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Prognostic factors in carcinoma
Carcinoma of breast is most common malignancy
and is the leading cause of death in women.
A woman who lives to age 90 has a one in eight
chance of developing breast cancer.
WHO classification of carcinomas of breast:
With Paget’s disease.
Lobular carcinoma in situ.
Invasive ductal carcinoma.
With Paget’s disease.
Invasive ductal carcinoma with a predominant intraductal
Pregnancy and oral contraceptives.
Keratin staining pattern
CEA staining pattern.
Vimentin staining pattern.
P53 and nm23.
Bcl2 and cyclin D1.
Cell kinetics and DNA ploidy.
Women < 50 years –Best prognosis.
> 50 years- Bad prognosis.
< 35 years- Same as older patients
Higher risk of recurrence.
One of the strongest predictors of dissemination and rate of
relapse in node negative Ca breast.
Inverse correlation with survival.
Size determination has a greater prognostic significance when
measured microscopically than grossly .
Tumor size can be assessed macroscopically in the fresh state
(in three planes) and subsequently confirmed following
Size is one of the two criteria's for the definition of minimal
breast carcinomas which includes all in situ carcinomas
regardless of size and invasive carcinomas of 1 cm or less in
< 10 mm in diameter/ Large in situ component- Vernier scale.
9-10 mm- Minimally invasive carcinoma with good
< 15 mm- good prognosis.
The frequency of axillary lymph node metastases in small
carcinomas is approximately 15-20% in contrast to >40 % in
tumours measuring > 15mm in diameter.
In tumours having both an in situ and invasive component ,
the size of latter is the better predictor than is the total tumour
Women with node negative carcinomas <1cm in diameter
have a prognosis approaching that of a women without breast
10 year survival rate in such women without treatment is
Over half of the women with cancers > 2cm in diameter
present with lymph node metastases.
No relationship found between prognosis and quadrant
However, in one recent large study it was found that medial
location of the tumour was associated with 50% risk of
systemic relapse and tumour death when compared with
Tumour configuration or shape:
Stellate ( Spiculated, infiltrative, radial and serrated)
Circumscribed (Rounded, pushing, encapsulated, smooth)
Carcinomas having circumscribed margins grossly or
mammographically may exhibit an invasive growth pattern
Infiltrative tumours tend to be larger and are more likely to
have nodal metastases than those with circumscribed margins.
Tumours with stellate configuration with focal necrosis- Poor
No significant prognostic difference between invasive ductal
and invasive lobular carcinoma.
Favourable prognosis- Tubular carcinoma, medullary
carcinoma, cribriform carcinoma, pure mucinous carcinoma,
papillary carcinoma, adenoid cystic carcinoma and juvenile
Bad prognosis: Signet ring carcinoma.
Aggressive than ductal carcinoma with little difference in
survival rates- Squamous cell carcinoma, metaplastic
carcinoma and carcinomas with neuroendocrine features.
Presence or absence of invasiveness:
Single most important prognostic determinator in Ca breast.
In situ- Curable with mastectomy.
Tumours of ductal type that have both in situ and invasive
component , a relationship exists between the proportion of
the invasive component and the probability of nodal
Amount of in situ component correlates with the incidence of
multicentricity and indirectly with the probability of occult
Extent of ductal carcinoma in situ associated
with invasive cancers:
Infiltrating carcinoma with prominent DCIS within the
confines of the invasive tumour or adjacent to it or cases of
DCIS with foci of invasion.
Presence of an extensive intraductal component is a
prognostic factor for local recurrence in the breast in patients
treated with conservative surgery and radiation therapy when
the status of excision margin is unknown.
Some studies have shown that even in patients with
negative margins the amount of DCIS near the margins is
predictive of breast recurrence.
Higher grade- Distant metastases and poor survival rate.
May provide information with regard to response to
Several studies have suggested that the presence of high
histologic grade is associated with a better response to certain
chemotherapy regimens than low histologic grade.
Nottingham, Modification of the Scarff-Bloom-Richardson
histologic grading system by Elston and Ellis.
