The impact of a pathologist's personality on the interobserver variability and diagnostic accuracy of predictive PD-L1 immunohistochemistry in lung cancer.

OBJECTIVES: Programmed death-ligand 1 (PD-L1) is the only approved predictive biomarker for immunotherapy in non-small cell lung cancer (NSCLC). However, predictive PD-L1 immunohistochemistry is subject to interobserver variability. We hypothesized that a pathologist's personality influences the interobserver variability and diagnostic accuracy of PD-L1 immunoscoring. MATERIALS AND METHODS: Seventeen pathologists performed PD-L1 immunoscoring on 50 resected NSCLC tumors in three categories (<1%;1-49%;≥50%). Also, the pathologists completed a certified personality test (NEO-PI-r), assessing five personality traits: neuroticism, extraversion, openness, altruism and conscientiousness. RESULTS: The overall agreement among pathologists for a series of 47 tumors was substantial (kappa = 0.63). Of these, 23/47 (49%) tumors were entirely negative or largely positive, resulting in a kappa value of 0.93. The remaining 24/47 (51%) tumors had a PD-L1 score around the cutoff value, generating a kappa value of 0.32. Pathologists with high scores for conscientiousness (careful, diligent) had the least interobserver variability (r = 0.6, p = 0.009). Also, they showed a trend towards higher sensitivity (74% vs. 68%, p = 0.4), specificity (86% vs. 82%, p = 0.3) and percent agreement (83% vs. 79%, p = 0.3), although not significant. In contrast, pathologists with high scores for neuroticism (sensitive, anxious) had significantly lower specificity (80% vs. 87%, p = 0.03) and percent agreement (78% vs. 85%, p = 0.03). Also, a trend towards high interobserver variability (r = -0.3, p = 0.2) and lower sensitivity (68% vs. 74%, p = 0.3) was observed, although not significant. Pathologists with relatively high scores for conscientiousness scored fewer tumors PD-L1 positive at the ≥ 1% cut-off (r = -0.5, p = 0.03). In contrast, pathologists with relatively high scores for neuroticism score more tumors PD-L1 positive at ≥ 1% (r = 0.6, p = 0.017) and ≥ 50% cut-offs (r = 0.6, p = 0.009). CONCLUSIONS: This study is the first to demonstrate the impact of a pathologist's personality on the interobserver variability and diagnostic accuracy of immunostaining, in the context of PD-L1 in NSCLC. Larger studies are needed for validation of these findings.

Absence of PD-L1 expression on tumor cells in the context of an activated immune infiltrate may indicate impaired IFNγ signaling in non-small cell lung cancer.

BACKGROUND: In non-small cell lung cancer (NSCLC), PD-L1 expression on either tumor cells (TC) or both TC and tumor-infiltrating immune cells (IC) is currently the most used biomarker in cancer immunotherapy. However, the mechanisms involved in PD-L1 regulation are not fully understood. To provide better insight in these mechanisms, a multiangular analysis approach was used to combine protein and mRNA expression with several clinicopathological characteristics. PATIENTS AND METHODS: Archival tissues from 640 early stage, resected NSCLC patients were analyzed with immunohistochemistry for expression of PD-L1 and CD8 infiltration. In addition, mutational status and expression of a selection of immune genes involved in the PD-L1/PD-1 axis and T-cell response was determined. RESULTS: Tumors with high PD-L1 expression on TC or on IC represent two subsets of NSCLC with minimal overlap. We observed that PD-L1 expression on IC irrespective of expression on TC is a good marker for inflammation within tumors. In the tumors with the highest IC expression and absent TC expression an association with reduced IFNγ downstream signaling in tumor cells was observed. CONCLUSIONS: These results show that PD-L1 expression on TC and IC are both independent hallmarks of the inflamed phenotype in NSCLC, and TC-negative/IC-high tumors can also be categorized as inflamed. The lack of correlation between PD-L1 TC and IC expression in this subgroup may be caused by impaired IFNγ signaling in tumor cells. These findings may bring a better understanding of the tumor-immune system interaction and the clinical relevance of PD-L1 expression on IC irrespective of PD-L1 expression on TC.

