Primary Central Nervous System Lymphoma (PCNSL) is an aggressive neoplasm with a poor prognosis. Although therapeutic progresses have significantly improved Overall Survival (OS), a number of patients do not respond to HD–MTX-based chemotherapy (15–25%) or experience relapse (25–50%) after an initial response. The reasons underlying this poor response to therapy are unknown. Thus, there is an urgent need to develop improved predictive models for PCNSL. In this study, we investigated whether radiomics features can improve outcome prediction in patients with PCNSL. A total of 80 patients diagnosed with PCNSL were enrolled. A patient sub-group, with complete Magnetic Resonance Imaging (MRI) series, were selected for the stratification analysis. Following radiomics feature extraction and selection, different Machine Learning (ML) models were tested for OS and Progression-free Survival (PFS) prediction. To assess the stability of the selected features, images from 23 patients scanned at three different time points were used to compute the Interclass Correlation Coefficient (ICC) and to evaluate the reproducibility of each feature for both original and normalized images. Features extracted from Z-score normalized images were significantly more stable than those extracted from non-normalized images with an improvement of about 38% on average (p-value < ${10}^{-12}$). The area under the ROC curve (AUC) showed that radiomics-based prediction overcame prediction based on current clinical prognostic factors with an improvement of 23% for OS and 50% for PFS, respectively. These results indicate that radiomics features extracted from normalized MR images can improve prognosis stratification of PCNSL patients and pave the way for further study on its potential role to drive treatment choice.

Background: Consolidation therapy has improved the outcome of newly diagnosed PCNSL patients. Whole-brain radiotherapy (WBRT) was the first consolidation strategy used and represented the gold standard for many years, but at the expense of a high risk of neurotoxicity. Thus, alternative strategies are being investigated in order to improve disease outcomes and to spare the neurocognitive side effects due to WBRT. Methods: We reviewed published studies on PCNSL patients treated with HDC/ASCT, focusing on the efficacy and safety of the conditioning regimens. Prospective and retrospective studies, published in the English language from 1992 to 2022, in high-quality international journals were identified in PubMed. Results: Consolidation with HDC containing highly CNS-penetrating agents (thiotepa, busulfan or BCNU) followed by ASCT provided long-term disease control and survival in PCNSL patients. Two prospective randomized studies, comparing HDC/ASCT versus WBRT, reported similar progression-free survival (PFS) and similar results on the decline in neurocognitive functions in a substantial proportion of patients after WBRT but not after HDC-ASCT. A recent randomized study comparing HDC/ASCT versus non-myeloablative consolidation reported a longer PFS in transplanted patients. Conclusion: ASCT conditioned with regimens, including highly CNS-penetrating agents, represents, to date, the best choice among the available consolidation strategies for fit newly diagnosed PCNSL patients.

Secondary central nervous system (CNS) lymphomas (SCNSL) include the systemic lymphoproliferative diseases with CNS involvement at presentation or at relapse or at both stages of disease. Potentially all lymphoproliferative diseases can present or relapse in the CNS, although with a different incidence. While for some of these the management of CNS localization can be considered standard for others a worldwide consensus on the management and treatment lacks. The incidence of CNS relapse in diffuse large B-cell lymphoma (DLBCL) is about 5%, and it is possibly slightly reduced over the last decades. Two possible reasons of this reduction are: (I) the improvement of systemic disease control obtained with the addition of rituximab to the chemotherapy; (II) the advances in identifying patients at high risk of CNS relapse and the application of prophylaxis. However, many unanswered questions remain and there is not a worldwide consensus on the criteria identifying patients at high risk of CNS and on the standard prophylaxis therapy. Patients who develop SCNSL have a poor prognosis, and the optimal treatment is unknown, and indeed often unsatisfactory. In this manuscript we report the important advances of the knowledge of this rare and fatal disease, obtained in the last years, thanks to the development of multicenter collaborations. However, this disease remains still highly fatal and the discovery of more and more efficient therapy strategies is becoming a priority. New therapeutic strategies alternative to or in combination with chemotherapy such as target and immunomodulatory therapy are being addressed in future trials. In this regard, a more accurate knowledge of the molecular and biological characteristics of this malignancy is becoming a priority for the development of innovative therapies that will be firstly investigated in refractory/relapsing patients and, if efficient, successively incorporated as part of first-line treatment.

Primary lymphoma of the female genital tract (PLFGT) is a rare type of extranodal lymphoma. In this retrospective study from the International Extranodal Lymphoma Study Group, we analyzed clinical data from 60 women diagnosed with PLFGT between 1982 and 2012. The median age was 52 years. Limited stage, as defined by the Ann Arbor and FIGO staging systems, was observed in 55% and 63% of cases, respectively. The uterus was the primary site of lymphoma in 25 cases, with the ovaries as the second most common site (n = 24). The most common histological subtype was diffuse large B‐cell lymphoma (DLBCL, n = 44), followed by follicular lymphoma and marginal zone lymphoma (6 patients each). Two patients received surgery alone as first‐line therapy, while 58 underwent systemic therapy, 16 following major surgery. Thirteen patients received consolidation radiotherapy and six were given central nervous system (CNS) prophylaxis. Twenty patients had disease progression or recurrence. Six patients with DLBCL (14%) experienced CNS relapse, which was the only site of recurrence in five of them. All but one patient with CNS relapse had primary ovarian involvement, and three had bulky disease; none of these patients had received CNS prophylaxis. With a median follow‐up of 60 months, the median overall survival of the DLBCL cohort was approximately 13 years, with a 5‐year survival rate of 77%. In multivariable analysis, advanced disease according to the FIGO system was the only parameter significantly associated with shorter overall, cause‐specific, and progression‐free survival in patients with DLBCL.

Primary central nervous system lymphoma (PCNSL) arises in the central nervous system and remains confined into the brain, an organ with singular biological and immunological characteristics, where the structured lymphoid tissue is not normally present. Early diagnosis represents one of the main tasks for clinicians approaching PCNSL patients, because it would allow both a reduction of the risk of cerebral damage due to the presence of lymphomatous tissue and a limited time of use of steroid therapy, that raises a higher risk of immunosuppression. To date, diagnostic stereotactic biopsy is required in the most of the cases with suspicious PCNSL, however the use of less invasive and alternative diagnostic procedures would limit the surgery related-risks and morbidities, that are described in 8% of the cases. The PCNSL molecular profile and biological characteristics are poorly known, and the researchers’ efforts have been focused on studying these aspects only in the last years. In particular, the progressive knowledge on the genomic and molecular profile of lymphomatous cells and their microenvironment have helped to better characterize the pathophysiology of PCNSL. However, their diagnostic predictive and prognostic roles still remain unclear and have not yet been applied into the clinical practice. In this review we have reported the important advances on the knowledge of the main biomarkers detectable on biological fluids [blood, cerebrospinal fluid (CSF) and vitreous humor] that include genomic fragments, cytokines and their receptors, surface molecules. These biomarkers demonstrated a potential role in the early diagnosis of PCNSL, particularly when they are detected in combination, and some of them showed to have a prognostic value and a role in monitoring disease response.