> For the complete documentation index, see [llms.txt](https://www.parapathology.com/llms.txt). Markdown versions of documentation pages are available by appending `.md` to page URLs; this page is available as [Markdown](https://www.parapathology.com/clippings/recommendations-for-reporting-tumor-budding-in-colorectal-cancer-based-on-the-international-tumor-bu.md).

# Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016

Consensus recommendations from the International Tumor Budding Consensus Conference (ITBCC) 2016 establishing standardized criteria, a 0.785 mm² hotspot area, H\&E assessment, and a 3-tier scoring syst

**Alessandro Lugli, Richard Kirsch, Yoichi Ajioka, Fred Bosman, Gieri Cathomas, Heather Dawson, Hala El Zimaity, Jean-François Fléjou, Tine Plato Hansen, Arndt Hartmann, Sanjay Kakar, Cord Langner, Iris Nagtegaal, Giacomo Puppa, Robert Riddell, Ari Ristimäki, Kieran Sheahan, Thomas Smyrk, Kenichi Sugihara, Benoît Terris, Hideki Ueno, Michael Vieth, Inti Zlobec, Phil Quirke.**

*Modern Pathology* (2017) 30, 1299–1311.

* **DOI:** [10.1038/modpathol.2017.46](https://doi.org/10.1038/modpathol.2017.46)
* **PII:** [S0893-3952(22)00738-4](https://www.sciencedirect.com/science/article/pii/S0893395222007384?via%3Dihub)
* **PMID:** [28548122](https://pubmed.ncbi.nlm.nih.gov/28548122/)

***

## Abstract

Tumor budding is a well-established independent prognostic factor in colorectal cancer but a standardized method for its assessment has been lacking. The primary aim of the International Tumor Budding Consensus Conference (ITBCC) was to reach agreement on an international, evidence-based standardized scoring system for tumor budding in colorectal cancer. The ITBCC included nine sessions with presentations, a pre-meeting survey and an e-book covering the key publications on tumor budding in colorectal cancer. The 'Grading of Recommendation Assessment, Development and Evaluation' (GRADE) method was used to determine the strength of recommendations and quality of evidence.

The following 10 statements achieved consensus:

1. Tumor budding is defined as a single tumor cell or a cell cluster consisting of four tumor cells or less (22/22, 100%).
2. Tumor budding is an independent predictor of lymph node metastases in pT1 colorectal cancer (23/23, 100%).
3. Tumor budding is an independent predictor of survival in stage II colorectal cancer (23/23, 100%).
4. Tumor budding should be taken into account along with other clinicopathological features in a multidisciplinary setting (23/23, 100%).
5. Tumor budding is counted on H\&E (19/22, 86%).
6. Intratumoral budding exists in colorectal cancer and has been shown to be related to lymph node metastasis (22/22, 100%).
7. Tumor budding is assessed in one hotspot (in a field measuring 0.785 mm²) at the invasive front (22/22, 100%).
8. A three-tier system should be used along with the budding count in order to facilitate risk stratification in colorectal cancer (23/23, 100%).
9. Tumor budding and tumor grade are not the same (23/23, 100%).
10. Tumor budding should be included in guidelines/protocols for colorectal cancer reporting (23/23, 100%).

Members of the ITBCC were able to reach strong consensus on a single international, evidence-based method for tumor budding assessment and reporting. It is proposed that this method be incorporated into colorectal cancer guidelines/protocols and staging systems.

***

## Core Methodological Standards

### 1. Definition of a Tumour Bud

* An isolated single cancer cell or a cluster of **$\le 4$ cancer cells** completely detached from neoplastic gland structures at the invasive margin.
* Morphologically distinct from poorly differentiated gland clusters ($>4$ cells).
* Represents histological evidence of epithelial–mesenchymal transition (EMT), loss of E-cadherin, and active local invasion.

