Breast cancer staging

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor in Chief(s): Soroush Seifirad, M.D.[2], Jack Khuri

Overview

Breast cancer used to be staged according to the TNM system. Recently, the American Joint Committee on Cancer (AJCC) Staging Manual (8th edition, last updated 1/25/2018) extensively revised their staging system. The 8th edition of the AJCC TNM breast cancer staging system delivers a flexible platform for prognostic classification based on traditional anatomic factors, which may be modified and enhanced with respect to patient biomarkers and other prognostic panel data. Nevertheless, in order to maintain worldwide value, AJCC tumor staging system remained based on classic TNM anatomic factors. Prognosis is closely linked to results of staging, and staging is also used to allocate patients to treatments both in clinical trials and clinical practice.

Staging

• The 8th edition of the AJCC TNM breast cancer staging system delivers a flexible platform for prognostic classification based on traditional anatomic factors, which may be modified and enhanced with respect to patient biomarkers and other prognostic panel data.
• Nevertheless, in order to maintain worldwide value, AJCC tumor staging system remained based on classic TNM anatomic factors.
• Major changes in the 8th edition of AJCC TNM staging system were discussed below.
• AJCC panel incorporated biologic factors into the staging system as follows:

• Tumor grade
• Proliferation rate
• Estrogen and progesterone receptor expression
• Human epidermal growth factor 2 (HER2) expression
• Gene expression prognostic panels

• Hence components of recent breast cancer staging system are as follows:

• The extent (size) of the tumor (T)
• The spread to nearby lymph nodes (N)
• The spread (metastasis) to distant sites (M)
• Estrogen Receptor (ER) presence
• Progesterone Receptor (PR) presence
• Her2/neu (Her2) presence
• Histopathologic grade of the cancer (G):
• In certain circumstances, gene expression panels might also be used such as The Oncotype DX® and the MammaPrint® .

Gene expression panels

• Oncotype DX®:

• For small hormone receptor-positive tumors that have not spread to more than 3 lymph nodes
• Also may be used for more advanced tumors
• Might be used for DCIS (ductal carcinoma in situ or stage 0 breast cancer). as well looks at a set of 21 genes in tumor biopsy samples to get a “recurrence score,” which is a number between 0 and 100.
• The score reflects the risk of breast cancer coming back (recurring) in the next 10 years and how likely you will benefit from getting chemo after surgery.
• The lower the score (usually 0-10) the lower the risk of recurrence.
• Benefit from chemotherapy is in doubt in most women with low scores
• An intermediate score (usually 11-25): intermediate risk of recurrence.
• Benefit from chemotherapy is in doubt in most women with intermediate-recurrence scores,
• Nevertheless chemotherapy is believed to be beneficial for women younger than 50 with a higher intermediate score (16-25)
• The possible risks and benefits of chemo should be weighted and discussed prior to decision making.
• A high score (usually 26-100): higher risk of recurrence.Chemotherapy is recommended for women with high scores in order to help lower the chance of cancer *recurrence.

• MammaPrint®:

• To determine likelihood of cancer recurrence in distant part of the body after treatment.
• May be used in any type of breast cancer with stage 1 or 2 that has spread to no more than 3 lymph nodes.
• Hormone and HER2 status are also evaluated in this test. Seventy different genes are examined in this test to determine the 10 years cancer recurrence
• The test results are reported as either “low risk” or “high risk.”

TNM Staging

T categories for breast cancer

• TX: Primary tumor cannot be assessed.
• T0: No evidence of primary tumor.
• Tis: Carcinoma in situ (DCIS, or Paget disease of the nipple with no associated tumor mass)
• T1 (includes T1a, T1b, and T1c): Tumor is 2 cm (3/4 of an inch) or less across.
• T2: Tumor is more than 2 cm but not more than 5 cm (2 inches) across.
• T3: Tumor is more than 5 cm across.
• T4 (includes T4a, T4b, T4c, and T4d): Tumor of any size growing into the chest wall or skin. This includes inflammatory breast cancer.

