Invasive ductal carcinoma

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Author: Mikael Häggström [notes 1]

Gross examination

Gross appearance of invasive ductal carcinoma.

As per:

or mastectomy.

Microscopic evaluation

Invasive ductal carcinoma, with occasional entrapped normal ducts (arrow).

Characteristics

Low power:[1]

  • Sheets, nests, cords or individual cells
  • Prominent tubular formations in well differentiated tumors, but absent when poorly differentiated
  • The stroma is usually desmoplastic

High power typically shows tumor cells that are more pleomorphic than in lobular carcinoma.[1]

Differential diagnosis

Invasive versus in situ

In invasive ductal carcinoma, malignant cells have penetrated the basement membrane, in contrast to ductal carcinoma in situ. In uncertain cases, use immunohistochemistry stain for calponin (has the highest sensitivity) and p63 (has the highest specificity).

Ductal versus lobular

  • Invasive lobular carcinoma typically has single files of tumor cells rather than duct-forming tumor cells. In uncertain cases, stain for E-cadherin and p120:

Staging

Stage by the TNM system as follows in sections below.

Also, look for any angiolymphatic invasion. If present, check whether it reaches outside the tumor, and if so, how far.[2] Give greatest dimension (,or 3 dimensions, generally by adding up the estimated thicknesses of involved slices)).[2]

Primary Tumor (T)

Tumor – Depends on the tumor at the primary site of origin, as follows:[3]

Measurements can be made by marking the tumor on microscopy, and then measuring between the markings, which may overlap between multiple slides as shown.
  • T1: Less than 2 cm
  • T1a: 0.1 to 0.5 cm
  • T1b: 0.5 to 1.0 cm
  • T1c: 1.0 to 2.0 cm
  • T2: 2 to 5 cm
  • T3: Larger than 5 cm
  • T4
  • T4a: Chest wall involvement
  • T4b: Skin involvement
  • T4c: Both 4a and 4b
  • T4d: Inflammatory breast cancer, a clinical circumstance where typical skin changes involve at least a third of the breast.

Regional Lymph Nodes (N)

Lymph Node – The lymph node values depend on the number, size and location of breast cancer cell deposits in various regional lymph nodes, such as the armpit (axillary lymph nodes), the collar area (supraclavicular lymph nodes), and inside the chest (internal mammary lymph nodes.)[4][5] Each stage is as follows:[3]

  • N0: There is some nuance to the official definitions for N0 disease, which includes:
  • N0(i+) : Isolated Tumor Cell clusters (ITC),[2] which are small clusters of cells not greater than 0.2 mm, or single tumor cells, or a cluster of fewer than 200 cells in a single histologic cross-section, whether detected by routine histology or immunohistochemistry;
  • N0(mol-): regional lymph nodes have no metastases histologically, but have positive molecular findings (RT-PCR).
  • N1: Mobile ipsilateral axillary nodes. Lymph node clusters 0.2 - 2.0 mm can be called "micrometastasis". At least one carcinoma focus over 2.0 mm is called "Lymph node metastasis". If one node qualifies as metastasis, count all other nodes even with smaller foci as metastases as well.[2]

Critical numbers of involved nodes: 1-3, 4-9, and 10 and over. Note any extranodal extension.[2]

  • N2: Fixed/matted ipsilateral axillary nodes.
  • N3
  • N3a – Ipsilateral infraclavicular nodes
  • N3b – Ipsilateral internal mammary nodes
  • N3c – Ipsilateral supraclavicular nodes

Distant Metastases (M)

  • M0: No clinical or radiographic evidence of distant metastases
  • M0(i+): Molecularly or microscopically detected tumor cells in circulating blood, bone marrow or non-regional nodal tissue, no larger than 0.2 mm, and without clinical or radiographic evidence or symptoms or signs of metastases, and which, perhaps counter-intuitively, does not change the stage grouping, as staging for in M0(i+) is done according to the T and N values
  • M1: Distant detectable metastases as determined by classic clinical and radiographic means, and/or metastasis that are histologically larger than 0.2 mm.

