Invasive breast cancer

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Breast cancer at cut-up. (WC/John Hayman)

The article deals with invasive breast cancer and the evaluation of hormone receptor & HER2 status. Non-invasive breast cancer is dealt with in non-invasive breast cancer.

Contents

Introduction

Overview of invasive breast cancer subtypes

Common epithelial subtypes

Type and percentage of breast carcinomas:[1]

Common stromal types

Good prognosis subtypes

Three good prognosis subtypes:[3]

  • Tubular carcinoma.
  • Mucinous carcinoma.
  • Papillary carcinoma.

Comprehensive list of invasive breast cancer subtypes

Epithelial

Counterparts of in situ lesions:

Other epithelial tumours:

Epithelial tumours seen in the salivary gland:

Seen in the skin:

Clinically diagnosed:

  • Inflammatory carcinoma.

In situ lesions:

Proliferative lesions:

Non-specific:

  • Microinvasive carcinoma.

Papillary:

  • Papilloma.
  • Atypical papilloma.
  • Intraductal papillary carcinoma.

Adenomas:

Myoepithelial

  • Myoepitheliosis.
  • Adenomyoepithelial adenosis.
  • Adenomyoepithelioma.
  • Malignant adenomyoepithelioma.

Mesenchymal tumours

See: Soft tissue lesions.

Fibroepithelial tumours

Nipple lesions

Other

Familial breast cancer

Breast IHC

Molecular classification of invasive carcinoma

A molecular classification:[4]

Type Percentage IHC Histology Prognosis/clinical
Luminal A ~45% ER+ PR+ HER2- well-differentiated good, chemo resistant
Luminal B 17% ER+ PR+ HER2+ high grade poor, +/- chemo responsive
Normal breast-like ~8% ER+ PR+ (?) HER2- well-differentiated good
Basal-like ~20% ER- PR- HER2- poorly differentiated aggressive, may have good chemo response, classic for BRCA1 mutation
HER2 positive ~10% ER- PR- (?) HER2+ poorly differentiated poor

The above is not applied clinically. A panel of immunostains (ER, PR, HER2, EGFR, CK5/6) can reproduce the molecular groupings; however, these groupings originate from gene expression profiling studies[5]

A newer classification outlines 10 subtypes based on molecular drivers identified by analysis of genomic and transcriptomic data from 2,000 breast tumors.[6]

Basal-like breast carcinoma

  • Overview:[7]
    • A category of breast carcinomas defined by gene expression profiling.
    • Not used in clinical practice.
    • Somewhere between 15-30% of breast carcinomas.
    • Can be roughly be identified by immunohistochemistry - basal markers (CK14, p63, calponin, SMA).
    • Not derived from myoepithelial cells, merely express a phenotype more in keeping with basal cells than ductal cells.
    • Most triple negative (ER, PgR, Her-2); therefore cannot be treated with the usual therapeutic agents.
    • There is an association in young women between basal-like breast cancer and BRCA1 mutation.
    • Discussions of BRCA1 associated tumors, TNBC and BLBC are typically muddied by the overlap.
    • Increased incidence in some populations - African-Americans, young women
    • Sporadic basal-like cancers do not have a BRCA1 mutation but may have a dysfunctional BRCA1 pathway.
    • p53 mutations are frequent.
  • Classic morphological clues of a basal type cancer usually refer to medullary carcinoma features:
    • Relatively circumscribed.
    • Geographic necrosis.
    • Abundant mitoses.
    • Pushing margins.
    • Central fibrosis or necrosis.
    • High histological grade.
    • Exceptionally high mitotic rate.
    • Pushing borders.
    • Conspicuous lymphocytic infiltrate.
  • Behaviour:
    • Basal-like breast cancer is a heterogeneous group.
    • The behaviour of basal-like breast cancer appears to fall into two groups:
      • The tumours that are by nature low grade (ie adenoid cystic carcinoma) and/or do not metastasise have a better prognosis than other types of breast carcinoma.
      • The tumours with early metastasis that may behave more aggressively
        • Hematogenous spread -greater tendency to metastasise to visceral sites (notably lung and brain) instead of to nodes and bone.
    • Many have a complete response to chemotherapy and survival rates similar to typical breast cancer
    • Non-complete response to chemotherapy is associated with low survival at 5 years.

