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Invasive breast carcinomaand its variants
WHO classification of
Invasive breast carcinoma
Invasive ductal carcinoma of no special type• Mixed type carcinoma
• Pleomorphic carcinoma
•Carcinoma with osteoclastic giant cells
•Carcinoma with choriocarcinomatous
features
•Carcinoma with melanotic featuresInvasive lobular carcinoma
Tubular carcinoma
Invasive cribriform carcinoma
Medullary carcinoma
Mucinous carcinoma and other tumours with abundant mucin
• Mucinous carcinoma
•Carcinoma with Signet ring cell differentiation
Neuroendocrine tumours
• Solid neuroendocrine carcinoma
• Atypical carcinoid tumour
• Small cell / oat cell carcinoma
• Large cell neuroendocrine carcinoma
Mucinous carcinoma and other tumours with abundant mucin
• Mucinous carcinoma
•Cystadenocarcinoma and columnar cell mucinous
carcinoma
• Signet ring cell carcinoma
Neuroendocrine tumours
• Solid neuroendocrine carcinoma
• Atypical carcinoid tumour
• Small cell / oat cell carcinoma
• Large cell neuroendocrine carcinoma
Invasive papillary carcinoma
Invasive micropapillary carcinoma
Apocrine carcinoma
Metaplastic carcinomas
• low grade adenosquamous carcinoma
•Squamous cell carcinoma
•Fibromatosis like metaplastic carcinoma
•Spindle cell carcinoma
• Mixed epithelial/mesenchymal metaplastic
carcinomas
Lipid-rich carcinoma
Secretory carcinoma
Oncocytic carcinoma
Adenoid cystic carcinoma
Acinic cell carcinoma
Glycogen-rich clear cell
carcinoma
Sebaceous carcinoma
Inflammatory carcinoma
BREAST CARCINOMA – RISK FACTORS
BREAST CARCINOMA – RISK FACTORS
BREAST CARCINOMA – RISK FACTORS
PATHOGNESIS – GENETIC FACTORS
Most common genes implicated
in Breast carcinoma
BRCA -1Breast Cancer 1,Early onset
(Chr.17)
BRCA-2, Breast Cancer 2,Early onset (Chr.13)
P53 (Chr.17) CHEK2 (Chr. 22)
FUNCTIONS:1. Transcription2. DNA Repair of
double stranded breaks
3. Ubiquitination4. Transcriptional
regulation.
FUNCTIONS:1.Stability of the human genome2.DNA double strand break repair.
FUNCTIONS1. Cell cycle control2. DNA replication3. DNA repair4. Apoptosis.
FUNCTIONS1. Cell cycle
checkpoint kinase, recognition and repair of DNA damage.
2. Activates BRCA1 and p53 by phosphorylation
Germline point mutations/Deletions of BRCA1 gene Hereditary breast & ovarian cancers.
Mutations 20% Hereditary breast cancer, ovarian cancer, increased cancer risk in male carriers.
Mutations Sporadic breast cancers. Li fraumeni syndrome
Mutations - rare (<5%). Li fraumeni variantIncrease breast cancer risk after radiation exposure
HER2/neu• Human Epidermal growth factor Receptor2
• Member of ErbB protein family.
• HER2 is a cell membrane surface-bound receptor tyrosine kinase - normally involved in signal transduction pathways cell growth and differentiation.
• Approximately 30 % of breast cancers amplification of the HER2/neu gene/ overexpression of its protein product.
• Overexpression of this receptor in breast cancer increased disease recurrence and worse prognosis.
Invasive Carcinoma of no special typeMajority (70% to 80%).NO SPECIFIC HISTOLOGICAL TYPE
Gross appearance: • - firm to hard ,irregular border . • Less frequently - well-
circumscribed border , softer consistency.
• May be gritty on cut
Score 1: nuclei only slightly larger than benign breast epithelium (< 1.5 × RBC size or ductal epithelial cell); minor variation in size, shape and chromatin pattern
Score 2: nuclei distinctly enlarged (1.5–2 × RBC size or ductal epithelial cell ), often vesicular, nucleoli visible; may be distinctly variable in size and shape but not always
Score 3: markedly enlarged vesicular nuclei (> 2 × RBC size or ductal epithelial cell ), nucleoli often prominent; generally marked variation in size and shape but atypia not necessarily extreme
Score for nuclear atypia/ pleomorphism
Mixed type carcinoma
IC NST- it must have a non-specialized pattern in over
50% of its mass.
