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