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LABORATORY DIAGNOSIS

OF CANCER
Dr RAMASWAMY A S
ASSISTANT PROFESSOR
DEPARTMENT OF PATHOLOGY
PESIMSR
KUPPAM
OBJECTIVES
• HOW TO APPROACH A CASE OF
CANCER?
• MODALITIES AVAILABLE IN
DIAGNOSING CANCER
• CONCEPT OF TUMOR MARKERS
• BEFORE ANY FORM OF
EVALUATION CLINICAL
HISTORY AND
EXAMINATION IS A MUST
• WHATEVER SAMPLE WHICH IS SENT
FOR DIAGNOSIS SHOULD BE
ADEQUATE, REPRESENTATIVE
AND PROPERLY PRESERVED
• WHENEVER POSSIBLE EXCISIONAL
BIOPSY, OTHERWISE INCISIONAL
BIOPSY
PRESERVATION
• Formalin fixative – for routine
hematoxylin and eosin staining of
tissue sections
• Bouin’s fixative for testicular biopsy
• Glutaraldehyde for electron
microscopy
• Refrigeration – for hormone, receptor
or other molecular analysis
• Frozen section – for determining the
nature of the lesion and the margin
METHODS OF EVALUATION
1. Cytologic methods
2. Histologic methods
3. Special tests
i. Immunohistochemistry
ii. Molecular diagnosis
iii. flow cytometry
iv. Tumor markers
CYTOLOGIC METHODS
• EXFOLIATIVE CYTOLOGY
• ASPIRATION CYTOLOGY
CYTOLOGY
• Commonest example quoted for the
early detection and diagnosis of
cancer is the PAPANICOLAOU SMEAR
( Pap smear ) examination for
carcinoma cervix.
TUMOR MARKERS
• They are biochemical indicators for
the presence of a tumor
• They cannot be construed as primary
diagnostic modalities for cancer
• They only support a diagnosis of
cancer
• They also help in determining the
response of a cancer to therapy
• Useful in detecting relapse during
follow up period
CLASSES OF TUMOR
MARKERS
1. HORMONES
2. ONCOFETAL ANTIGENS
3. ISO ENZYMES
4. SPECIFIC PROTEINS
5. MUCINS AND GLYCOPROTEINS
6. NEW MOLECULAR MARKERS
HORMONES
HORMONES ASSOCIATED CANCER

HCG Trophoblastic tumors, non seminomatous germ


cell tumors

Calcitonin Medullary carcinoma of thyroid

Catecholamine and Pheochromocytoma and related tumors


metabolites

Ectopic hormones Paraneoplastic syndromes of many cancers


ONCO FETAL ANTIGENS
• These are the antigens which are
normally expressed during
embryonic life
• These get re expressed in many
diseased states including malignancy
• They are not specific for any cancer
• The two main onco fetal antigens are
1. α fetal protein
2. Carcino embryonic antigen
α FETAL PROTEIN
• It is a glyco protein
• Normally synthesised in early fetal
life by
- Yolk sac
- Fetal liver
- Fetal gastro intestinal tract
Non neoplastic conditions in
which α feto protein is
elevated
1. Cirrhosis
2. Toxic liver injury
3. Hepatitis
4. Pregnancy especially with fetal
distress or death
Neoplastic conditions in which
α feto protein is elevated
1. Hepato cellular carcinoma
2. Germ cell tumor of testis
Less commonly elevated in
4. Carcinoma colon
5. Carcinoma lung
6. Carcinoma pancreas
• Markedly elevated AFP levels in the
plasma is an useful indicator of
hepato cellular carcinoma and germ
cell tumor of testis
• AFP levels rapidly decline after
surgical resection of these tumors
• Serial post therapy levels of AFP in
these patients indicate a sensitive
index of response to therapy and
recurrence
CARCINO EMBRYONIC ANTIGEN
(CEA)
• It is a complex glycoprotein
• Normally synthesised in the
embryonic tissue of
- gut
- pancreas
- liver
Non neoplastic conditions in
which CEA is elevated
1. Alcoholic cirrhosis
2. Hepatitis
3. Ulcerative colitis
4. Crohn disease
5. Smokers
Neoplastic conditions in which
CEA is elevated
1. Colorectal carcinoma – 60-90%
2. Pancreatic carcinoma – 50-80%
3. Gastric carcinoma – 25-50%
4. Breast carcinoma – 25-50%
• CEA lacks the sensitivity and specificity
required for the detection of early
cancers
• Pre operative CEA levels corelate with
the tumor burden
• In patients with CEA positive colon
cancers, the presence of elevated CEA
levels 6 weeks after surgery indicates
residual disease
• Rising CEA levels indicates recurrence
• Serum CEA is also useful in monitoring
metastatic breast cancer
SPECIFIC PROTEINS
PROTEIN CANCER

Immunoglobulins Multiple myeloma and


gammopathies
Prostate specific antigen (PSA) Carcinoma prostate
and Prostate specific membrane
antigen (PSMA)
ISO ENZYMES
ISOENZYME CANCER