Combines nuclear grade, tubule formation and mitotic rate.
Glandular or tubule formation-
1. > 75% of tumour area forming glandular or tubular
2. 10-75% of tumour.
3.< 10 % of tumour.
Nuclei small with little increase in size in comparison with
normal breast epithelial cell.
Uniform nuclear chromatin.
Little variation in size.
Cells larger than normal with
Open vesicular nuclei.
Moderate variability in both size and shape.
Vesicular nuclei often with prominent nucleoli.
Marked variation in size and shape.
Occasionally very large and bizzare forms.
Depends on number of mitosis per high power fields.
Size of high power fields is very variable so it is necessary
to standardize the mitotic count.
Field diameter of the microscope is measured using the
stage graticule or Vernier scale and the scoring categories
are read from following table.
Objective X 25 X 40 X40
0.59 0.44 0.63
Field area (sq
0.274 0.152 0.312
1 point 0-9 0-5 0-11
2 points 10-19 6-10 12-22
3 points > 20 > 11 > 23
Scores are added together and are assigned grades
Grade 1- scores 3-5.
Grade 2- scores 6 or 7.
Grade 3- scores 8 or 9.
Grade 1 carcinomas- Pure tubular and invasive cribriform
Grade 2- Infiltrating lobular carcinomas.
Minority of lobular carcinomas fall into grade 1 or 3.
Grade 3- Medullary carcinomas.
H&E stained section of a well differentiated breast
cancer with a tubular pattern, little nuclear
pleomorphism and occasional mitosis (Score
1+1+1=3). This is a Grade 1.
Large foci of invasive breast cancer with no tubules
(Score 3). Nuclei show moderate variation in size and
shape (Score 2). No mitotic figures are noted (Score 1).
This is another moderately differentiated invasive ductal
This invasive ductal carcinoma forms no tubules
(Score 3). Nuclei are displaying marked variation in
size and shape (Score 3). Arrows point to mitoses that
are seen at a rate of 10-19/ten high power fields
(Grade 2). This is a poorly differentiated breast cancer
Combining prognostic factors:
Nottingham prognostic index takes into consideration tumor
size, lymph node status and histologic grade.
Tumour size in cm X 0.2 + Histologic grade (1-3) + lymph
node stage (1-3).
Higher the value worse the prognosis.
Five prognostic groups-
Excellent- NPI score <2.41, 15 year survival 84%.
Good- < 3.41, 15 year survival 74%.
Moderate-I- 3.41-4.4, 15 year survival 63%.
Moderate-II- 4.41-5.4, 15 year survival 46%.
Poor- >5.4, 15 year survival 18%.
Adjuvant chemotherapy is not indicated in an excellent
prognostic group and good prognostic group.
Moderate prognostic group and poor prognostic group may
benefit from adjuvant polychemotherapy.
Axillary lymph node metastases:
Most important prognostic indicator.
Survival rate also depends on -
1. level of axillary nodes involved
2. absolute number
3. the amount of metastatic tumour
4. the presence or absence of extranodal spread and
5. the presence or absence of tumour cells in the efferent
Pattern of lymph node reaction:
Microscopic appearance of the regional node is an
indication of the type of host response to the tumour and
it relates to prognosis.
Internal mammary lymph node metastases:
Lower survival rate.
Sentinel lymph node
The sentinel node procedure in breast cancer was pioneered
by surgical oncologist Armando Giuliano, MD at the John
Wayne Cancer Institute in the 1990s.
Based on the concept that if the sentinel node is negative,
the other nodes of that group will also be negative in nearly
all instances, whereas if its positive, the chance that there
will be additional metastases in that nodal group is about
Most breast carcinomas drain to one or two sentinel nodes.
Highly predictive of the status of the remaining nodes.
Biopsy can spare women the increased morbidity of a
complete axillary dissection.
Limphoscintigraphy is performed wherein a harmless
radioactive substance is injected in the dermis over the
The injected substance, Filtered Sulfur Colloid, is tagged with
the radionuclide Technetium-99m.