MIXED -If the IDC NOS pattern comprises between 10 and
49% of the tumour, the rest being of a recognized special
type, then it will fall into one of the mixed groups:
Mixed ductal and special type
Mixed ductal and lobular carcinoma
VARIANTS OF DUCTAL NOS
Pleomorphic carcinoma
•Rare variant of high grade ductal nos
carcinoma
•Pleomorphic and bizarre tumour giant
cells comprising >50% of the tumour
cells in a background of
adenocarcinoma or adenocarcinoma
with spindle and squamous
differentiation
•The tumour giant cells account for
more than 75% of tumour cells in most
cases.
• Mitotic > 20 per 10 Hpf
•Nuclear atypia grade 3
•ER PR –
•LN METS>50%
•POOR PROGNOSIS
•Osteoclastic giant cells in the stroma
•carcinomatous part of the
lesion is most frequently a well
to moderately differentiated
infiltrating ductal carcinoma
• Prognosis is related to the
characteristics of the
associated carcinoma and does
not appear to be influenced by
the presence of stromal giant
cells
Carcinoma with
osteoclastic giant cells
Microinvasive carcinoma
•One or more clearly separate microscopic foci of
infiltration of tumor cells into stroma each less than or
equal to 1mm.
•In association with high grade DCIS
•Infrequent
•Commonly overdiagnosed
•Upto 20% have been reported to have axillary metastasis
•Sentinel node biopsy is done in many centres
INVASIVE LOBULAR CARCINOMA
5-15%mammographic density
with irregular borders Sometimes tumor
infiltrates the tissue diffusely
little desmoplasia not palpableno mammographic density
Bilateral - 5 – 10 %.
E -CADHERIN
Solid pattern
• Sheets of uniform small cells of lobular morphology
•Cells lack cell to cell cohesion
•Pleomorphic cells
• Higher frequency of mitoses than the classical type
Alveolar variant
• Tumour cells arranged in globular aggregates of at least 20
cells
•Cell morphology and growth pattern being otherwise
typical of lobular carcinoma
Pleomorphic lobular carcinoma
•Retains the distinctive growth
pattern of lobular
• Greater degree of cellular atypia
and pleomorphism than
the classical form.
• Intra-lobular lesions composed of
signet ring cells or pleomorphic
cells are features frequently
associated with it
Carcinoma with medullary like features
•Medullary carcinoma
•Atypical medullary carcinoma
•IDC with medullary like features
MEDULLARY CARCINOMA1-7%
• 45-56 yearsMay closely mimic a benign
lesion clinically and radiologically/ present as a rapidly growing mass.
Well circumscribed,soft,fleshy mass
(medulla -“marrow”).
• Solid, syncytium-like sheets of large cells with vesicular, pleomorphic nuclei, prominent nucleoli in
> 75% of the tumor • Absence of tubule • Atypical cells with
moderate to marked nuclear pleomorphism and frequent mitotic figures
• Moderate to marked lymphoplasmacytic infiltrate surrounding and within the tumor.
• Pushing (noninfiltrative) border.
Lymph node metastases - infrequent.
favourable prognosisER, PR, HER2 – (triple negative)
Increased expression of
ICAM-1 and p- CADHERIN
•Atypical medullary carcinomaSyncitial growth
+Two or three of the above histological criterias
Less favourable prognosis than medullary carcinoma
•IDC with medullary features
Mucinous carcinomas and carcinoma with signet ring cell differentiationcolloid, mucoid, gelatinous, mucinous adenocarcinoma
2%> 55 years
• Well circumscribed • Soft ,gelatinous• Pushing margins
• >90%
•Detached epithelial elements floating
trabecular, cribriform, micropapillary
•No areas of usual type of invasion of stroma in the
absence of mucin
•Low grade cytology
•In situ component may be present
•May be seen in association with neuroendocrine
differentiation
•should always be diagnosed with qulifier pure or mixed if
assosiated with Invasive CA NST.