Overall stage

A combination of T, N and M, as follows:[3]

  • Stage 0: Tis
  • Stage I: T1N0
  • Stage II: T2N0, T3N0 T0N1, T1N1, or T2N1
  • Stage III: Invasion into skin and/or ribs, matted lymph nodes, T3N1, T0N2, T1N2, T2N2, T3N2, AnyT N3, T4 any N, locally advanced breast cancer
  • Stage IV: M1, advanced breast cancer
Further information: Evaluation of tumors

Grading

The Nottingham system[6] is recommended for breast cancer grading.[7] The Nottingham system is also called the Bloom–Richardson–Elston system (BRE)[8], or the Elston-Ellis modification[9] of the Scarff-Bloom-Richardson grading system.[10][11] It grades breast carcinomas by adding up scores for tubule formation, nuclear pleomorphism, and mitotic count, each of which is given 1 to 3 points. The scores for each of these three criteria are then added together to give an overall final score and corresponding grade as follows.

Tubule formation

Tubule formation score in the Nottingham system

The overall appearance of the tumor is considered.[12]

  • 1 point: tubular formation in more than 75% of the tumor (it may in addition be termed "majority of tumor")
  • 2 points: tubular formation in 10 to 75% of the tumor ("moderate")
  • 3 points: tubular formation in less than 10% of the tumor ("little or none")

Nuclear pleomorphism

Such as nuclei being larger, darker, or irregular/pleomorphic. Note: The cancer areas having cells with the greatest atypia should be evaluated.

  • 1 point: Nuclei are small or mildly increased in size compared to normal breast epithelial cells. They have uniform nuclear chromatin and only mild pleomorphism.
  • 2 points: nuclei with moderate variation in size and shape. Cells are larger than normal, display open vesicular nuclei, have visible nucleoli.
  • 3 points: nuclei with marked variation in size and shape. Cells display vesicular nuclei, often prominent nucleoli. Often very large and bizarre cells.

Mitotic count

Mitosis appearances in breast cancer

Mitotic figures are counted only at the periphery of the tumor, and counting should begin in the most mitotically active areas.

  • 1 point: Between 0-5 and 0-11 mitotic counts per 10 high-power fields (HPFs), depending on type of microscope used.[notes 2]
  • 2 points: Between 6-10 and 12-22 mitotic counts per 10 HPFs.[notes 2]
  • 3 points: Over 10 to 22 mitotic counts per 10 HPFs.[notes 2]

Overall grade

The scores for each of these three criteria are added together to give a final overall score and a corresponding grade as follows:

  • 3-5 Grade 1 tumor (well-differentiated). Best prognosis.
  • 6-7 Grade 2 tumor (moderately differentiated). Medium prognosis.
  • 8-9 Grade 3 tumor (poorly differentiated). Worst prognosis.

Immunohistochemistry

Ki-67 index

Ki-67 in an invasive breast cancer: cancer nuclei are stained (brown). There is tumor cell positivity in 70% of the cells (Ki-67 labelling index = 70%).

For Ki-67 index, there are two main methods, a faster "hot spot" method and the more comprehensive IKWG global average:

Hot spot:

Hot spots are areas in which Ki-67 staining is particularly higher relative to the adjacent tumor areas.[13] Usually, the invasive edge of a tumor is a hot spot.[13] When a tumor had several hot spots, the “hottest” spot is selected.[13] Aim to count at least 500 cells in each case, but this is not always possible in cases with low tumor cell density and small tumor size.[13] Also aim to include at least three high-power (×40 objective) fields.[14]

IKWG global average:[15]
  1. Before first use, access the IKWG website (https://www.ki67inbreastcancerwg.org/) and complete the Ki67 calibration exercise
  2. From Tools, link to the Online scoring app (or download and install the Ki67 counting app) and use the global method
  3. Using a regular light microscope, review the Ki67-stained breast cancer slide and input estimates of the percent area with negligible, low, medium, or high Ki67 index
  4. Score 100 nuclei negative or positive in each field type (as directed by the app)
  5. Record “Weighted global score” output as the Ki67 index for that slide

Regardless of method:[14]

  • If a comparisons must be made between core biopsies and sections from an excision, evaluation of the latter should be across the whole tumor.
  • Only nuclear staining counts. Staining intensity of a positive nucleus is not relevant.

