Invasive breast cancer

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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.

Introduction

Types of invasive breast cancer

Types:Ref.: [1]

  • Ductal - also known as no specific type (NST) - 79%.
  • Lobular 10%.
  • Cribriform (tubular) 6%.
  • Mucinous (colloid) 2%.
  • Medullary 2%.
  • Papillary 1%.
  • Metaplastic <1%.

Others:

Familial breast cancer

BRCA1 vs. BRCA2:[3]

  • BRCA1:
    • Younger.
    • Ovarian cancer.
    • Worse types of breast cancer (e.g. triple negative breast cancer: PR-, ER-, HER2/neu-).
  • BRCA2:
  • BOTH are associated with increased risk of (memory device CPP):

Breast IHC

Subtyping breast cancer

  • DCIS vs LCIS:[4]
    • E-cadherin (+ve DCIS, -ve LCIS).
    • antibody 34betaE12 (+ve perinuclear LCIS, -ve DCIS).
    • CAM5.2 (peripheral stain = DCIS, perinuclear stain = LCIS).
      • CAM5.2 is against CK8.
    • Beta-catenin (-LCIS, +DCIS).
  • D2-40:[5][6]
    • Monoclonal antibody to podoplanin.
    • Useful to assess lymphovascular invasion.
  • ADH and DCIS:[7]
    • E-cadherin.
      • Present in most epithelial cells.
      • Lost in LCIS & invasive lobular carcinoma.
    • SMMHC (smooth muscle cell myosin heavy chain).
      • Marks myoepithelial cells.

Treatment-related markers - overview

  • Immunostaining of any sentinel lymph nodes - to look for isolated tumour cells and small lymph node mets.
    • Sunnybrook uses CAM5.2.
  • ER (estrogen receptor).
    • Positive in most breast cancers; +ve in ~75-80%.[8]
  • PR (progesterone receptor).
    • Positive in most breast cancers; +ve in ~65-70%.[8]
  • HER2/neu.
    • Usually negative; -ve in 70-80%.[8]
    • Positivity association with a worse prognosis.

ER & PR scoring[8]

  • 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[8]

Score Staining intensity Cells stained (%) Membrane staining Management Percentage of cases
0 nil <10% incomplete No HER2 blocker ~60%
1+ minimum >10% incomplete No HER2 blocker ~10%
2+ weak >10% complete Needs SISH or FISH ~10%
3+ strong >10% complete HER2 blocker ~20%

Notes:

  • Normal breast epithelial cells do not stain with HER2.
  • Evaluated on the invasive component.
  • SISH = silver in situ hybridization.
  • FISH = fluorescence in situ hybridization.

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

List of subtypes

Epithelial

Counterparts of in situ lesions:

  • Invasive ductal carinoma, not otherwise specified.
  • Invasive lobular carcinoma.
  • Invasive cribriform carcinoma.
  • Invasive papillary carcinoma.
  • Invasive micropapillary carcinoma.

Other epithelial tumours:

  • Tubular carcinoma.
  • Medullary carcinoma.
  • Mucinous carinoma.
  • Neuroendocrine tumours.
  • Apocrine carcinoma.
  • Lipid-rich carcinoma.
  • Secretory carcinoma.
  • Oncocytic carcinoma.
  • Glycogen-rich clear cell carcinoma.

Epithelial tumours seen in the salivary gland:

  • Adenoid cystic carcinoma
  • Acinic cell carcinoma.

Clinically diagnosed:

  • Inflammatory carcinoma.

In situ lesions:

  • Ductal carcinoma in situ.
  • Lobular carcinoma in situ.

Proliferative lesions:

  • Usual ductal hyperplasia.
  • Flat epithelial atypia.
  • Atypical ductal hyperplasia.

Ductal carcinoma

  • AKA "NST" = No Specific Type.

Microscopic

Features:

  • Cohesive cells - forming ducts or in sheets.
  • Nuclear pleomorphism.

Clinical

  • Typically: ER+, PR+, HER2-.