N categories for breast cancer

• NX: Nearby lymph nodes cannot be assessed (for example, if they were removed previously).
• N0: Cancer has not spread to nearby lymph nodes.
• N0(i+): The area of cancer spread contains less than 200 cells and is smaller than 0.2 mm. The abbreviation "i+" means that a small number of cancer cells (called isolated tumor cells) were seen in routine stains or when a special type of staining technique, called immunohistochemistry, was used.
• N0(mol+): Cancer cells cannot be seen in underarm lymph nodes (even using special stains), but traces of cancer cells were detected using a technique called RT-PCR. RT-PCR is a molecular test that can find very small numbers of cancer cells. (This test is not often used to find breast cancer cells in lymph nodes because the results do not influence treatment decisions.)
• N1: Cancer has spread to 1 to 3 axillary (underarm) lymph node(s), and/or tiny amounts of cancer are found in internal mammary lymph nodes (those near the breast bone) on sentinel lymph node biopsy.
• N1mi: Micrometastases (tiny areas of cancer spread) in the lymph nodes under the arm. The areas of cancer spread in the lymph nodes are at least 0.2mm across, but not larger than 2mm.
• N1a: Cancer has spread to 1 to 3 lymph nodes under the arm with at least one area of cancer spread greater than 2 mm across.
• N1b: Cancer has spread to internal mammary lymph nodes on the same side as the cancer, but this spread could only be found on sentinel lymph node biopsy (it did not cause the lymph nodes to become enlarged).
• N1c: Both N1a and N1b apply.
• N2: Cancer has spread to 4 to 9 lymph nodes under the arm, or cancer has enlarged the internal mammary lymph nodes
• N2a: Cancer has spread to 4 to 9 lymph nodes under the arm, with at least one area of cancer spread larger than 2 mm.
• N2b: Cancer has spread to one or more internal mammary lymph nodes, causing them to become enlarged.
• N3: Any of the following:
• N3a: either:

• Cancer has spread to 10 or more axillary lymph nodes, with at least one area of cancer spread greater than 2 mm,

OR

• Cancer has spread to the lymph nodes under the collarbone (infraclavicular nodes), with at least one area of cancer spread greater than 2 mm.

• N3b: either:

• Cancer is found in at least one axillary lymph node (with at least one area of cancer spread greater than 2 mm) and has enlarged the internal mammary lymph nodes,

OR

• Cancer has spread to 4 or more axillary lymph nodes (with at least one area of cancer spread greater than 2 mm), and tiny amounts of cancer are found in internal mammary lymph nodes on sentinel lymph node biopsy.

• N3c: Cancer has spread to the lymph nodes above the collarbone (supraclavicular nodes) with at least one area of cancer spread greater than 2 mm.

M categories for breast cancer

• MX: Distant spread (metastasis) cannot be assessed.
• M0: No distant spread is found on x-rays (or other imaging tests) or by physical exam.
• cM0(i+): Small numbers of cancer cells are found in blood or bone marrow (found only by special tests), or tiny areas of cancer spread (no larger than 0.2 mm) are found in lymph nodes away from the underarm, collarbone, or internal mammary areas.
• M1: Cancer has spread to distant organs (most often to the bones, lungs, brain, or liver).

The following TNM staging system (anatomic stage group table) should solely be used in global regions with no or limited access to the biomarker tests.

Tis	N0	M0	0
T1	N0	M0	IA
T0	N1mi	M0	IB
T1	N1mi	M0	IB
T0	N1	M0	IIA
T1	N1	M0	IIA
T2	N0	M0	IIA
T2	N1	M0	IIB
T3	N0	M0	IIB
T0	N2	M0	IIIA
T1	N2	M0	IIIA
T2	N2	M0	IIIA
T3	N1	M0	IIIA
T3	N2	M0	IIIA
T4	N0	M0	IIIB
T4	N1	M0	IIIB
T4	N2	M0	IIIB
Any T	N3	M0	IIIC
Any T	Any N	M1	IV