Scintigraphic imaging is usually started within 5 minutes of
injection and the node appears from 5 min to 1 hour.
This is usually done several hours before the actual biopsy.
About 15 minutes before the biopsy the blue dye is injected
in the same manner.
Then, during the biopsy, lymph nodes are inspected for
staining and Gamma Probe or Geiger counter are used to
assess which lymph nodes have taken up the radionuclide.
One or several nodes may take up the dye and radioactive
tracer, and these nodes are designated the sentinel lymph
Pitfalls: Keratin positive reticulum cells, mesothelial cell
inclusions, ectopic breast tissue, traumatic displacement of
breast tissue by the biopsy procedure and floater.
Macrometastases: > 2 mm
Micrometastases: 0.2 – 2 mm
Isolated tumor cells: <0.2 mm
Subcapsular micrometastasis - this deposit is < 2mm on
the H&E but the immuno stain for pan CK was on a
section taken after cutting into the block further and
measures just over 0.2mm qualifying as a
Lymphatic vessel invasion:
Important prognostic factor.
With no involvement the
10 year diease survival rate- 70-80%.
1-3 positive nodes- 35-40%.
> 10 poisitive nodes- 10-15%.
Identifies node negative patients at increased risk for
axillary lymph node involvement and adverse outcome.
Increased risk of tumour recurrence.
Blood vessel invasion:
Predominantly seen in thin walled channels and rarely in
muscular blood vessels.
Higher correlation with tumour size, histologic grade, tumour
type, lymph node status, development of distant metastases
and poor prognosis.
Decreased survival rate.
Associated with higher incidence of axillary metastases.
Types of margins:
Tumours with pushing margins have better prognosis than
tumours with infiltrating margins.
Associated with increased incidence of lymph node
metastases and decreased survival rate .
Absence of inflammatory reaction at periphery have lesser
degree of nodal metastases and thus better prognosis.
• Mononuclear inflammatory cell infiltrate:
Its presence has been correlated with high histologic
• Perineural invasion:
Seen in association with lymphatic vessel invasion but
it has not been shown to be an independent prognostic
Invasive breast carcinomas having a prominent vascular
component in the surrounding stroma are more aggressive.
Microvessel density is a phenomenon independent from
intratumoural endothelial cell proliferation and increase in
microvessel density has also been noted in intraductal
carcinoma particularly of comedo type.
Breast carcinomas with no associated elastosis have a lower
rate of response to endocrine therapy than those with gross
Pregnancy and oral contraceptives:
Carcinoma breast manifesting during pregnancy or lactation
are generally aggressive tumour with low expression of
hormone receptors and high expression of Her2/neu---Poor
No convincing evidence has found that prior use of OCPs has
an effect on evolution or survival of Ca breast.
Risk increases if there are multiple affected first degree
Mutated BRCA1- risk of developing ovarian carcinoma.
Mutated BRCA2- small risk for ovarian carcinoma but it is
associated more frequently with male breast cancers.
BRCA1 and BRCA2 are also susceptible to colon, prostate
and pancreatic cancers.
BRCA 1 associated breast cancers are poorly differentiated,
with pushing margins, do not express hormone receptors or
over express HER2/neu.
BRCA1 mutation carriers- Worse prognosis if they have not
received adjuvant therapy.
Cell cycle check point kinase gene(CHEK2)
Muttion in p53.
Hormone receptor status:
Estrogen stimulation of cells takes place through binding of
the hormone to the estrogen receptor.
Coupling the hormone receptor complex to regulatory DNA
regions which initiate transcription of various genes.
Production of proteins Regulation of DNA synthesis .
Estrogens stimulate tumour proliferation via growth factors as
secondary messengers such as PDGF, TGF , IGF-I.
G1 phase. G1 to S phase.
Estrogen antgonists results in inhibition of the production of
autocrine stimulatory factors thus impending tumour growth.
They stimulate secretion of TGF by tumour cells which
inhibits proliferation of epithelial cells.
In ER positive tumours. The expression of PR, which is also
estrogen regulated gives a better prediction of estrogen
70-80% of breast carcinomas express ER and are thought to
arise from intrinsically ER positive luminal cells.
