What's behind 68 Ga-PSMA-11 uptake in primary prostate cancer PET? Investigation of histopathological parameters and immunohistochemical PSMA expression patterns

Purpose: Prostate-specific membrane antigen (PSMA-) PET has become a promising tool in staging and restaging of prostate carcinoma (PCa). However, specific primary tumour features might impact accuracy of PSMA-PET for PCa detection. We investigated histopathological parameters and immunohistochemical PSMA expression patterns on radical prostatectomy (RPE) specimens and correlated them to the corresponding 68Ga-PSMA-11-PET examinations. Methods: RPE specimens of 62 patients with preoperative 68Ga-PSMA-11-PET between 2016 and 2018 were analysed. WHO/ISUP grade groups, growth pattern (expansive vs. infiltrative), tumour area and diameter as well as immunohistochemical PSMA heterogeneity, intensity and negative tumour area (PSMA%neg) were correlated with spatially corresponding SUVmax on 68Ga-PSMA-11-PET in a multidisciplinary analysis. Results: All tumours showed medium to strong membranous (2-3 +) and weak to strong cytoplasmic (1-3 +) PSMA expression. Heterogeneously expressed PSMA was found in 38 cases (61%). Twenty-five cases (40%) showed at least 5% and up to 80% PSMA%neg. PSMA%neg, infiltrative growth pattern, smaller tumour area and diameter and WHO/ISUP grade group 2 significantly correlated with lower SUVmax values. A ROC curve analysis revealed 20% PSMA%neg as an optimal cutoff with the highest sensitivity and specificity (89% and 86%, AUC 0.923) for a negative PSMA-PET scan. A multiple logistic regression model revealed tumoural PSMA%neg (p < 0.01, OR = 9.629) and growth pattern (p = 0.0497, OR = 306.537) as significant predictors for a negative PSMA-PET scan. Conclusions: We describe PSMA%neg, infiltrative growth pattern, smaller tumour size and WHO/ISUP grade group 2 as parameters associated with a lower 68Ga-PSMA-11 uptake in prostate cancer. These findings can serve as fundament for future biopsy-based biomarker development to enable an individualized, tumour-adapted imaging approach. Keywords: Glutamate carboxypeptidase II; Immunohistochemistry; Neoplasm staging; Positron emission tomography; Prostatic neoplasm

Factors Indicating Surgical Excision in Classical Type of Lobular Neoplasia of the Breast

Purpose: Classical type of lobular neoplasia (LN) encompassing both atypical lobular hyperplasia and classical lobular carcinoma in situ of the breast is a lesion with uncertain malignant potential and has been the topic of several studies with conflicting outcome results. The aim of our study was to clarify outcome-relevant factors and treatment options of classical LN. Methods: We performed a pathological re-evaluation of the preoperative biopsy specimens and a retrospective clinical and radiological data analysis of 160 patients with LN from the Breast Center Zurich. Open surgery was performed in 65 patients, vacuum-assisted biopsy (VAB) in 79 patients, and surveillance after breast core needle biopsy (CNB) in 16 patients. Results: The upgrade rate into ductal carcinoma in situ/invasive cancer was the highest in case of imaging/histology discordance (40%). If the number of foci in the biopsy specimen was ≥3, the upgrade rate in the consecutive surgical specimens was increased (p = 0.01). The association of classical LN with histological microcalcification correlated with shortened disease-free survival (p < 0.01), whereas other factors showed no impact on follow-up. Conclusions: Surveillance or subsequent VAB after CNB of LN is sufficient in most cases. Careful consideration of individual radiological and histological factors is required to identify patients with a high risk of upgrade into malignancy. In those cases, surgical excision is indicated

Atypical ductal hyperplasia and the risk of underestimation: tissue sampling method, multifocality, and associated calcification significantly influence the diagnostic upgrade rate based on subsequent surgical specimens

BACKGROUND Risk assessment and therapeutic options are challenges when counselling patients with an atypical ductal hyperplasia (ADH) to undergo either open surgery or follow-up only. METHODS We retrospectively analyzed a series of ADH lesions and assessed whether the morphological parameters of the biopsy materials indicated whether the patient should undergo surgery. A total of 207 breast biopsies [56 core needle biopsies (CNBs) and 151 vacuum-assisted biopsies (VABs)] histologically diagnosed as ADH were analyzed retrospectively, together with subsequently obtained surgical specimens. All histological slides were re-analyzed with regard to the presence/absence of ADH-associated calcification, other B3 lesions (lesion of uncertain malignant potential), extent of the lesion, and the presence of multifocality. RESULTS The overall underestimation rate for the whole cohort was 39% (57% for CNB, 33% for VAB). In the univariate analysis, the method of biopsy (CNB vs VAB, p = 0.002) and presence of multifocality in VAB specimens (p = 0.0176) were significant risk factors for the underestimation of the disease (ductal carcinoma in situ or invasive cancer detected on subsequent open biopsy). In the multivariate logistic regression model, the absence of calcification (p = 0.0252) and the presence of multifocality (unifocal vs multifocal ADH, p = 0.0147) in VAB specimens were significant risk factors for underestimation. CONCLUSIONS Multifocal ADH without associated calcification diagnosed by CNB tends to have a higher upgrade rate. Because the upgrade rate was 16.5% even in the group with the lowest risk (VAB-diagnosed unifocal ADH with calcification), we could not identify a subgroup that would not require an open biopsy

