Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2018 Aug 1;29(8):1853-1860.
doi: 10.1093/annonc/mdy218.

Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC)

T R Cottrell  1 , E D Thompson  2 , P M Forde  3 , J E Stein  4 , A S Duffield  1 , V Anagnostou  5 , N Rekhtman  6 , R A Anders  7 , J D Cuda  8 , P B Illei  9 , E Gabrielson  9 , F B Askin  1 , N Niknafs  5 , K N Smith  3 , M J Velez  6 , J L Sauter  6 , J M Isbell  10 , D R Jones  10 , R J Battafarano  11 , S C Yang  11 , L Danilova  12 , J D Wolchok  13 , S L Topalian  14 , V E Velculescu  3 , D M Pardoll  3 , J R Brahmer  3 , M D Hellmann  15 , J E Chaft  16 , A Cimino-Mathews  9 , J M Taube  17
Affiliations
Clinical Trial

Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC)

T R Cottrell et al. Ann Oncol. .

Abstract

Background: Neoadjuvant anti-PD-1 may improve outcomes for patients with resectable NSCLC and provides a critical window for examining pathologic features associated with response. Resections showing major pathologic response to neoadjuvant therapy, defined as ≤10% residual viable tumor (RVT), may predict improved long-term patient outcome. However, %RVT calculations were developed in the context of chemotherapy (%cRVT). An immune-related %RVT (%irRVT) has yet to be developed.

Patients and methods: The first trial of neoadjuvant anti-PD-1 (nivolumab, NCT02259621) was just reported. We analyzed hematoxylin and eosin-stained slides from the post-treatment resection specimens of the 20 patients with non-small-cell lung carcinoma who underwent definitive surgery. Pretreatment tumor biopsies and preresection radiographic 'tumor' measurements were also assessed.

Results: We found that the regression bed (the area of immune-mediated tumor clearance) accounts for the previously noted discrepancy between CT imaging and pathologic assessment of residual tumor. The regression bed is characterized by (i) immune activation-dense tumor infiltrating lymphocytes with macrophages and tertiary lymphoid structures; (ii) massive tumor cell death-cholesterol clefts; and (iii) tissue repair-neovascularization and proliferative fibrosis (each feature enriched in major pathologic responders versus nonresponders, P < 0.05). This distinct constellation of histologic findings was not identified in any pretreatment specimens. Histopathologic features of the regression bed were used to develop 'Immune-Related Pathologic Response Criteria' (irPRC), and these criteria were shown to be reproducible amongst pathologists. Specifically, %irRVT had improved interobserver consistency compared with %cRVT [median per-case %RVT variability 5% (0%-29%) versus 10% (0%-58%), P = 0.007] and a twofold decrease in median standard deviation across pathologists within a sample (4.6 versus 2.2, P = 0.002).