Tis N0 M0	Any	Any	Any	Any	0
T1* N0 M0 T0 N1mi M0 T1* N1mi M0	G1	Positive	Positive	Positive	IA
				Negative	IA
			Negative	Positive	IA
				Negative	IA
		Negative	Positive	Positive	IA
				Negative	IA
			Negative	Positive	IA
				Negative	IB
T1* N0 M0 T0 N1mi M0 T1* N1mi M0	G2	Positive	Positive	Positive	IA
				Negative	IA
			Negative	Positive	IA
				Negative	IA
		Negative	Positive	Positive	IA
				Negative	IA
			Negative	Positive	IA
				Negative	IB
T1* N0 M0 T0 N1mi M0 T1* N1mi M0	G3	Positive	Positive	Positive	IA
				Negative	IA
			Negative	Positive	IA
				Negative	IA
		Negative	Positive	Positive	IA
				Negative	IB
			Negative	Positive	IB
				Negative	IB
T0 N1¶ M0 T1* N1¶ M0 T2 N0 M0	G1	Positive	Positive	Positive	IB
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIA
		Negative	Positive	Positive	IB
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIA
T0 N1¶ M0 T1* N1¶ M0 T2 N0 M0	G2	Positive	Positive	Positive	IB
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIA
		Negative	Positive	Positive	IB
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIB
T0 N1¶ M0 T1* N1¶ M0 T2 N0 M0	G3	Positive	Positive	Positive	IB
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIA
		Negative	Positive	Positive	IIA
				Negative	IIB
			Negative	Positive	IIB
				Negative	IIB
T2 N1Δ M0 T3 N0 M0	G1	Positive	Positive	Positive	IB
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIB
		Negative	Positive	Positive	IIA
				Negative	IIB
			Negative	Positive	IIB
				Negative	IIB
T2 N1Δ M0 T3 N0 M0	G2	Positive	Positive	Positive	IB
				Negative	IIA
			Negative	Positive	IIA
				Negative	IIB
		Negative	Positive	Positive	IIA
				Negative	IIB
			Negative	Positive	IIB
				Negative	IIIB
T2 N1Δ M0 T3 N0 M0	G3	Positive	Positive	Positive	IB
				Negative	IIB
			Negative	Positive	IIB
				Negative	IIB
		Negative	Positive	Positive	IIB
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIB
T0 N2 M0 T1* N2 M0 T2 N2 M0 T3 N1Δ M0 T3 N2 M0	G1	Positive	Positive	Positive	IIA
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIA
		Negative	Positive	Positive	IIA
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIB
T0 N2 M0 T1* N2 M0 T2 N2 M0 T3 N1Δ M0 T3 N2 M0	G2	Positive	Positive	Positive	IIA
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIA
		Negative	Positive	Positive	IIA
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIB
T0 N2 M0 T1* N2 M0 T2 N2 M0 T3 N1Δ M0 T3 N2 M0	G3	Positive	Positive	Positive	IIB
				Negative	IIIA
			Negative	Positive	IIIA
				Negative	IIIA
		Negative	Positive	Positive	IIIA
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIC
T4 N0 M0 T4 N1Δ M0 T4 N2 M0 Any T N3 M0	G1	Positive	Positive	Positive	IIIA
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIB
		Negative	Positive	Positive	IIIB
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIC
T4 N0 M0 T4 N1Δ M0 T4 N2 M0 Any T N3 M0	G2	Positive	Positive	Positive	IIIA
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIB
		Negative	Positive	Positive	IIIB
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIC
T4 N0 M0 T4 N1Δ M0 T4 N2 M0 Any T N3 M0	G3	Positive	Positive	Positive	IIIB
				Negative	IIIB
			Negative	Positive	IIIB
				Negative	IIIB
		Negative	Positive	Positive	IIIB
				Negative	IIIC
			Negative	Positive	IIIC
				Negative	IIIC
Any T Any N M1	Any	Any	Any	Any	IV

==============================

The breast cancer stage is based on the results of testing that is done on the tumor and lymph nodes removed during surgery and other tests.

Stage 0

There are 3 types of breast carcinoma in situ:

• Ductal carcinoma in situ (DCIS)

A *noninvasive condition in which abnormal cells are found in the lining of a breast duct

• Abnormal cells have not spread outside the duct to other tissues in the breast
• May become invasive cancer and spread to other tissues

• Lobular carcinoma in situ (LCIS)

• Abnormal cells are found in the lobules of the breast
• This condition seldom becomes invasive

• Paget's disease of the nipple

• Abnormal cells are found in the nipple only

Stage 1

• Cancer has formed
• Stage I is divided into stages IA and IB
• Stage IA:

• Tumor is < 2 centimeters
• Cancer has not spread outside the breast

• Stage IB:

• Small clusters of breast cancer cells (0.2 mm - 2 mm) are found in the lymph nodes and either:
• no tumor is found in the breast; or
• Numor is < 2 centimeters

Stage II

Stage II is divided into stages IIA and IIB.

