gene)
53. A 38-year-old woman has abdominal distention that has
been worsening for the past 6 weeks. An abdominal CT scan
shows bowel obstruction caused by a 6-cm mass in the
jejunum. At laparotomy, a portion of the small bowel is
resected. Microscopic examination shows that the mass is a
Burkitt lymphoma. Flow cytometry analysis of a portion of
the tumor shows a high S phase. Mutational activation of
which of the following nuclear oncogenes is most likely to
be present in this tumor?
□ (A) ERBB2
□ (B) p53
□ (C) RAS
□ (D) MYC
□ (E) APC
54. A 62-year-old man has had several episodes of hematuria in
the past week. On physical examination, there are no
abnormal findings. A urinalysis shows 4+ hematuria, and
cytologic examination of the urine shows that atypical cells
are present. The urologist performs a cystoscopy and
observes a 4-cm sessile mass with a nodular, ulcerated surface
in the dome of the bladder. Which of the following terms
best describes this lesion?
□ (A) Papilloma
□ (B) Carcinoma
□ (C) Adenoma
□ (D) Sarcoma
□ (E) Fibroma