Breast

• Most commonly used system is Elston / Nottingham modification of Bloom-Richardson system, based on (a) tumor tubule formation, (b) number of mitotic figures in most active areas and (c) nuclear pleomorphism (Br J Cancer 1957;11:359, Histopathology 1991;19:403)
• Tumor should be graded based on representative portion of tumor, not the least differentiated part (Arch Pathol Lab Med 1983;107:411)

Tumor tubule formation:

• 1 point: > 75% of tumor
• 2 points: 10 - 75% of tumor
• 3 points: < 10% of tumor

Note: the overall appearance of the tumor must be taken into consideration in scoring tubule formation
Note: tubules must have clear central lumina to be counted

Number of mitotic figures in most active area, counting 10 high power fields:

	(a)	(b)	(c)
1 point:	0 - 5	0 - 9	0 - 11
2 points:	6 - 11	10 - 19	12 - 22
3 points:	11+	20+	23+

(a) Nikon or Labophot 40x objective or comparable with field diameter of 0.44 mm
(b) Leitz or Ortholux 25x objective or comparable with field diameter of 0.59 mm
(c) Leitz or Diaplan 40x objective or comparable with field diameter of 0.63 mm

Notes:

• Count mitotic figures at periphery of tumor in most mitotically active area; count 10 high power fields in the same area, but not necessarily contiguous; select fields with as much tumor as possible; avoid poorly preserved areas; ignore cells with hyperchromatic and pyknotic nuclei, which may be undergoing apoptosis
• Quick scan mitotic impression is less accurate (Hum Pathol 2008;39:584)

Nuclear pleomorphism:

• 1 point: minimal nuclear variation in size and shape; small regular uniform cells
• 2 points: moderate nuclear variation in size and shape
• 3 points: marked nuclear variation in size and shape
  
  
• Note: evaluate areas with greatest atypia
• Note: for infiltrating lobular carcinoma, two tiered grading system for nuclear pleomorphism is recommended (Ann Diagn Pathol 2009;13:223)

Scoring

• 3 - 5 points: well differentiated (grade I)
• 6 - 7 points; moderately differentiated (grade II)
• 8 - 9 points: poorly differentiated (grade III)

Criticisms of Nottingham Bloom Richardson grading system

• Grading has been criticized for low reproducibility (Mod Pathol 2005;18:1067, Virchows Arch 2007;450:627)
• The concept of a moderately differentiated category has been criticized (Pathobiology 2008;75:104, J Natl Cancer Inst 2006;98:262)
• Tumors with 3 + 3 + 1 pattern (i.e. < 10% tubules, marked nuclear pleomorphism but few mitotic figures) may have low mitotic count due to failure to fix tumor immediately after excision, which allows tumor cells to complete cell division and leads to reduction in observed mitotic figures; Ki67 may serve as surrogate for mitotic figure counting in these cases (Oncologist 2008;13:477)

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