### 2. Standardised Assessment Area (0.785 mm²)

* Scanning begins at low-to-medium magnification (4×–10×) along the entire invasive front to locate the area with the densest budding (**hotspot**).
* Once the hotspot is identified, buds are enumerated within **one single microscopic field at 20× magnification** covering an area of **0.785 mm²**.
* Microscopes with different eyepiece field numbers (FN) require area normalization: $$\text{Field Area} = \pi \times \left(\frac{\text{FN}}{2 \times \text{Objective Magnification}}\right)^2$$ The raw bud count is divided by a normalization factor ($0.785 / \text{Field Area}$) to standardize across optical hardware.

### 3. The Three-Tier Scoring System (Bd1–Bd3)

Along with reporting absolute numerical bud counts, scores are categorized into a 3-tier system:

* **Bd1 (Low budding):** 0 to 4 buds per 0.785 mm²
* **Bd2 (Intermediate budding):** 5 to 9 buds per 0.785 mm²
* **Bd3 (High budding):** 10 or more buds per 0.785 mm²

### 4. Stain of Choice: H\&E vs Cytokeratin IHC

* **H\&E is the international standard:** Recommended for routine diagnostics due to universality, low cost, and alignment with outcome cohorts.
* **IHC caveat:** Cytokeratin immunostaining (e.g. pan-CK AE1/AE3) improves visibility and inter-observer concordance, particularly in regions with dense peritumoural inflammation or stromal fibrosis where isolated tumor cells mimic histiocytes, fibroblasts, or endothelial cells. However, cytokeratin systematically yields higher bud counts; hence, the Bd1–Bd3 thresholds derived on H\&E cannot be directly applied to IHC without recalibration.

***

## Clinical Implications

1. **pT1 Colorectal Carcinoma (Malignant Polyps):**
   * High budding (Bd2/Bd3) is a major adverse feature strongly predicting lymph node metastasis (LNM risk $\approx 15\text{--}25%$).
   * Used alongside histological differentiation, depth of submucosal invasion (Kikuchi / Haggitt levels), lymphovascular invasion (LVI), and resection margin status to decide between endoscopic management vs completion oncologic surgical resection.
2. **Stage II Colorectal Carcinoma (pT3-4 N0 M0):**
   * Identifies a high-risk subset of stage II patients with recurrence and survival rates comparable to stage III disease.
   * Incorporated into clinical guidelines (e.g., ESMO, NCCN, CAP, RCPath) as an adverse prognosticator supporting adjuvant 5-FU/oxaliplatin chemotherapy in microsatellite-stable (MSS) tumours.

***

## Computational & Digital Pathology Connections

* **Anchor for Deep Learning & GNNs:** The 0.785 mm² ITBCC hotspot is the spatial region of interest analyzed in automated computational workflows, such as Tumor budding T-cell graphs for pT1 colorectal cancer (Studer et al., MIDL 2023) and the pT1-HBTG benchmark dataset.
* **Detector Targets:** Used by automated detection models (e.g. U-Net, Faster R-CNN, YOLO, Bokhorst student–teacher CNN) trained to locate and count $\le 4$-cell clusters.
* **Reducing Inter-Observer Variability:** Pathologist inter-observer agreement for manual bud counts on H\&E ranges between $\kappa = 0.40\text{--}0.70$. Computer vision pipelines offer reproducible hotspot identification, automated area normalization, and integrated bud–lymphocyte spatial interaction analysis.
* **Spatial Dispersion vs. Bud Density:** Evaluated in [Distance-based evaluation of tumor budding in colorectal cancer](/clippings/distance-based-evaluation-of-tumor-budding-in-colorectal-cancer.md) (Äijälä et al., *Virchows Arch* 2026; $N=1,876$), confirming that while spatial migration distance (TB-distance $\ge 123,\mu\text{m}$) correlates with aggressive disease in isolation, it adds no independent prognostic value over the ITBCC 3-tier count due to collinearity.