Other sources Minireview: Basal-Like Breast Cancer: From Molecular Profiles to Targeted Therapies <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3035993/>

Triple Negative Breast Carcinoma

Features:[8]

    • A category of breast carcinomas defined by immunohistochemical/FISH expression of ER, PR and HER2.
    • Important to identify in clinical practice.
    • About 15% of breast carcinomas.
    • Important group due to a lack of tailored therapies for this group
      • Some triple negatives also express androgen receptor and have and [apocrine carcinoma] morphology.[9]
        • May respond to therapies targeting the androgen receptor.
      • BCL11A overexpression recently identified as an oncogenic driver for some triple negatives [10]
        • Targeted therapies may include inhibitors of BCL11A.
    • Triple-negative and basal-like phenotypes are not synonymous but overlap
      • About 70% of triple-negative tumours are basal-like.
      • About 70% of basal-like tumors are triple-negative tumours.
    • Discussions of BRCA1 associated tumors, TNBC and BLBC are typically muddied by the overlap.
    • Classic 'morphological clues' to a triple negative cancer usually refer to medullary carcinoma features.

Immunostains for typing and diagnosis

DCIS versus LCIS

Tabular comparison for DCIS versus LCIS:[11][12]

Disease E-cadherin Beta-catenin 34betaE12 CAM5.2 (CK8)
DCIS +ve +ve -ve +ve peripheral cytoplasm
LCIS -ve -ve +ve perinuclear +ve perinuclear

Invasive versus non-invasive

Myoepithelial markers - typically lost in invasive carcinoma:[13]

Stain Location Notes
p63 nuclear up to 10% of invasive tumours +ve[14]
Smooth muscle actin (SMA) cytoplasmic stains myofibroblasts & blood vessels
Calponin cytoplasmic stains myofibroblasts & blood vessels
Smooth muscle myosin
heavy chain (SMM-HC)
cytoplasmic stains myofibroblasts & blood vessels

Respecting findings that might indicate a more extensive search for microinvasion be undertaken in cases of pure ductal carcinoma in situ (DCIS), a recent study found 1) intermediate or high DCIS grade, 2) tumor thickness, and 3) diffuse peritumoral retraction clefts, but not such things as lymph node metastases, or HER2 score, independently increased the likelihood of finding a microinvasive component. [15]

Usual ductal hyperplasia versus ductal carcinoma in situ

Markers for UDH versus DCIS:[14]

Disease CK5/6 ER
UDH diffuse +ve patchy +ve
DCIS -ve diffuse +ve

Lymphovascular invasion

  • D2-40 - marks the lymphatic spaces.[16][17]
  • CD31 - marks lymphovascular spaces.
  • CD34 - marks lymphovascular spaces, less specific than CD31.

Lymph node metastases

Immunostaining of sentinel lymph nodes to look for isolated tumour cells and small lymph node metastases may be done.

  • CAM5.2 may be used.
  • Not done routinely.

Treatment-related markers - overview

  • ER (estrogen receptor).
    • Positive in most breast cancers; +ve in ~75-80%.[18]
  • PR (progesterone receptor).
    • Positive in most breast cancers; +ve in ~65-70%.[18]
  • HER2/neu (HER2).
    • Usually negative; -ve in 70-80%.[18]
    • Positivity associated with a worse prognosis.
    • In the context of HER2 positivity, PTEN/PI3K/Akt/mTOR pathway dysregulation is a poor prognosticator.[19][20]

Notes:

  • Male breast cancer is usually hormone receptor positive (~97%), and HER2 positivity is quite rare (~6%).[21]
  • ASCO/CAP guidelines recommend that cold ischemia time be <1 hour.[22]

ER & PR scoring

Nuclear staining:[18]

  • Give a percentage, i.e. 0-100%.
    • Important cut points: 1% and 10%.
      • 0% = negative - not treated.
      • <10% = low positivity - treated.

Notes:

  • Normal breast epithelial cells have a patchy staining for ER and PR.
  • Evaluated on the invasive component.