Lobular carcinoma

General

  • May be associated with a CDH-1 mutation - seen in diffuse type gastric cancer.[9]

Microscopic

Features:

  • "Single file" - cell line-up in a row.
    • Cell should not be cohesive -- lymphoma should briefly come to mind.
      • primary lymphoma of the breast exists... but it is extremely rare.
  • NO gland formation.
    • If it forms glands... it is more likely NST.
  • May have signet ring morphology.
  • NO desmoplastic reaction, i.e. the stroma surrounding the tumour cells should look benign and undisturbed.

Note:

  • commonly have low grade nuclear features

Subclassification:

  • Classic lobular carcinoma.
    • Low nuclear grade - NO significant variation of nucleus size.
  • Pleomorphic lobular carcinoma.
    • Significant nuclear atypia.

Note: Some pathologist grade lobular carcinoma like other types and avoid the term "pleomorphic lobular carcinoma."[10]

Medullary carcinoma

General

  • Some pathologists don't believe this exists.

Epidemiology:

  • Thought to have a better prognosis that no special type (NST).
  • Association with BRCA1 mutations.

Microscopic

Features:

  1. Lesion has well-circumscribed border.
  2. Syncytial growth pattern = clumps of cells with poorly defined cell borders.
  3. Lymphocytic infiltrate.
  4. High nuclear grade (as per Nottingham grading system).
  5. No tubule formation.

Tubular carcinoma

General

Epidemiology:

  • Typically excellent prognosis.
  • Hormone receptors commonly present.

Microscopic

Features:[11][12][13]

  • Well-formed tubules.
  • Myoepithelial cells absent.
  • +/- Cribriform spaces.
  • Apocrine snouts typical.
  • +/- Calcification.
  • Angled ducts common: "prows" - important feature (low power).
  • Looks benign to the uninitiated -- IMPORTANT.

Notes:

  • Prow = front of a ship.

DDx:

Metaplastic carcinoma

General

  • May be difficult to diagnosis.
  • Prognosis - poor.

Microscopic

Features:[14]

  • Malignant mesenchymal elements:
    • Spindle cells
  • +/-Adenocarcinoma.
  • +/-Squamous carcinoma.

Notes:

  • If it looks like squamous cell carcinoma... in the breast it is metaplastic carcinoma.

Images: Metaplastic carcinoma (breastpathology.info).[14]

IHC

  • S100 -ve (r/o melannoma).
  • AE1/AE3 +ve (epithelial elements only).
  • CK7 +ve (epithelial elements only).
  • p63 +ve (epithelial elements only).
  • Vimentin +ve.
  • Desmin -ve.
  • EMA -ve. (???)

Grading breast cancer

Most common system: Nottingham (aka Scarff-Bloom-Richardson) which is based on:

  1. Nuclear grade.
    • Small, regular (1.5-2x RBC dia.) = 1.
    • Moderated variability = 2.
    • Marked variation (>2.5x RBC dia.) = 3.
  2. Tubule formation.
    • Majority of tumour - tubules >75% = 1.
    • Moderate - 10% to 75% = 2.
    • Minimal <10% = 3.
  3. Mitotic rate.
    • 0-5 mitosis/10 HPF (1.52 mm^2 --or-- 0.0152 mm^2 * 10) = 1.
    • 6-10 mitosis/10 HPF (1.52 mm^2) = 2.
    • >11 mitosis/10 HPF (1.52 mm^2) = 3.

Mnemonic: TMN = tubule formation, mitotic rate, nuclear grade.

Notes:

  • Elston & Ellis devised the system that is used.[15] They also wrote a follow-up article in 2002.[16]

Note about mitosis counting

  • One MUST adjust for the size of the field of view.
  • Most of the Resident scopes have an eye piece diameter of 22 mm. Therefore, the field diameter at 40 X is approximately 22 mm / 40 X ~= 0.55 mm and the field of view is pi/4*(0.55 mm)^2 = 0.2376 mm^2.
    • Thus, on a resident scope (with a FOV of 0.2376 mm^2) one should sample 6 or 7 fields of view (FsOV).
      • Calculation: 1.52 mm^2 (sampling area) / 0.2376 mm^2 (area / FOV ) = 6.40 FsOV.
  • RANT: Sampling 10 fields, where the field of view (FOV) is 0.152 mm^2, is not the same as sampling ten fields, where the FOV is 0.312 mm^2. It surprises me that Elston & Ellis ignore the fact that "10 HPFs" on different microscopes represent different sample areas and that they do not standardize the sampling area.