Hypercellular variant
D/DNeuroendocrine carcinoma
Hypocellular variant
D/D
• MUCOCELE like lesions with extravasated mucin
• Ducts distended by mucin
• Adherent myoepithelial cells
Lymph node metastases - uncommon.
Overall prognosis is better.
pure > mixed
Carcinomas with signet ring cell differentiation
• Intacellular mucin• Primary breast ca with
exclusive signet ring cells is rare.
• Most common in ILC• Can also be seen with
invasive ca NST
Signet ring cell differentiation
• Assosiated with lobular carcinoma
• Intracytoplasmic lumina• Target appearance • PAS/Alcian blue and
HMGF-2 positive
•Assosiated with DCIS
•Acidic mucin
D/D
• METASTASTIC CARCINOMA
• Stomach• ER, PR GCDFP -
Tubular carcinoma• 2-7%
• Small irregular mammographic densities
• Well-formed tubules
• absent myoepithelial cell layer
• Apocrine snouts
• Calcifications within the lumens.
• Desmoplastic stroma
• Minimal pleomorphism and scattered mitosis
• Atleast 90% tubular structure for pure variant
• Can not be diagnosed on biopsy, suggestion can be given
• Low grade DCIS in vicinity
• 100% ER, PR+
• Excellent prognosis• Low LN metastasis and
recurrence• Ideal candidate for
breast conservation surgery
D/D
Sclerosing adenosis –
•lobular architecture
•marked compression and distortion of the glandular
structures.
• Myoepithelial cells
• retained basement membrane can be shown by IHC for
collagen IV and laminin in tubules of SA
Microglandular adenosis -
•tubules are more rounded
•contain colloid-like secretory
material
• ring of basement membrane
present around tubules
Complex sclerosing lesions/radial scars –
• central fibrosis and elastosis containing a
few small, tubular structures
• myoepithelial cells
• surrounding glandular structures show
varying degrees of dilatation and ductal
epithelial hyperplasia
Invasive cribriform carcinoma
• 0.8-3.5% of breast carcinomas• mean age -53-58 years• clinically occult• Mammography-spiculated mass microrocalcifications• Multifocality – 20%• Favourable prognosis
• >90% of invasive cribriform pattern
• Apical snouts • low or moderate degree
of nuclear pleomorphism.
• Mitoses are rare• fibroblastic stroma
D/D
Carcinoid tumour- intracytoplasmic argyrophilic granules
Adenoid cystic carcinoma-• second cell population • intracystic secretory and basement membrane like material
Extensive cribriform DCIS -• myoepithelial cell layer• Regular distribution
Invasive papillary carcinoma
• Papillary morphology in > 90% of invasive component
• Solid and encysted carcinoma with invasive component are not labelled as invasive papillary carcinoma.
Papilloma
Intraductal papillary carcinoma
Invasive micropapillary carcinoma•Pure < 2%•Asso with IDC in upto 7%
• Hollow aggregates of malignant cells
•Appearance of tubules with
obliterated lumens
• Pyknotic nuclei
•Peripharaly bulging out nuclei with
knobby appearance, hedgehog tumor
• Tumour cell cluster lie within
artifactual stromal spaces caused by
shrinkage of the surrounding tissue
MUC 1 STAINS THE STROMAL SURFACE
Frequent
•lymphovascular invasion
• lymph node metastasis
Metaplastic carcinoma
•Differentiation of neoplastic epithelial elements into spindle cell, squamous, and/or mesenchymal looking elements.(Matrix producing carcinoma, carcinosarcoma, spindle cell carcinoma)
•0.2-5%
•Low grade adenosquamous ca
•Fibromatosis like metaplastic carcinoma
•Squamous cell ca
•Spindle cell ca
•Carcinoma with mesenchymal differentiation
Chondroid
Osseous
Others
•Mixed metaplastic carcinoma
Descriptive classification
Low grade adenosquamous carcinomasyringomatous squamous tumour
• glands and tubules
•Epithelial squamous cells in
spindle cell background
•Neoplastic glands infiltrate the
normal breast as long slender
extensions
•good prognosis
•May be locally aggressive
•Reccur in incomplete excision
Fibromatosis like metaplastic carcinoma
•Interlacing fascicles of bland spindle cells with elongated
nuclei in a collagenised stroma
•Cords and finger like extensions extending into adjacent
stroma
•Minimal nuclear pleomorphism
•Plump epitheloid cells may be seen
•Focal squamous differentition
•P63 +
Squamous cell carcinoma
Acantholytic squamous cell carcinomaD/DAngiosarcoma
