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.

BackgroundWe recently reported a 56% objective response rate in patients with advanced Merkel cell carcinoma (MCC) receiving pembrolizumab. However, a biomarker predicting clinical response was not identified.MethodsPretreatment FFPE tumor specimens (n = 26) were stained for CD8, PD-L1, and PD-1 by immunohistochemistry/immunofluorescence (IHC/IF), and the density and distribution of positive cells was quantified to determine the associations with anti-PD-1 response. Multiplex IF was used to test a separate cohort of MCC archival specimens (n = 16), to identify cell types expressing PD-1.ResultsTumors from patients who responded to anti-PD-1 showed higher densities of PD-1+ and PD-L1+ cells when compared to non-responders (median cells/mm2, 70.7 vs. 6.7, p = 0.03; and 855.4 vs. 245.0, p = 0.02, respectively). There was no significant association of CD8+ cell density with clinical response. Quantification of PD-1+ cells located within 20 μm of a PD-L1+ cell showed that PD-1/PD-L1 proximity was associated with clinical response (p = 0.03), but CD8/PD-L1 proximity was not. CD4+ and CD8+ cells in the TME expressed similar amounts of PD-1.ConclusionsWhile the binomial presence or absence of PD-L1 expression in the TME was not sufficient to predict response to anti-PD-1 in patients with MCC, we show that quantitative assessments of PD-1+ and PD-L1+ cell densities as well as the geographic interactions between these two cell populations correlate with clinical response. Cell types expressing PD-1 in the TME include CD8+ T-cells, CD4+ T-cells, Tregs, and CD20+ B-cells, supporting the notion that multiple cell types may potentiate tumor regression following PD-1 blockade.Electronic supplementary materialThe online version of this article (10.1186/s40425-018-0404-0) contains supplementary material, which is available to authorized users.

No abstract

PD-L1 expression in the tumor immune microenvironment is recognized as both a prognostic and predictive biomarker in patients with cutaneous melanoma, a finding closely related to its adaptive (IFN-γ-mediated) mechanism of expression. Approximately 35% of cutaneous melanomas express PD-L1, however, the expression patterns, levels, and prevalence in rarer melanoma subtypes are not well described. We performed immunohistochemistry for PD-L1 and CD8 on 200 formalin-fixed paraffin-embedded specimens from patients with acral (n = 16), mucosal (n = 36), uveal (n = 103), and chronic sun-damaged (CSD) (n = 45) melanomas (24 lentigo maligna, 13 ‘mixed’ desmoplastic, and 8 ‘pure’ desmoplastic melanomas). CD8+ tumor-infiltrating lymphocyte (TIL) densities were characterized as mild, moderate, or severe, and their geographic association with PD-L1 expression was evaluated. Discrete lymphoid aggregates, the presence of a spindle cell morphology, and the relationship of these features with PD-L1 expression were assessed. PD-L1 expression was observed in 31% of acral melanomas, 44% of mucosal melanomas, 10% of uveal melanomas, and 62% of CSD melanomas (P<0.0001). Compared to our previously characterized cohort of cutaneous melanomas, the proportion of PD-L1(+) tumors was lower in uveal (P = 0.0002) and higher in CSD (P = 0.0073) melanomas, while PD-L1 expression in the acral and mucosal subtypes was on par. PD-L1 expression in all subtypes correlated with a moderate–severe grade of CD8+ TIL (all, P<0.003), supporting an adaptive mechanism of expression induced during the host antitumor response. The tumor microenvironments observed in CSD melanomas segregated by whether they were the pure desmoplastic subtype, which showed lower levels of PD-L1 expression when compared to other CSD melanomas (P = 0.047). The presence of lymphoid aggregates was not associated with the level of PD-L1 expression, while PD-L1(+) cases with spindle cell morphology demonstrated higher levels of PD-L1 than those with a nested phenotype (P<0.0001). Our findings may underpin the reported clinical response rates for anti-PD-1 monotherapy, which vary by subtype.

No abstract

This series provides further histopathologic support that EMPSGC represents a multistage progression to mucinous carcinoma. Additional studies are needed to understand its molecular mechanisms.

https://www.wileyhealthlearning.com/acs.aspx In this report, a team of surgical pathologists has provided a review of intraepithelial neoplasia in a host of (but not all) anatomic sites of interest to colleagues in various medical specialties, namely, uterine cervix, ovary, breast, lung, head and neck, skin, prostate, bladder, pancreas, and esophagus. There is more experience with more readily accessible sites (such as the uterine cervix and skin) than with other anatomic sites, and the lack of uniform terminology, together with divergent biology in various sites, makes it difficult to paint a unifying, relevant portrait. The authors' aim was to provide a framework from which to move forward as we care for patients with such precancerous lesions. CA Cancer J Clin 2016;66:408–436. © 2016 American Cancer Society.

Background/Aims: Sestamibi scintigraphy and neck ultrasonography have both been proposed as screening modalities for the detection of abnormal parathyroid glands in patients with primary hyperparathyroidism. As a result, many surgeons use both techniques prior to surgery. The goal of this study was to independently evaluate both ultrasound and sestamibi as single-modality preoperative screening tools for primary hyperparathyroidism. Methods: A retrospective review of consecutive patients who underwent surgery for primary hyperparathyroidism from January 1999 to December 2009. Imaging results were compared to surgical findings. Results: 440 patients were found to meet inclusion criteria. Sensitivities for correct localization of a single parathyroid adenoma for sestamibi versus ultrasound were: 83% (95% CI 78–86) versus 72% (95% CI 67–76). Ultrasound operator had no influence on sensitivity, and ultrasound identified nodular thyroid disease in 31% of patients. Conclusion: Ultrasonography alone can be used as the primary screening modality in patients with primary hyperparathyroidism. Ultrasound sensitivity is conserved despite operator variability, and identifies concomitant thyroid pathology.