Calculating Nottingham score

  • Grade I = 3-5 points.
  • Grade II = 6-7 points.
  • Grade III = 8-9 points.

Notes:

  • I've found most tumours are grade II.
  • The mitotic score is usually 1/3.
  • The nuclear score is rarely 1/3 -- even in the tubular subtype.[17]

Staging breast cancer

Definitions:[18]

  • Isolated tumour cells: <=0.2 mm and <200 cells.
  • Micrometastasis: <=0.2 cm and ( >0.2 mm or >=200 cells ).

Tumour:[19][20]

  • pT1: <= 2 cm.
    • pT1mic <= 0.1 cm.
    • pT1a > 0.1 cm and <= 0.5 cm.
    • pT1b > 0.5 cm and <= 1.0 cm.
    • pT1c > 1.0 cm and <= 2.0 cm.
  • pT2: > 2 cm and <= 5 cm
  • pT3: > 5 cm.
  • pT4: chest wall or skin involvement.

Lymph nodes:[21]

  • pN0: nil.
    • pN0(i+): <=0.2 mm and <200 cells.
  • pN1: 1-3 axillary LNs or internal mammary LNs.
    • pN1mi: <=0.2 cm and ( >0.2 mm or >=200 cells ).
    • pN1a.
    • pN1b.
    • PN1c.
  • pN2 4-9 positive LNs; internal mammary LNs or axillary LNs.
  • pN3.

Lymphovascular invasion

There are famous criteria for lymphovascular invasion (LVI).

Rosen criteria for LVI:[22][23]

  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.

Other

Paget's disease

Main article: Paget disease of the breast

General

  • Associated with underlying breast carcinoma.[24]

Notes:

Microscopic

Features:[24]

  • 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:

Sentinel lymph node biopsy

General

  • Used for staging, positive LNs = poorer prognosis.

Notes:

  • If there is no palpable disease, there is no mortality benefit from axillary lymph node dissection, i.e. positive axillary lymph nodes can be left in situ without affecting outcome.[25]
    • This does not negate the fact that a positive sentinel LN biopsy (vs. negative sentinel LN biopsy) portends a poorer prognosis.

Microscopic

Features:

  • Atypical cells.
    • Nuclear changes of malignancy:
      • Nuclear enlargement + variation in size.
      • Variation in shape.
      • Hyperchromasia and variation in staining.
    • Usually in the subcapsular sinuses.

Pitfalls:

  • Naevus cell rests.[26]

IHC

Some hospitals use:

  • CAM5.2 (LMWK) - to look for isolated tumour cells and small lymph node metstases.

Trivia

Tumour size and lymph node metastases

There is a paper[27] that calculates the probability of lymph node mets based on tumour size. The developed formula is:

 

Where:

  •   = the probability of the lymph nodes being positive.
  • D = the largest dimension of the tumour in millimetres.
  • Z = 1.0041.
  •   = 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.[28] The study is supported by NCI's SEER data.[29] Also, it generated many comments.[28]

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.[30]