D/D
metastasis
Spindle cell carcinoma
• Atypical Spindle cells
•Herring bone , storiform pattern
•Moderate to high nuclear
pleomorphism
Focal squamous diffrentiation
•CK+
•Constitute a spectrum of spindle
squamous cell ca to myoepithelial
ca
•No definite criteria to distinguish
IHC:
•HMWCK+
•p63+ >90%
Differentiation from
other spindle and
mesenchymal tumors
vs phyllodes tumor
with sarcomatous
overgrowth
CD34+
Bcl2 +
CK-
p63-
Mixed epithelial / mesenchymal metaplastic carcinomas
ChondroidOsseousRhabdoidNeuroglialMay be of any grade
Epithelial element may include squamous differentiation
•Less frequent LN metastasis
•Distant metastasis +
•Metaplastic cracinoma- poor resposne to chemotherapy
•Worse outcome as compared to other triple negative tumors
•Express neuroendocrine markers in more than 50% of the cell population•2-5%•60-70 yrs
Neuroendocrine carcinoma
D/D•Metastatic carcinoid•Small cell carcinoma lung
Negative for• CK7•CK20•GCDFP-15•ER•PR
Lobular carcinoma Negative for E-cadherin
• Histological grading - important prognostic parameter
• NE breast carcinomas may be graded using classical criteria
described elsewhere
• 45% of NE breast carcinomas - well differentiated
• 40% are moderately differentiated
• 15% are poorly differentiated
• Small cell NE carcinomas should be considered as
undifferentiated carcinomas
• Mucinous differentiation is a favourable prognostic factor
Apocrine carcinoma
• Carcinoma showing cytological and immunohistochemical features of apocrine cells in >90% of the tumour cells.• Two types of cells variously intermingled-
Type A cell abundant granular intensely eosinophilic cytoplasm PAS positive diastase resistantmimic granular cell tumours referred as myoblastomatoid
Type B cell abundant cytoplasm with fine empty vacuoles foamy appearance resemble histiocytes and sebaceous cells. designated as sebocrine May resemble a histiocytic proliferation or even an inflammatory reaction
•Juvenile or secretory carcinoma found often in children, but majority of cases have been reported in adults •0.15%
•periareolar
•papillary, microcystic, and glandular patterns •Associated intraductal component
Secretory carcinoma
•Secretion is usually pale pink or amphophilic with H&E vacuolated or “bubbly•PAS + diastase resistant•Minimal cellular pleomorphism
3 patterns present in varying combinations: 1.A microcystic (honeycombed) pattern composed of small cysts often merge into larger spaces closely simulate thyroid follicles 2. A compact more solid3. A tubular pattern consisting of numerous tubular spaces containing secretions
•Exceptionally favorable prognosis in
children
•Local excision is the preferred initial
treatment in children
•More aggressive in adults requiring
mastectomy.
Adenoid cystic Carcinoma( adenoides cysticum, adenocystic basal
cell carcinoma, cylindromatous carcinoma)
•Histologically similar to the
salivary gland counterpart
•0.1%
The cribriform pattern is the most characteristic as the neoplastic areas are perforated by small apertures like a sieve.
•Pseudolumens lined by basaloid cells•Intratumoral invaginations of the stroma•Contains myxoid acidic stromal mucosubstances which stain with alcian blue { or straps of collagen with small capillaries. Hyaline collagen •Laminin and collagen IV positive material outlines the stromal spaces
•Secretory glandular lined by eosinophilic cells•structures contain eosinophilic granular secretion of neutral mucosubstances•Periodic acid-schiff positive after diastase digestion
D/D Invasive cribriform carcinoma ER+PR+
SMA staining the basaloid cells
•Low malignant potential
•t/t mastectomy
•Inflammatory carcinoma is a form of advanced breast
carcinoma classified as T4d. •Carcinoma must involve dermal lymphatics
•Parenchymal peritumoral lymphatic involvement is not sufficient•Dermal invasion without lymphatic involvement is not sufficient
•Marked lymphocytic and plasmacytic reaction may be present
Inflammation not required-Perivascular lymphocytic aggregates should lead to careful examination for carcinoma emboli
Dermal lymphatic invasion without the characteristic
clinical picture is insufficient to qualify as inflammatory
carcinoma.