Microscopic disease extensions as a risk factor for loco-regional recurrence of NSCLC after SBRT.

PURPOSE: Stereotactic body radiotherapy (SBRT) is a highly conformal technique that allows a more accurate irradiation of lung tumors. However, a highly conformal dose distribution may underdose undetected microscopic disease extensions (MDE) near the tumor leading to loco-regional failure in tumor control. The purpose of the current work is to assess the risk of loco-regional failure in SBRT by analyzing pre-treatment scans. METHODS AND MATERIALS: A model to predict the risk of occurrence of MDE from pretreatment images was developed based on pathology samples of 47 lung cancer patients. This model was used to assess the outcome of 238 SBRT treatments. RESULTS: Patients with high risk of MDE presence showed significantly lower 2-year loco-regional control (82.0% vs. 91.8%) and shorter time to loco-regional failure (8.4 months vs. 20.7 months) than low risk patients. The minimum dose delivered in the volume surrounding the GTV affected the model predictive power. The model remained predictive for patients who received less than 31 Gy in that volume. For patients who received larger doses, the MDE risk classification was not significant. CONCLUSIONS: The results show that MDEs are, at least partially, responsible of loco-regional failure in highly conformal radiotherapy. This information could be used to optimize dose distributions.

Erythromycin precipitation in vena femoralis: investigation of crystals found in postmortem material of an intensive care unit patient.

A case of intravenous precipitation of erythromycin is reported along with the patient history, pathologic findings, and a description of the analytical methods and results. The patient was a 75-year-old woman with a history of myocardial infarction, deep venous thrombosis, and diabetes mellitus who underwent aortic valve replacement. She developed endocarditis and recurrent episodes of urosepsis, with multiple organ failure including severe gastric retention, for which she was treated with erythromycin intravenously. She died because of refractory septic shock. Autopsy revealed aortic valve endocarditis, thrombi in the right femoral vein, arterial (nonfungal) thromboemboli in the celiac trunk, and coarse material in the right femoral vein where the tip of the central venous catheter had been located. Microscopical examination of the coarse material showed that it was birefringent crystalline material. Part of the postmortem material was analyzed in the laboratory of the department of clinical pharmacy and revealed the presence of erythromycin. Erythromycin was detected using Fourier transform infrared spectroscopy. An additional specific color test and thin-layer chromatography confirmed this finding. On the basis of the postmortem findings, patient history, and analytical-toxicologic results, we conclude that erythromycin precipitation can occur in vivo after intravenous administration in patients with impaired blood flow.

Thymic epithelial tumours: a population-based study of the incidence, diagnostic procedures and therapy.

The population-based incidence, diagnostic procedures, therapy and survival of thymic epithelial tumours were determined using the Netherlands National Pathological Archives and the Netherlands Cancer Registry. Excess mortality compared to the Netherlands standard population was estimated by relative survival analysis. Between 1994 and 2003, 537 thymic epithelial tumours were diagnosed. The incidence of all thymic epithelial tumours was 3.2/1,000,000. Diagnosis was obtained by primary resection in 56% of cases. Survival data were available for 232 cases. Not only thymic carcinomas (type C) but also thymomas (types B1-B3) were associated with excess mortality. Cases that underwent resection (78%) had a better survival than non-operated cases (median survival >10 years versus 1.1 years, p<0.001). Amongst the surgically treated cases (n=180), the completeness of resection did not predict survival (p=0.53). Thymic epithelial tumours are rare. Excess mortality was observed in the majority of tumours. Surgery offers the best perspectives, even if the resection is incomplete.

Non-Hodgkin lymphoma of the female genital tract. A five case series.

Non-Hodgkin lymphoma (NHL) of the female genital tract is extremely rare. We report five cases of NHL, which were collected during an 8-year period from the files of the Department of Pathology at the Onze Lieve Vrouwe Gasthuis, Amsterdam. In these five cases, the NHL was clinically not considered and the genital location was the primary site of presentation.