See also

References

  1. ↑ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. pp. 1143. ISBN 0-7216-0187-1.
  2. ↑ URL: http://www.breastpathology.info/Case_of_the_month/2007/COTM_1007%20discussion.html. Accessed on: 28 November 2010.
  3. ↑ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. pp. 1133. ISBN 0-7216-0187-1.
  4. ↑ Yeh IT, Mies C (March 2008). "Application of immunohistochemistry to breast lesions". Arch. Pathol. Lab. Med. 132 (3): 349-58. PMID 18318578. http://journals.allenpress.com/jrnlserv/?request=get-abstract&issn=0003-9985&volume=132&page=349.
  5. ↑ Ordóñez NG (March 2006). "Podoplanin: a novel diagnostic immunohistochemical marker". Adv Anat Pathol 13 (2): 83-8. doi:10.1097/01.pap.0000213007.48479.94. PMID 16670463.
  6. ↑ Kahn HJ, Marks A (September 2002). "A new monoclonal antibody, D2-40, for detection of lymphatic invasion in primary tumors". Lab. Invest. 82 (9): 1255-7. PMID 12218087.
  7. ↑ Lester, Susan Carole (2005). Manual of Surgical Pathology (2nd ed.). Saunders. pp. 122. ISBN 978-0443066450.
  8. ↑ 8.0 8.1 8.2 8.3 8.4 Lester, Susan Carole (2005). Manual of Surgical Pathology (2nd ed.). Saunders. pp. 241-2. ISBN 978-0443066450.
  9. ↑ URL: http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=33006. Accessed on: 19 April 2011.
  10. ↑ MUA. Jan 22, 2009.
  11. ↑ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. pp. 1146. ISBN 0-7216-0187-1.
  12. ↑ URL: http://www.bweems.com/nsj3mp2.jpg.
  13. ↑ URL: http://surgpathcriteria.stanford.edu/breast/tubularcabr/.
  14. ↑ 14.0 14.1 URL: http://www.breastpathology.info/Case_of_the_month/2007/COTM_0807%20discussion.html. Accessed on: 28 November 2010.
  15. ↑ Elston CW, Ellis IO (September 2002). "Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. C. W. Elston & I. O. Ellis. Histopathology 1991; 19; 403-410". Histopathology 41 (3A): 151–2, discussion 152–3. PMID 12405945.
  16. ↑ Elston CW, Ellis IO (November 1991). "Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up". Histopathology 19 (5): 403–10. PMID 1757079.
  17. ↑ MUA. 20 January 2009.
  18. ↑ URL: http://www.cancer.org/Cancer/BreastCancer/DetailedGuide/breast-cancer-staging. Accessed on: 8 July 2010.
  19. ↑ URL: http://www.cancer.org/Cancer/BreastCancer/DetailedGuide/breast-cancer-staging. Accessed on: 8 July 2010.
  20. ↑ URL: http://www.cancerhelp.org.uk/type/breast-cancer/treatment/tnm-breast-cancer-staging. Accessed on: 9 July 2010.
  21. ↑ URL: http://www.cancer.org/Cancer/BreastCancer/DetailedGuide/breast-cancer-staging. Accessed on: 8 July 2010.
  22. ↑ Rosen, PP. (1983). "Tumor emboli in intramammary lymphatics in breast carcinoma: pathologic criteria for diagnosis and clinical significance.". Pathol Annu 18 Pt 2: 215-32. PMID 6674861.
  23. ↑ URL: http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2009/InvasiveBreast_09protocol.pdf. Accessed on: 5 August 2011.
  24. ↑ 24.0 24.1 URL: http://emedicine.medscape.com/article/1101235-diagnosis
  25. ↑ Giuliano AE, Hunt KK, Ballman KV, et al. (February 2011). "Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial". JAMA 305 (6): 569–75. doi:10.1001/jama.2011.90. PMID 21304082.
  26. ↑ URL: http://www.breastpathology.info/Case_of_the_month/2007/COTM_1107%20discussion.html. Accessed on: 28 November 2010.
  27. ↑ Porembka, MR.; Abraham, RL.; Sefko, JA.; Deshpande, AD.; Jeffe, DB.; Margenthaler, JA. (Oct 2008). "Factors associated with lymph node assessment in ductal carcinoma in situ: analysis of 1988-2002 seer data.". Ann Surg Oncol 15 (10): 2709-19. doi:10.1245/s10434-008-9947-5. PMID 18483831. http://onlinelibrary.wiley.com/doi/10.1002/cncr.24592/pdf.
  28. ↑ 28.0 28.1 Zahl, PH.; Maehlen, J.; Welch, HG. (Nov 2008). "The natural history of invasive breast cancers detected by screening mammography.". Arch Intern Med 168 (21): 2311-6. doi:10.1001/archinte.168.21.2311. PMID 19029493.
  29. ↑ Jatoi, I.; Anderson, WF. (May 2009). "Breast cancer overdiagnosis with screening mammography.". Arch Intern Med 169 (10): 999-1000, author reply 1000-1. doi:10.1001/archinternmed.2009.95. PMID 19468099.
  30. ↑ Weaver, DL.; Ashikaga, T.; Krag, DN.; Skelly, JM.; Anderson, SJ.; Harlow, SP.; Julian, TB.; Mamounas, EP. et al. (Feb 2011). "Effect of occult metastases on survival in node-negative breast cancer.". N Engl J Med 364 (5): 412-21. doi:10.1056/NEJMoa1008108. PMID 21247310.
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