Inflammatory carcinoma
Sentinel lymph node biopsy
•Injection of vital blue dye and/or radiolabeled colloid around the area of the tumor permits identification of a SLN
•In patients with clinically node-negative breast cancer, sentinel lymph node biopsy (SLNB) identifies patients without axillary node involvement, thereby obviating the need for more extensive surgery.
•One of the greatest concerns with SLNB is the potential
of a false-negative (5 - 10 %) result.
•Several series suggest that axillary recurrence rates
are low after a negative SLNB alone in early-stage
breast cancer (0 - 4.5 %).
The guideline updates three recommendations based on evidence from
randomized controlled trials:
• Women without sentinel lymph node (SLN) metastases should not receive
axillary lymph node dissection (ALND).
• Most women with 1 to 2 metastatic SLNs planning to receive breast
conserving surgery with whole breast radiotherapy should not undergo
ALND.
•Women with SLN metastases who will receive mastectomy may be offered
ALND.
Sentinel Lymph Node Biopsy for Patients With Early-Stage Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update, 2014
The guideline updates two groups of recommendations based on
cohort studies and/or informal consensus:
• Women with operable breast cancer and multicentric tumors, and/or
DCIS who will have mastectomy, and/or had prior breast and/or
axillary surgery, and/or had preoperative/neoadjuvant systemic
therapy may be offered sentinel lymph node biopsy (SNB).
• Women who have large or locally advanced invasive breast
cancers (tumor size T3/T4), and/or inflammatory breast cancer,
and/or DCIS, when breast-conserving surgery is planned, and/or are
pregnant should not receive SNB.
MULTIFOCAL- Two or more foci of cancer within
the same breast quadrant or at < 5cm distance
MULTICENTRIC- two or more foci of cancer in
different quadrants of the same breast
Detailed serial-sectioning of mastectomy specimens
identifies additional separate tumor deposits in
approximately 30% of women with breast cancer
Increased risk of
-Axillary lymph node metastasis
-recurrence
IHC:
•ER positive clinically as > 1% strong positivity in presence of internal and external controls
•PR > 1%
•Her2 – 3+ >10% strong compete membranous staining
•2+ > 10% moderately strong circumferential staining
FISH:
HER2:CEP17- > 2.2
Allred scoring for ER
p53 and ki67
•Higher ki67 index and positive p53 is associated with triple negative tumors
•p53 expression is seen in `basal type` of tumors
•Associated with worse outcome and decreased overall survival
STAGING
•7th editioin of TNM staging
stage IB- PT1+ pN1mi ( micromatastasis)
Vs stage II with macromatastasis
•LVI is independant prognostic factor ( without LN mets
15%)
•LVI WITHOUT LN mets is more often seen in Triple
negative carcinomas.
•Dermal LVI is poor prognostic factor
Molecular classification
• Studies of breast cancers using gene expression
profiling have identified several major breast cancer
subtypes beyond the traditional hormone receptor
positive and hormone receptor-negative types.
• These breast cancer molecular subtypes differ with
regard to their patterns of gene expression, clinical
features, response to treatment, and prognosis,
Hormone receptors genetics
ER PR HER2
IDC NOS 70-80%
60-70%
15% BRCA-1 medullary featureBRCA-2 tubule
Invasive lobular ca
70-95%
60-70%
Luminal A Loss of E-CADHERIN at 16q
Tubular ca ++ ++ - Luminal A 16q-, 8p-, 3p FHIT, 11p ATM
Medullary ca - - - Basal like BRCA-1, p53, p cadherin, caveolin
Mucinous ca ++ 70%
Micropapillary ca 60-100%
40-80%
10-30% Luminal A and B
8q+.17q+,20q+
Papillary ca
Neuroendocrine ca
+ +
Metaplastic ca - - - Basal like p53