• In stage IIA:

• no tumor is found in the breast or the tumor is 2 centimeters or smaller. Cancer (larger than 2 millimeters) is found in 1 to 3 axillary lymph nodes or in the lymph nodes near the breastbone (found during a sentinel lymph node biopsy); or
• the tumor is larger than 2 centimeters but not larger than 5 centimeters. Cancer has not spread to the lymph nodes.

• In stage IIB, the tumor is:

• larger than 2 centimeters but not larger than 5 centimeters. Small clusters of breast cancer cells (larger than 0.2 millimeter but not larger than 2 millimeters) are found in the lymph nodes; or
• larger than 2 centimeters but not larger than 5 centimeters. Cancer has spread to 1 to 3 axillary lymph nodes or to the lymph nodes near the breastbone (found during a sentinel lymph node biopsy); or
• larger than 5 centimeters. Cancer has not spread to the lymph nodes.

Stage III

Stage III is divided into IIIA, IIIB, and IIIC.

• Stage IIIA

• no tumor is found in the breast or the tumor may be any size. Cancer is found in 4 to 9 axillary lymph nodes or in the lymph nodes near the breastbone (found during imaging tests or a physical exam); or
• the tumor is larger than 5 centimeters. Small clusters of breast cancer cells (larger than 0.2 millimeter but not larger than 2 millimeters) are found in the lymph nodes; or
• the tumor is larger than 5 centimeters. Cancer has spread to 1 to 3 axillary lymph nodes or to the lymph nodes near the breastbone (found during a sentinel lymph node biopsy).

• Stage IIIB

• the tumor may be any size and cancer has spread to the chest wall and/or to the skin of the breast and caused swelling or an ulcer.
• cancer may have spread to:

• up to 9 axillary lymph nodes; or
• the lymph nodes near the breastbone

• Stage IIIC

• no tumor is found in the breast or the tumor may be any size. Cancer may have spread to the skin of the breast and caused swelling or an ulcer and/or has spread to the chest wall.
• cancer has spread to:

• 10 or more axillary lymph nodes; or
• lymph nodes above or below the collarbone; or
• axillary lymph nodes and lymph nodes near the breastbone

• For treatment, stage IIIC breast cancer is divided into operable and inoperable stage IIIC.

Stage IV

• In stage IV, cancer has spread to other organs of the body, most often the bones, lungs, liver, or brain.

Inflammatory Breast Cancer

• In inflammatory breast cancer, cancer has spread to the skin of the breast and the breast looks red and swollen and feels warm. The redness and warmth occur because the cancer cells block the lymph vessels in the skin. The skin of the breast may also show the dimpled appearance called peau d’orange (like the skin of an orange). There may not be any lumps in the breast that can be felt.
• Inflammatory breast cancer may be stage IIIB, stage IIIC, or stage IV.

Tumor - There are five tumor classification values (Tis, T1, T2, T3 or T4) which depend on the presence or absence of invasive cancer, the dimensions of the invasive cancer, and the presence or absence of invasion outside of the breast (e.g. to the skin of the breast, to the muscle, or to the rib cage underneath):

• Tx - Primary tumor cannot be assessed
• T0 - No evidence of primary tumor
• Tis - Carcinoma in situ
  • Tis(DCIS) - Intraductal Carcinoma in situ
  • Tis(LCIS) - Lobular Carcinoma in situ
  • Tis(Paget's) - Paget's disease of the nipple with no tumor
• T1 - Tumor 2cm or less in its greatest dimension
  • T1mic - Microinvasion 0.1cm or less in greatest dimension
  • T1a - Tumor more than 0.1cm but not more than 0.5cm in its greatest dimension
  • T1b - Tumor more than 0.5cm but not more than 1.0cm in its greatest dimension
  • T1c - Tumor more than 1.0cm but not more than 2.0cm in its greatest dimension
• T2 - Tumor more than 2.0cm but not more than 5.0cm in its greatest dimension
• T3 - Tumor more than 5cm in its greatest dimension
• T4 - Tumor of any size with direct extension to (a) chest wall or (b) skin as described below:
  • T4a - Extension to chest wall
  • T4b - Edema (including peau d'orange) or ulceration of the breast skin, or satellite skin nodules confined to the same breast
  • T4c - Both T4a and T4b
  • T4d - Inflammatory breast cancer

Lymph Node - There are four lymph node classification values (N0, N1, N2 or N3) which depend on the number, size, and location of breast cancer cell deposits in lymph nodes.

