CC – Cervical carcinoma

Important

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Introduction

In May 2022, the EMA granted pembrolizumab in combination with chemotherapy, and both with and without bevacicumab, marketing authorization for the treatment of persistent, recurrent, or metastatic cervical carcinoma (adenocarcinoma, squamous cell carcinoma, adeno-squamous cell carcinoma) in adults without prior therapy who have a PD-L1 expression of CPS ≥1. Accordingly, an immunohistological investigation will also be performed for this entity in the future with the aim of quantifying PD-L1 expression.

		Atezolizumab (anti-PD-L1-Antibody)	Avelumab (anti-PD-L1-Antibody)	Cemiplimab (anti-PD-1-Antibody)	Durvalumab (anti-PD-L1-Antibody)	Ipilimumab (anti-CTLA-4-Antibody)	Nivolumab (anti-PD-1-Antibody)	Pembrolizumab (anti-PD-1-Antibody)	Tislelizumab (anti-PD-L1-Antibody)
Female genital tract
CC
EN	After platinum containing therapy
	2L

Last Update: 4. December 2024

Scores

CPS

CPS calculation is by now a familiar procedure. This calculation is regularly performed in the context of HNSCCs, urothelial carcinomas, gastric carcinoma, and carcinomas of the esophagus.

CPS is a cell score. The abbreviation CPS stands for Combined Positive Score. In this, the positively stained tumor cells and immune cells are placed in relation to the viable tumor cells.

Calculation is completed as for HNSCCs. Accordingly, we need to interpret not only staining in the membrane for carcinoma cells but also the positively stained lymphocytes and macrophages: these are then placed in relation to all viable carcinoma cells and multiplied by 100. The result is a dimensionless number. The calculated value can theoretically be over 100 although this rarely occurs in practice. Plasma cells and granulocytes do not count towards the score.

Summed up, this results in the following calculation:

Interpretation guidance for CPS in cervical carcinoma

Use a high magnification: Since the intensity is irrelevant for the evaluation of PD-L1 and staining in the membrane may be very weak, the tissue under investigation should also always be screened at higher magnifications. Interpretation is made more difficult by keratin pearls, cornoid lamellae, dyskeratosis, and desmosis, which often stain but must be excluded from the evaluation. A greater magnification also helps here to exclude cases of desmosis. Necrotic or apoptotic cells must also be excluded.

PD-L1 prevalence in cervical carcinoma

According to the KN826 marketing authorization trial ^1,2, prevalence for CPS ≥1 is around 88%.

Guidance for practice

Specific interpretation guidance for cervical carcinoma

Support for interpretation is available from Agilent DAKO² at the following link: Agilent DAKO Interpretation Handbook

Please note the following:

A least 100 carcinoma cells should be available for interpretation.
Necrotic cells, plasma cells, and granulocytes are excluded from CPS and TPS scoring.
When evaluating cervical cancer, a carcinoma in situ component is excluded from CPS scoring.

The following tables provide you with full details and guidance for interpreting the CPS score. (Agilent DAKO ³, page 26)

Interpretation guidance for CPS definition numerator

	Tumor cells	Immune cells	Other cells
Included in numerator	Convincing partial or complete linear membrane staining (at any intensity) of viable invasive tumor cells	Membrane and/or cytoplasmic* staining (at any intensity) of mononuclear inflammatory cells (MICs) within tumor nests and adjacent supporting stroma Lymphocytes (including lymphocyte aggregates) Macrophages ‡ Only MICs directly associated with the response to the tumor are scored.	Excluded
Excluded from numerator	Non-staining tumor cells Tumor cels with only cytoplasmic staining	Non-staining MICs MICs (including lymphoid aggregates) associated with ulcers, chronic cystitis, or other, non-tumor-associated processes MICs associated with carcinoma in situ MICs associated with benign structures neutrophil/eosinophil granulocytes and plasma cells	Carcinoma in situ normal/benign cells Stromal cells (including fibroblasts) Necrotic cells and/or cellular debris

* In MICs, membrane and cytoplasmic stainings often cannot be distinguished due to the high nucleus-plasma relation. For this reason, both membrane and cytoplasmic stained MICs are contained in the score.
† “Neighboring MICs” is the definition of cells that are inside the same 20x field as the tumor. However, MICs that are not directly associated with the reaction to the tumor should be ruled out.
‡ Macrophages and histiocytes are assigned to the same kind of cell.

The following tables provide you with full details and guidance for interpreting the CPS score. (Agilent DAKO ⁵, page 24)

Tumor cells

Immune cells

Other cells

Included in denuminator

All viable invasive tumor cells

Excluded

Excluded from denuminator

Any necrotic or non-viable tumor cells
Dysplastic cells

All immune cells of any type

Carcinoma in situ
normale/benign cells

Stromal cells (including fibroblasts) necrotic cells and/or cellular debris

Literature

Supplementary Appendix; Supplement to: Colombo N, Dubot C, Lorusso D, et al. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. DOI: 10.1056/NEJMoa2112435
Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer NEJM, N. Colombo, C. Dubot, D. Lorusso, M.V. Caceres, K. Hasegawa, R. Shapira-Frommer, K.S. Tewari, P. Salman, E. Hoyos Usta, E. Yañez, M. Gümüş, M. Olivera Hurtado de Mendoza, V. Samouëlian, V. Castonguay, A. Arkhipov, S. Toker, K. Li, S.M. Keefe, and B.J. Monk, for the KEYNOTE-826 Investigators
PD-L1 IHC 22C3 pharmDx Interpretation Manual – Cervical Cancer DAKO Agilent