HER2/neu

Score[16] Status[16]
0 to 1+ HER2 negative
(not present)
2+ Borderline
3+ HER2 positive

Neoadjuvant cases

Invasive ductal carcinoma with partial response to chemotherapy, seen as fibroelastic areas between tumor nests.[17]

edit
In neoadjuvant cases (patient has received chemotherapy, endocrine therapy and/or radiotherapy before the excision), perform:

  • Measurement of the tumor bed which generally manifests as a fibroelastic area.
  • Classification of residual cancer, for which there are multiple systems, mainly Residual Cancer Burden (RCB)[notes 3] and the American Joint Committee on Cancer post-neoadjuvant therapy staging system (yAJCC).[18]
Further information: Evaluation of tumors

Report

Breast excision

  • Tumor size, if not already given from gross report.[2] Give 3 dimensions or greatest dimension.[2]
  • Histopathologic subtype if apparent, but "invasive carcinoma" is acceptable.
  • Stage[2]
  • Grade, preferably by overall BRE grade. Optionally, give scores for the components thereof.[2]
  • Extent of any angiolymphatic invasion.[2]
  • Margins of resection,[2] either as minimal distance to margin, or as radical vs. not radical excision.
  • Results of any immunohistochemistry and other tests[2]
  • HER2 as a score or status.
  • Ki-67, preferably as labeling index

Example:

Breast excision with 70 x 55 x 18 mm ductal invasive breast cancer. Nottingham grade II. Estrogen receptor positive, progesterone receptor negative, HER2 receptor score 0, Ki-67 index 17%, T1b. Radically removed.

Needle or core biopsy

  • Histopathologic subtype if apparent, but "invasive carcinoma" is acceptable.
  • Results of any immunohistochemistry and other tests, as per excision[2]
  • Presence of absence of angiolymphatic invasion[2]
  • Optionally: Provisional grading. Grading can alternatively be deferred to excision.[2]
  • State if studies are deferred for a later excision sample[2]

Notes

  1. For a full list of contributors, see article history. Creators of images are attributed at the image description pages, seen by clicking on the images. See Patholines:Authorship for details.
  2. 2.0 2.1 2.2 Mitotic count:
    • 1 point: 0-9 mitotic counts per 10 fields under X25 objective using the Leitz Ortholux microscope, 0-5 mitotic counts per 10 fields under X40 objective using the Nikon Labophot microscope, or 0-11 mitotic counts per 10 fields under X40 objective using the Leitz Daiplan microscope
    • 2 points: 10-19 mitotic counts per 10 fields under X25 objective using the Leitz Ortholux microscope, 6-10 mitotic counts per 10 fields under X40 objective using the Nikon Labophot microscope, or 12-22 mitotic counts per 10 fields under X40 objective using the Leitz Daiplan microscope
    • 3 points: Over 19 mitotic counts per 10 fields under X25 objective using the Leitz Ortholux microscope, over 10 mitotic counts per 10 fields under X40 objective using the Nikon Labophot microscope, or over 22 mitotic counts per 10 fields under X40 objective using the Leitz Daiplan microscope
  3. A calculator and explanations for calculating RCB is found at: http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=jsconvert3

Main page

References

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  2. 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 . Infiltrating Ductal Carcinoma of the Breast (Carcinoma of No Special Type). Stanford Medical School. Retrieved on 2019-10-02.
  3. 3.0 3.1 3.2 Originally copied from Fadi M. Alkabban; Troy Ferguson. Cancer, Breast. National Center for Biotechnology Information. Last Update: June 4, 2019. Creative Commons Attribution 4.0 International License
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  5. "Internal mammary lymphadenopathy: imaging of a vital lymphatic pathway in breast cancer ". Radiographics 10 (5): 857–70. September 1990. doi:10.1148/radiographics.10.5.2217975. PMID 2217975. 
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  10. Bloom, H.J.; Richardson, W.W. (1957). "Histological grading and prognosis in breast cancer; A study of 1409 cases of which 359 have been followed for 15 years ". British Journal of Cancer 11 (3): 359–77. doi:10.1038/bjc.1957.43. PMID 13499785. 
  11. Genestie, C.; Zafrani, B.; Asselain, B.; Fourquet, A.; Rozan, S.; Validire, P.; Vincent-Salomon, A.; Sastre-Garau, X. (1998). "Comparison of the prognostic value of Scarff-Bloom-Richardson and Nottingham histological grades in a series of 825 cases of breast cancer: Major importance of the mitotic count as a component of both grading systems ". Anticancer Research 18 (1B): 571–6. PMID 9568179. 
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  17. Image by: Mikael Häggström, M.D. Public Domain
    - Author info
    - Reusing images
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