# Breast Carcinoma: Typing, Grading, and Biomarkers

## Introduction

Breast carcinoma is the most common malignancy in women worldwide. Accurate histologic typing, grading, and biomarker assessment are critical for treatment planning and prognostication. The pathologist's report directly guides decisions regarding surgery, chemotherapy, endocrine therapy, and targeted agents.

## Histologic Types of Invasive Breast Carcinoma

### Invasive Carcinoma of No Special Type (NST)

Formerly known as invasive ductal carcinoma, NOS, this is the most common type, accounting for 70 to 80 percent of breast cancers. It has heterogeneous morphology without features of a special type and is diagnosed by exclusion of special-type patterns.

### Invasive Lobular Carcinoma (ILC)

Invasive lobular carcinoma is the second most common type at approximately 10 to 15 percent. The classic pattern shows single-file infiltration, targetoid growth around ducts, and dyscohesive cells. E-cadherin loss (negative immunostain) results from CDH1 mutation or promoter methylation. Variants include pleomorphic, solid, alveolar, and tubulolobular patterns.

### Special Histologic Types

Tubular carcinoma consists of well-formed angulated tubules with low nuclear grade and carries an excellent prognosis. Mucinous (colloid) carcinoma features tumor cells floating in extracellular mucin pools. Micropapillary carcinoma is associated with high rates of lymphovascular invasion and nodal metastasis. Metaplastic carcinoma contains heterologous elements (squamous, spindle, chondroid) and is often triple-negative.

## Histologic Grading: Nottingham (Elston-Ellis) System

The Nottingham grading system evaluates three components, each scored from 1 to 3.

### Tubule Formation

A score of 1 is assigned when more than 75 percent of the tumor forms tubules, score 2 when 10 to 75 percent shows tubule formation, and score 3 when less than 10 percent forms tubules.

### Nuclear Pleomorphism

Score 1 indicates small, uniform nuclei. Score 2 reflects moderate variation in size and shape. Score 3 represents marked variation with prominent nucleoli.

### Mitotic Count

Mitoses are scored per 10 high-power fields, with thresholds depending on field diameter. The count must be assessed at the tumor periphery in the most mitotically active area.

### Final Grade

Grade 1 (well differentiated) corresponds to a total score of 3 to 5. Grade 2 (moderately differentiated) corresponds to a score of 6 to 7. Grade 3 (poorly differentiated) corresponds to a score of 8 to 9.

## Biomarker Assessment

### Estrogen Receptor (ER) and Progesterone Receptor (PR)

ER and PR are assessed by immunohistochemistry on formalin-fixed, paraffin-embedded tissue. A result is considered positive when 1 percent or more of tumor nuclei show staining, per ASCO/CAP guidelines. ER-low positive (1 to 10 percent) is a distinct reporting category with uncertain clinical benefit from endocrine therapy. Pre-analytical factors are critical: cold ischemia time should be less than 1 hour, and fixation in 10 percent neutral buffered formalin should last 6 to 72 hours.

### HER2 (Human Epidermal Growth Factor Receptor 2)

HER2 is assessed by IHC and/or in situ hybridization (ISH). IHC scoring classifies results as 0 and 1+ (negative), 2+ (equivocal, requiring ISH), or 3+ (positive). For ISH, a HER2/CEP17 ratio of 2.0 or greater with an average of 4.0 or more HER2 signals constitutes a positive result. HER2-low (IHC 1+ or 2+/ISH-negative) is now clinically relevant as it determines eligibility for trastuzumab-deruxtecan.

### Ki-67 Proliferation Index

Ki-67 represents the percentage of tumor nuclei positive for the Ki-67 antigen. It is useful for distinguishing Luminal A-like (less than 20 percent) from Luminal B-like (20 percent or greater) disease in hormone receptor-positive cancers. Scoring methodology and cutoffs remain subjects of ongoing standardization efforts.

## Molecular Subtypes

| Subtype       | ER  | PR  | HER2 | Ki-67  | Prognosis  |
|---------------|-----|-----|------|--------|------------|
| Luminal A     | +   | +   | -    | Low    | Favorable  |
| Luminal B     | +   | +/- | -/+  | High   | Intermediate|
| HER2-enriched | -   | -   | +    | High   | Variable   |
| Triple-negative| -  | -   | -    | High   | Poor       |

## Reporting Requirements

Synoptic reporting following CAP cancer protocols is mandatory. The report must include histologic type, Nottingham grade, tumor size, margins, lymphovascular invasion, nodal status, ER, PR, HER2, and staging. Tumor infiltrating lymphocytes (TILs) are increasingly reported, especially in triple-negative breast cancer where they carry prognostic significance.

## Clinical Pearls

Nottingham grade is one of the strongest prognostic factors in breast carcinoma and must be reported for all invasive tumors. HER2 testing requires strict adherence to ASCO/CAP guidelines, and equivocal results must be reflexed to ISH to avoid both false-positive and false-negative assignments. Tissue handling, particularly fixation time and cold ischemia, directly impacts biomarker reliability; inadequate fixation can produce falsely negative ER, PR, and HER2 results. Special histologic types (tubular, mucinous, cribriform) carry distinct prognostic implications and may influence the decision regarding chemotherapy, as pure tubular and mucinous carcinomas have excellent outcomes even without systemic therapy.

## References

1. WHO Classification of Tumours Editorial Board. Breast Tumours. WHO Classification of Tumours, 5th ed. Lyon: IARC Press; 2019.
2. Wolff AC, et al. HER2 testing in breast cancer: ASCO/CAP clinical practice guideline focused update. *J Clin Oncol*. 2018;36(20):2105-2122.
3. Allison KH, et al. Estrogen and progesterone receptor testing in breast cancer: ASCO/CAP guideline update. *J Clin Oncol*. 2020;38(12):1346-1366.
4. Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. *Histopathology*. 1991;19(5):403-410.