Conclusions: irPRC may be used to standardize pathologic assessment of immunotherapeutic efficacy. Long-term follow-up is needed to determine irPRC reliability as a surrogate for recurrence-free and overall survival.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Radiographic and gross pathologic measurements of ‘tumor mass’ include areas of immune-mediated tumor regression. (A) There is a significant correlation between the radiographic measurement of the post-treatment lung mass on CT scan and pathologic measurement of the mass in the resected lung specimen. The grossly measured mass includes the microscopically evident regression bed. (B) Representative example of post-neoadjuvant anti-PD-1 treatment lung mass measured on CT scan and the corresponding resected lung specimen. The mass measures ∼3.8 cm in greatest dimension by both modalities, though microscopic examination shows the mass is composed of only 50% RVT. (C) Microscopic examination reveals post-treatment lung masses are composed of varying proportions of fibroinflammatory regression stroma and RVT. Representative photomicrographs from a complete pathologic responder (top), partial pathologic responder (middle; residual tumor with black asterisk, regression bed with white asterisk), and tumors showing no treatment effect (bottom). Original magnification: ×400, all panels.
Figure 2.
Figure 2.
Histologic features of pathologic response to neoadjuvant anti-PD-1 in NSCLC. (A) Post-treatment NSCLC specimens with MPR to therapy showed a distinct pattern of immune-mediated tumor regression, characterized by histologic features of immune activation, tumor cell death, and tissue repair. (B) Association of individual histologic features with MPR/complete pathologic response.
Figure 3.
Figure 3.
Individual features of pathologic response co-localize in the regression bed surrounding residual tumor. (A) Features of pathologic response identified in MPR specimens are also present in the regression bed of ‘partially responding tumors’. However, the tumors from patients 11, 14, and 16 (black box outlines on heat map) had minimal features suggestive of immune-mediated regression. These cases were notable for immune exclusion (patient 11, see Figure 5) and disease relapse (patients 14 and 16). (B) Photomicrograph of a partial responder with 30% cRVT (blue outline). The regression bed (green outline) typically surrounds the residual tumor foci, suggesting an ‘outside-in’ pattern of tumor regression. (C) A patient with a partially responding keratinizing, squamous cell NSCLC (bottom panel) had a regression bed containing residual keratin pearls (top panel, asterisk), further supporting the interpretation of this distinctive peritumoral region as ‘regression bed’. (D) Features of immune-mediated pathologic response may also be identified in lymph nodes, as shown here for patient 4. The double-headed arrow denotes the extent of the regression bed, which is positioned between normal lymph node tissue (asterisk) and RVT (black outline). These findings are notable, as they suggest that immune-mediated responses can be identified and potentially quantified using irPRC, even in tissues normally rich in immune cells. Additionally, the histologic features of regression bed are distinctive enough that responses in previously undiagnosed microscopic disease may also potentially be estimated. Original magnifications: (B) ×20, (C) ×400, (D) ×20 (top panel), and ×200 (bottom panels).
Figure 4.
Figure 4.
Proposal for reproducible, quantitative irPRC. (A) %irRVT is assessed by dividing the total surface area of RVT (circled in blue) by the total tumor bed area ×100. The total tumor bed area (circled in green) is composed of the regression bed area+RVT area+areas of necrosis (supplementary Table S1, available at Annals of Oncology online). The lymph node RVT (LN-irRVT) is calculated separately, but using the same approach, i.e. by measuring the cross-sectional area of RVT and dividing by total tumor bed area. If there are multiple lymph node foci, the areas of each component are summed together to give a %LN-irRVT that represents the total tumor burden in all the lymph nodes assessed. (B) irPRC improves interpathologist reproducibility for percent RVT (%irRVT). Four pathologists blinded to clinical outcome were trained on the tumor from patient 1, and then scored tumors from patients 2 to 20 by both irPRC and chemotherapy criteria. The mean±SD %irRVT and %cRVT scores for each case are shown in black and blue, respectively. Strong concordance was observed among pathologists for the specimens with very little residual tumor when using either the chemotherapy criteria or irPRC. In contrast, large discrepancies in scores for %cRVT were seen in specimens from partial responders. (C) The interpathologist variability in scoring of each case is presented as the range of %RVT scores from four pathologists using the chemotherapy (cRVT) and immune-related (irRVT) criteria (left), shown by blue and black lines, respectively. For each method, the median overall range is presented (right). The proposed immune-related response criteria significantly reduce interpathologist variability in scoring relative to the chemotherapy criteria in these post-immunotherapy specimens.
See this image and copyright information in PMC

Comment in

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Forde PM, Chaft JE, Smith KN. et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med 2018; 378: 1976–1986. - PMC - PubMed
    1. Yamane Y, Ishii G, Goto K. et al. A novel histopathological evaluation method predicting the outcome of non-small cell lung cancer treated by neoadjuvant therapy: the prognostic importance of the area of residual tumor. J Thorac Oncol 2010; 5(1): 49–55. - PubMed
    1. Liu-Jarin X, Stoopler MB, Raftopoulos H. et al. Histologic assessment of non-small cell lung carcinoma after neoadjuvant therapy. Mod Pathol 2003; 16(11): 1102. - PubMed
    1. Topalian SL, Sznol M, McDermott DF. et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 2014; 32(10): 1020–1030. - PMC - PubMed
    1. Le DT, Uram JN, Wang H. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015; 372(26): 2509–2520. - PMC - PubMed

Publication types

MeSH terms

Associated data