Hormone receptor positive cancers have better prognosis than
hormone negative carcinomas.
ER positive ductal carcinomas are usually well to moderately
differentiated and often show tubule formation.
ER positive Ca- Lobular, tubular, mucinous and papillary.
Estrogen receptor concentration are lower in tumours of
premenopausal women than in those of post menopausal
Immunohistochemistry is used to detect estrogen receptor
Positive tumours show distinct nuclear staining with
antibodies against this receptor.
Controls cell growth.
20-30% of breast cancers are associated with overexpression
of HER2/neu--- Poor prognosis.
Trastuzumab is a humanized monoclonal antibody to
HER2/neu developed to specifically target tumour cells.
In clinical trails, the combination of Trastuzumab with
chemotherapy have improved response in patients with
carcinomas expressing HER2/neu.
Scoring of HER-2 immunohistochemistry:
Score 0- No staining is observed or cell membrane staining is
observed in less than 10% of the tumour cells. (“negative”).
Score 1+ A faint perceptible membrane staining can be
detected in more than 10% of the tumour cells. The cells are
only stained in part of their membrane. (“negative”).
Score 2+ A weak to moderate complete membrane staining is
observed in more than 10% of the tumour cells. (“weakly
Score 3+ A strong complete membrane staining is observed in
more than 10% of the tumour cells.
Keratin staining pattern:
CK17, CK 5- Worse clinical outcome.
CEA staining pattern:
No relation with prognosis.
Vimentin staining pattern:
Poor prognosis in node negative ductal carcinomas.
Cathepsin D: Overexpression of CD in breast cancer is
associated with high risk of recurrence and poor survival.
Accumulation of p53 and low expression of nm23
correlates with reduced patient survival.
However some studies concluded that p53 was not a
reliable prognostic indicator.
Loss of heterozygosity for p53- high histologic and nuclear
Long term survival in breast carcinoma and
Correlates with estrogen receptor status.
Over expression does not indicate prognosis.
Level indicates proliferative index of breast carcinoma.
Can be measured by flow cytometry as the S phase
fraction by thymidine labeling index, mitotic counts or by
immunohistochemical detection of cellular proteins.
Cyclin E content when detected is very strong predictor
Tumours with high proliferation rate have a worse
Cell kinetics and DNA ploidy:
It reflects the growth rate and aggressivness of malignant
Determined by flow cytometry.
According to the DNA distribution, euploid and
aneuploid tumours are distinguished.
Euploid tumours- DNA of 2 or 4 fold diploid values, low
S phase compartment.
Aneuploid tumours: Irregular DNA expression, higher S
phase rate, faster growth.
Major prognostic factors by American joint
committee on Cancer:
Stage 0- DCIS or LCIS (5 year survival rate: 92%).
Stage I- Invasive carcinoma 2 cm or less in diameter
(including carcinoma in situ with microinvasion) without
nodal involvement (or any metastases< 0.02 cm in diameter)
(5 year survival rate:87%).
StageII- Invasive carcinoma 5 cm or less in diameter with up
to three involved axillary nodes or invasive carcinoma greater
than 5 cm without nodal involvement (5 year survival rate
Invasive carcinoma 5 cm or less in diameter with 4 or more
involved axillary nodes.
invasive carcinoma greater than 5 cm in diameter with nodal
invasive carcinoma with 10 or more involved axillary nodes
invasive carcinoma with involvement of the ipsilateral
internal mammary lymph nodes or invasive carcinoma with
skin involvement, chest wall fixation or clinical inflammatory
carcinoma (5 year survival rate: 46%).
Stage IV- Any breast cancer with distant metastases (5 year
survival rate :13%)
Robbins and Cotran, Pathologic basis of disease, 7th
Rosai and Ackerman’s, Surgical Pathology, 9th edition.
Steven Silverberg, Surgical Pathology and
Cytopathology, 14th edition.
Paul Peter Rosen, Rosen’s Breast Pathology, 3rd
Oxford textbook of Pathology.