HER2 scoring

Immunohistochemical based testing:[23][24]

Score Staining intensity Cells stained (%) Membrane staining Management Percentage of cases
0 no staining/barely visible ≤10% incomplete No HER2 blocker ~60%
1+ minimal/barely visible >10% incomplete No HER2 blocker ~10%
2+ weak-to-moderate >10% incomplete (circumferential) Needs SISH or FISH ~10% †
2+ intense ≤10% complete Needs SISH or FISH ~10% †
3+ intense staining >10% complete HER2 blocker ~20%

Note for IHC:

  • Normal breast epithelial cells do not stain with HER2.
  • Evaluated on the invasive component.
  • SISH = silver in situ hybridization.
  • FISH = fluorescence in situ hybridization.
  • † Together approximately 10%.
  • ‡ The cut point was 10%, changed to 30% and then changed back to 10%.[23]

ISH based testing:[25]

Result Ratio criteria Gene copy number criteria
Positive ≥2.0 HER2/CEP17 ≥6.0 copies of HER2/cell
Equivocal <2.0 HER2/CEP17 (required) 4.0-6.0 copies of HER2/cell
Negative <2.0 HER2/CEP17 <4.0 copies of HER2/cell

Note for ISH:

  • Can be called positive based on either ratio criteria or gene copy number criteria.

Clinical

  • ER & PR status determine whether a patient will get tamoxifen or other estrogen receptor modulators, such as raloxifene (Evista).
  • HER2 status determines whether patient will get traztuzumab (Herceptin) or other HER2/neu modulators.

Characteristics of the subtypes

Invasive ductal carcinoma of the breast

  • AKA "NST" = No Specific Type.
  • AKA invasive mammary carcinoma.

Invasive lobular carcinoma

  • Abbreviated ILC.
  • AKA lobular carcinoma.

Medullary breast carcinoma

  • AKA medullary carcinoma of the breast.

Tubular carcinoma of the breast

  • AKA tubular carcinoma.

Metaplastic breast carcinoma

  • AKA metaplastic carcinoma.

Invasive micropapillary carcinoma of the breast

  • AKA micropapillary carcinoma.

Apocrine carcinoma of the breast

Mucinous breast carcinoma

  • AKA mucinous carcinoma of the breast, AKA colloid carcinoma of the breast.

Adenoid cystic carcinoma of the breast

  • AKA breast adenoid cystic carcinoma.

Intracystic papillary breast carcinoma

  • AKA encapsulated or encysted papillary carcinoma of the breast, abbreviated EPC.

Glycogen-rich clear cell carcinoma of the breast

  • Abbreviated GRCC.

Secretory carcinoma of the breast

  • AKA secretory breast carcinoma, abbreviated SBC.

Invasive cribriform carcinoma of the breast

Invasive papillary carcinoma of the breast

Grading breast cancer

Staging breast cancer

Lymphovascular invasion

In the context of breast pathology, the Rosen criteria for LVI are widely excepted, and are as follows:[26][27]

  1. Must be outside of the tumour proper.
    • LVI is usually very close -- typically within 0.1 cm.
  2. Contour of cells should differ from possible vessel wall.
    • DCIS with retraction artifact mimicing LVI has a contour that matches its surrounding fibrous tissue.
  3. Endothelium (usu. flat) should be visible.
  4. Lymphatics are found adjacent to blood vessels - vessels should be present in the vicinity.

Memory device LUBE-O:

  • LVI has a Unique contour, Blood vessels and Endothelium in the vicinity, and is Outside of the tumour.

Note:

  • LVI does not affect the stage.

Other

Paget's disease

General

  • Associated with underlying breast carcinoma.[28]

Notes:

Microscopic

Features:[28]

  • Cells in the epidermis:
    • Epitheliod morphology (round/ovoid).
    • Cells nested or single.
    • Clear/pale cytoplasm key feature - may also be eosinophilic.
    • Large nucleoli.

Images:

IHC & DDx:

Trivia

Tumour size and lymph node metastases

There is a paper[29] that calculates the probability of lymph node mets based on tumour size. The developed formula is:

L_{To-Nodes}=1-exp(-Q_n D^Z)

Where:

  • L_{To-Nodes} = the probability of the lymph nodes being positive.
  • D = the largest dimension of the tumour in millimetres.
  • Z = 1.0041.
  • Q_n = 0.019.

Selected values

Tumour size (mm) Probability
5 9 %
10 17 %
15 25 %
20 32 %
25 38 %
30 44 %
35 49 %
40 54 %
45 58 %
50 62 %

Natural history

There is a theory that up to 22% of small (radiographically detected) breast tumours regress, based on an analysis in a large population.[30] The study is supported by NCI's SEER data.[31] Also, it generated many comments.[30]

Missed macrometastases

The effect of missed macrometastases is small; this implies using IHC to look for isolated tumour cells is money that isn't well spent.[32]

See also

References

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