Eight autopsy cases of melanoma brain metastases showing angiotropism and pericytic mimicry. Implications for extravascular migratory metastasis

BACKGROUND Metastatic tumor spread is a complex multistep process. Due to the blood-brain barrier, metastasis to the central nervous system is restrictive with a distinct predilection for certain tumor types. In melanoma patients, brain metastasis is a common endpoint with the majority showing evidence of widespread disease at autopsy. In a previous murine melanoma model, we have shown that melanoma cells migrate along preexisting vessels into the brain, showing angiotropism/vascular co-option and pericytic mimicry. METHODS Using conventional morphology and immunohistochemistry, we analyze brain metastases from eight autopsy cases. In addition, tissue clearing, which enables three-dimensional visualization over a distance of 100 μm is used. RESULTS We show the angiotropic localization of melanoma deposits in the brains in all eight autopsy cases. Tissue clearing techniques have allowed visualization of melanoma cells in one case exclusively along the abluminal surface of brain blood vessels over a distance of 100 μm, thus showing pericytic mimicry. CONCLUSIONS Our analyses show clear-cut evidence of angiotropism and pericytic mimicry of melanoma cells within the brain over some distance. In addition, these results support the hypothesis of metastasis along pathways other than hematogenous spread, or extravascular migratory metastasis (EVMM). During EVMM, melanoma cells may metastasize to the brain through pericytic mimicry, circumventing the blood-brain barrier

Clinical parameters associated with gastric portal hypertensive polyps

OBJECTIVES Portal hypertensive polyps (PHPs) are incompletely characterized lesions that can be found in the distal stomach of patients with portal hypertension. We aimed to delineate clinical factors associated with the appearance of these rare polyps. MATERIAL AND METHODS We conducted a cross-sectional study of a cohort with 513 cirrhotic patients comparing patients with and without PHP using descriptive analyses and multivariable logistic regression. To address the problem of missing values, in particular for HVPG and liver stiffness, we used multiple imputation of missing values. RESULTS The prevalence of macroscopically diagnosed PHP was 3.3% (95% confidence interval 2.0 - 5.4%). In 53% of cases, the correct classification was missed on index gastroscopy. Patients with PHP were older at gastroscopy (65 years vs. 59), had higher hepatic venous pressure gradients (HVPG, 28 mmHg vs. 19 mmHg), higher transient elastography (TE) measurements (50.7 kPa vs. 21.8 kPa) and more often had previous rubber band ligations (RBL, 64.7% vs. 25.8%). The multivariable logistic regression on the outcome macroscopically diagnosed PHP estimated an odds ratio (OR) for HPVG of 1.13 (CI 0.95-1.34), increased liver stiffness of 1.03 (1.00 - 1.07) and previous RBL of 3.84 (1.24 - 11.88), respectively. CONCLUSION The prevalence of PHPs in the stomach was higher than assumed in previous studies and misclassification was commonly observed. The appearance of these rare polyps is associated with previous RBL and may correlate with severity of PH. Thus, PHPs may be regarded as marker for relevant PH, but clinical significance of these polyps is still uncertain

MCL1 is Required for Maintenance of Intestinal Homeostasis and Prevention of Carcinogenesis in Mice

BACKGROUND & AIMS Intestinal epithelial homeostasis depends on a tightly regulated balance between intestinal epithelial cell (IEC) death and proliferation. Disruption of factors that promote IEC death result in intestinal inflammation, whereas loss of anti-apoptotic proteins, such as BCL2 or its family member BCL2L1, has no effect on intestinal homeostasis in mice. We investigated the functions of the anti-apoptotic protein MCL1, another member of the BCL2 family, in intestinal homeostasis in mice. METHODS We generated mice with IEC-specific disruption of Mcl1 (Mcl1$^{ΔIEC}$ mice) or tamoxifen-inducible IEC-specific disruption of Mcl1 (i-Mcl1$^{ΔIEC}$ mice); these mice and mice with full-length Mcl1 (controls) were raised under normal or germ-free conditions. Some mice were given antibiotics in their drinking water or the PORCUPINE WNT inhibitor WNT974. Mice were analyzed by endoscopy and for intestinal epithelial barrier permeability. Intestinal tissues were analyzed by histology, in situ hybridization, proliferation assays, and immunoblots. Levels of calprotectin, a marker of intestinal inflammation, were measured in intestinal tissues and feces. RESULTS Mcl1$^{ΔIEC}$ mice spontaneously developed apoptotic enterocolopathy, characterized by increased IEC apoptosis, hyperproliferative crypts, epithelial barrier dysfunction, and chronic inflammation. Loss of MCL1 retained intestinal crypts in a hyperproliferated state and prevented the differentiation of intestinal stem cells. Proliferation of intestinal stem cells in MCL1-deficient mice required WNT signaling and was associated with DNA damage accumulation. By 1 year of age, Mcl1$^{ΔIEC}$ mice developed intestinal tumors with morphologic and genetic features of human adenomas and carcinomas. Germ-free housing of Mcl1$^{ΔIEC}$ mice reduced markers of microbiota-induced intestinal inflammation but not tumor development. CONCLUSION The anti-apoptotic protein MCL1, a member of the BCL2 family, is required for maintenance of intestinal homeostasis and prevention of carcinogenesis in mice. Loss of MCL1 results in development of intestinal carcinomas, even under germ-free conditions, and therefore does not involve microbe-induced chronic inflammation. Mcl1$^{ΔIEC}$ mice might be used to study apoptotic enterocolopathy and inflammatory bowel diseases