• Nx - regional lymph nodes cannot be assessed, perhaps due to previous removal
• N0 - no regional lymph node metastasis
• N1 - metastasis to movable regional axillary lymph nodes on the same side as the affected breast
• N2 - metastasis to fixed regional axillary lymph nodes, or metastasis to the internal mammary lymph nodes, on the same side as the affected breast
• N3 - metastasis to supraclavicular lymph nodes or infraclavicular lymph nodes or metastasis to the internal mammary lymph nodes with metastasis to the axillary lymph nodes

Metastases - There are two metastatic classification values (M0 or M1) which depend on the presence or absence of breast cancer cells in locations other than the breast and lymph nodes (so-called distant metastases, e.g. to bone, brain, lung).

Grading

Grading is a way of classifying breast cancer cells based on their appearance and behaviour when viewed under a microscope. The most common grading system for breast cancer is the Nottingham modification of the Bloom-Richardson scale (may also be called the Scarff-Bloom-Richardson or the Elson-Ellis grade). It is used for invasive breast cancers. This grading system is based on 3 different features of the cells in the tumor. Each of these features is given a score of 1 to 3.

• Tubule formation – the percentage of the tumor that is made up of tubular structures

• 1 – The tumor is made up of more than 75% tubules.
• 2 – The tumor is made up of 10%–75% tubules.
• 3 – The tumor is made up of less than 10% tubules.

• Nuclear pleomorphism – the degree of change in the size and shape of the tumor cells’ nuclei (the part of the cell that holds the chromosomes, which contain genetic information)

• 1 – The nuclei are small and uniform in size and shape.
• 2 – The nuclei are medium to large in size, but are mostly the same size and shape.
• 3 – The nuclei are large and vary in size and shape.

• Mitotic count – the number of cells that are actively dividing

• 1 – The tumor cells are dividing at a slow rate.
• 2 – The tumor cells are dividing at a moderate rate.
• 3 – The tumor cells are dividing at a fast rate.

The individual scores from these 3 features are added together to give a total score between 3 and 9. A tumor grade is then assigned based on the total score. Bloom-Richardson Grade – Nottingham modification

Grade	Combined score	Description
I	3-5	Low-grade (well-differentiated) tumors that do not appear to be growing quickly and are less likely to spread
II	6-7	Intermediate-grade (moderately differentiated) tumors that have features between grade 1 and 3
III	8-9	High-grade (poorly differentiated) tumors that tend to grow faster and are more likely to spread

• Have bad prognosis

Summary of stages

• Stage 0 - Carcinoma in situ
• Stage I - Tumor (T) does not involve axillary lymph nodes (N).
• Stage IIA – T 2-5 cm, N negative, or T <2 cm and N positive.
• Stage IIB – T > 5 cm, N negative, or T 2-5 cm and N positive (< 4 axillary nodes).
• Stage IIIA – T > 5 cm, N positive, or T 2-5 cm with 4 or more axillary nodes
• Stage IIIB – T has penetrated chest wall or skin, and may have spread to < 10 axillary N
• Stage IIIC – T has > 10 axillary N, 1 or more supraclavicular or infraclavicular N, or internal mammary N.
• Stage IV – Distant metastasis (M)

Breast lesions are examined for certain markers, notably sex steroid hormone receptors. About two thirds of postmenopausal breast cancers are estrogen receptor positive (ER+) and progesterone receptor positive (PR+). Receptor status modifies the treatment as, for instance, only ER-positive tumors, not ER-negative tumors, are sensitive to hormonal therapy.

The breast cancer is also usually tested for the presence of human epidermal growth factor receptor 2, a protein also known as HER2, neu or erbB2. HER2 is a cell-surface protein involved in cell development. In normal cells, HER2 controls aspects of cell growth and division. When activated in cancer cells, HER2 accelerates tumor formation. About 20-30% of breast cancers overexpress HER2. Those patients may be candidates for the drug trastuzumab, both in the postsurgical setting (so-called "adjuvant" therapy), and in the metastatic setting.

References

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