J Pathol Transl Med.  2021 May;55(3):163-170. 10.4132/jptm.2021.02.22.

Programmed cell death-ligand 1 assessment in urothelial carcinoma: prospect and limitation

• Lee KS
• Choe G

• KMID: 2515921
• DOI: http://doi.org/10.4132/jptm.2021.02.22

Abstract

Programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) inhibition has revolutionized the treatment paradigm of urothelial carcinoma (UC). Several PD-L1 assays are conducted to formulate appropriate treatment decisions for PD-1/PD-L1 target therapy in UC. However, each assay has its own specific requirement of antibody clones, staining platforms, scoring algorithms, and cutoffs for the determination of PD-L1 status. These prove to be challenging constraints to pathology laboratories and pathologists. Thus, the present article comprehensively demonstrates the scoring algorithm used and differences observed in each assay (22C3, SP142, and SP263). Interestingly, the SP142 score algorithm considers only immune cells and not tumor cells (TCs). It remains controversial whether SP142 expressed only in TCs truly accounts for a negative PD-L1 case. Moreover, the scoring algorithm of each assay is complex and divergent, which can result in inter-observer heterogeneity. In this regard, the development of artificial intelligence for providing assistance to pathologists in obtaining more accurate and objective results has been actively researched. To facilitate efficiency of PD-L1 testing, several previous studies attempted to integrate and harmonize each assay in UC. The performance comparison of the various PD-L1 assays demonstrated in previous studies was encouraging, the exceptional concordance rate reported between 22C3 and SP263. Although these two assays may be used interchangeably, a clinically validated algorithm for each agent must be applied.

Keyword

Urothelial carcinoma; Programmed cell death-ligand 1; 22C3; SP142; SP263; Immunotherapy

Figure

• 

  Fig. 1 Representative pictures for the comparison of programmed death-ligand 1 (PD-L1) assays and differences in scoring algorithm of urothelial carcinoma (UC). (A) Scoring algorithm of SP142 is based on the proportion of tumor area that is occupied by PD-L1-expressed immune cells (ICs) at any intensity. (B) Scoring algorithm of 22C3 is determined by using the combined positive score (CPS) in UC, which is the number of PD-L1–stained cells (tumor cell [TC] plus IC) divided by the total number of viable TCs, multiplied by 100. (C) SP263 status is determined by the percentage of TCs obtained by performing any membrane staining or by the percentage of tumor-associated ICs obtained by staining at any intensity. SP263-expressed TC area proportion of the tumor area is determined. Also, the percentage of tumor area occupied by any tumor-associated IC (Immune Cells Present, ICP) is used to determine IC expression, and IC positivity is defined as the percentage of PD-L1–positive IC area in ICP.

• 

  Fig. 2 (A–C) Representative pictures of heterogeneity observed in programmed death-ligand 1 (PD-L1) assay results (22C3, SP142, and SP263). SP142 was an outlier that detected markedly less PD-L1 expression in tumor cells (TCs). (D–F) Biopsy sample of metastatic urothelial carcinoma with PD-L1 expression observed only in TCs. Although SP142 was expressed in TCs, the result obtained was negative. However, the result for 22C3 was positive. This patient may be administered with pembrolizumab, but not with atezolizumab, as first-line therapy. (G) It is difficult to distinguish between the various subtypes of immune cells. If the regions indicated by the red arrows are plasma cells, they should be excluded from the 22C3 score. (H) Investigation may be necessary to ascertain whether the SP142-stained cells are TCs or ICs. This picture shows SP142 expression on intra-tumoral macrophages. (I) In fragmented tissue samples, including transurethral resection or biopsy samples, where the distinction between intratumoral or peritumoral stroma cannot be clearly observed. The yellow area contiguous to the base of the tumor is considered part of the tumor area.

Reference

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