Prostatic acid Prostate cancer


phosphatase

Neuron specific Small cell cancer lung,


enolase neuroblastoma
MUCINS AND OTHER
GLYCOPROTEINS
MUCINS CANCER

CA-125 Ovarian cancer

CA 19-9 Colon cancer, pancreatic cancer

CA 15-3 Breast cancer


NEW MOLECULAR MARKERS
NEW MOLECULAR MARKERS CANCERS
P53, APC, RAS mutations in stool Colon cancer
and serum
P53 and RAS mutations in stool Pancreatic cancer
and serum
P53 and RAS mutations in sputum Lung cancer
and serum
P53 mutations in urine Bladder cancer
IMMUNOHISTOCHEMISTRY
• This is the special branch of
pathology where antibodies against
cellular antigens are used in
identification of cellular products or
surface markers
• The components are visualized using
chromogens which stain up when the
antigen antibody reaction is
completed.
• Depending on the location and the
staining intensity the results are
UTILITY OF IHC IN
NEOPLASMS
1. Categorisation of undifferentiated
malignant tumors
2. Categorisation of leukemias and
lymphomas
3. Determination of site of origin of
metastatic tumors
4. Detection of molecules that have
prognostic or therapeutic
significance
CATEGORISATION OF
UNDIFFERENTIATED MALIGNANT
TUMORS
• To differentiate anaplastic
carcinoma from malignant
lymphomas, melanomas and
sarcomas – antibodies to
intermediate filaments. Eg.,
cytokeratin – epithelial origin
desmin – muscle cell origin
CATEGORISATION OF
LEUKEMIA AND LYMPHOMA
• IHC used in conjuction with
immunofluorescence
• Separation of myeloid from lymphoid
neoplasms
• Separation of T, B cells and mono
nuclear phagocytic neoplasms
• Prognostication of leukemias and
lymphomas
DETERMINATION OF SITE OF
ORIGIN OF METASTATIC
TUMORS
• When origin of a metastatic tumor is
obscure on morphological grounds
then IHC is helpful by the utilisation
of tissue specific or organ specific
antigens.
• eg., PSA – prostate
thyroglobulin - thyroid
DETECTION OF MOLECULES OF
THERAPEUTIC OR PROGNOSTIC
IMPORTANCE
• Most useful parameter in certain
tumors.
• Eg., breast cancer – ER / PR receptor
status.
• In general receptor positive tumors
are responsive to anti estrogen
therapy and have a better prognosis.
• Product of oncogenes like ERB B2 if it
is overexpressed in ca breast then it
has got poor prognosis
Cytokeratin positive gastric
adenocarcinoma
Sarcoma positive for
vimentin
Bcl-2 positivity in lymphoma
C – erb – B2 positivity in breast
cancer
MOLECULAR DIAGNOSIS
• Diagnosis of malignant neoplasms
• Prognosis of malignant neoplasms
• Detection of minimal residual disease
• Diagnosis of hereditary pre
disposition to cancer
• DNA micro array analysis and
proteomics
DETECTION OF MALIGNANT
NEOPLASMS
• Not the primary modality of cancer
diagnosis
• Useful in differentiating monoclonal from
polyclonal proliferations off cells like T / B
cells
• Specific translocations which cause
neoplasms can be identified by techniques
like routine cytogenetic analysis or FISH or
PCR . Eg., detection of BCR – ABL transcripts
in CML
• It is also helpful in the differential diagnosis
of morphologically similar neoplasms. Eg.,
ewing sarcoma has all the small round blue
cell tumors in its differential diagnosis. It
can be diagnosed by demonstration of t
PROGNOSIS OF MALIGNANT
NEOPLASMS
• Certain genetic alterations have a
bearing on the tumor prognosis
• Detection of these helps in the
prognostication
• Eg., amplification of N – MYC and
deletion of 1p = poor prognosis in
neuroblastoma.
• t(15;17) in AML M3 carries good
prognosis
DETECTION OF MIMINAL
RESIDUAL DISEASE
• After the treatment of patients with
leukemia or lymphoma the presence
of minimal residual disease can be
monitored by PCR based
amplification of specific tumor
genetic sequences
DETECTION OF HEREDITARY
PREDISPOSITION TO CANCERS
• Detection of germ line mutations in
tumor suppressor genes helps in
early detection of cancers or warns
the persons of increased risk of
developing neoplasm
• eg,., RET gene analysis in multiple
endocrine neoplasia (MEN syndrome)
FLOW CYTOMETRY
• This procedure can rapidly and
quantitatively measure several
individual cell characteristics like
- Membrane antigens
- DNA content
- Cell surface antigens
this information can be used both
diagnostically and prognostically.
Flow cytometry - aneuploidy
NEWER TECHNIQUES
1. Spectral karyotyping
2. Comparative genomic hybridisation
3. DNA micro array analysis
4. Proteomics
5. Tissue arrays
6. Electron microscopy
Tissue microarray
Spectral karyotyping of a
tumor
Electron microscopy of
adenocarcinoma
Summary
• Clinical history a must in evaluation
of tumor
• Morphological approach adopted first
in any cancer both gross and
microscopic
• Hematoxylin and eosin stained tissue
sections first line of investigation in
all solid cancers
• Additional newer techniques should
be used judiciously
REFERENCES
• GENERAL PATHOLOGY – WALTER &
ISRAEL
• PATHOLOGIC BASIS OF DISEASE –
ROBBINS AND COTRAN
• TEXT BOOK OF SURGERY – BAILEY
AND LOVE
• HARRISON PRINCIPLES OF INTERNAL
MEDICINE

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