Immune deficiency/dysregulation -associated lymphoproliferative disorders. Revised classification and management.

Significant advances in the field of lymphoma have resulted in two recent classification proposals, the International Consensus Classification (ICC) and the 5th edition WHO. A few entities are categorized differently in the ICC compared to the WHO. Nowhere is this more apparent than the immunodeficiency lymphoproliferative disorders. The three previous versions of the WHO classification (3rd, 4th and revised 4th editions) and the ICC focused on four clinical settings in which these lesions arise for primary categorization. In contrast the 2023 WHO 5th edition includes pathologic characteristics including morphology and viral status, in addition to clinical setting, as important information for lesion classification. In addition, the 2023 WHO recognizes a broader number of clinical scenarios in which these lesions arise, including not only traditional types of immune deficiency but also immune dysregulation. With this classification it is hoped that new treatment strategies will be developed leading to better patient outcomes.

Tumor microenvironment contribution to checkpoint blockade therapy: lessons learned from Hodgkin lymphoma.

Classic Hodgkin lymphoma (cHL) is characterized by a tumor microenvironment (TME) containing inflammatory/immune cells. Follicular lymphoma, mediastinal gray zone lymphoma, and diffuse large B-cell lymphomas may show a TME containing inflammatory/immune cells, but the TMEs are quite different. In B-cell lymphomas and cHL, programmed cell death 1 (PD-1)-PD ligand 1 pathway blockade drugs differ in their effectiveness among patients with refractory/relapsed disease. Further research should explore innovative assays that could reveal which molecules influence sensitivity or resistance to therapy in an individual patient.

HIV-related lymphomas.

PURPOSE OF REVIEW: To summarize the recent evidence on the pathology, current standard of care and recent advances in the treatment of HIV-related lymphomas. RECENT FINDINGS: Lymphomas remain a major cause of morbidity and mortality in people living with HIV, even in the era of combination antiretroviral therapy (cART). However, treatment outcomes for these malignancies have improved in recent decades, due to full-dose chemotherapy, effective cART and supportive care. Recent advances include the identification of novel driving signaling pathways as promising molecular targets to improve lymphoma outcomes. SUMMARY: Patients with HIV-related lymphomas who receive effective cART should be treated like the general population.

Prevalence and determinants of quitting smoking after cancer diagnosis: a prospective cohort study.

OBJECTIVE: To describe smoking behaviours of patients with incident cancer attending an Italian cancer centre and to examine changes in their smoking habits within 12 months from cancer diagnosis, evaluating determinants of smoking cessation. METHODS: A hospital-based prospective cohort included patients hospitalized in an Italian cancer centre (2016-2018). Patients were mostly female (74%) and included a limited proportion of aerodigestive cancers (7%). Face-to-face interviews were performed during hospital stay to gather information on patient characteristics and smoking history. Changes in smoking habits were assessed through telephone interviews at 3, at 6, and at 12 months after cancer diagnosis. RESULTS: Among 1011 enrolled patients, 222 (22%) were current smokers at cancer diagnosis. Smoking prevalence was high in male patients (30%), in patients <50 years old (28%), in those with aerodigestive cancers (50%), and in those diagnosed at advanced stages (26%). Among current smokers at cancer diagnosis, 38% quit smoking after 12 months, 26% reduced intensity, and 36% did not modify smoking habits. Smoking cessation was associated with chemotherapy and, although not statistically significant, with female sex, older age, and advanced cancer stage. Patients with gastrointestinal, breast, or genitourinary cancer and those treated with surgery were less likely to quit smoking. CONCLUSIONS: Our results highlighted that 62% of smoking patients with cancer did not quit the habit. Smoking cessation programs targeted to patients with cancer need intensification, particularly for those who may underestimate smoking effects after diagnosis.

Hematologic cancers in individuals infected by HIV.

HIV infection increases cancer risk and is linked to cancers associated to infectious agents classified as carcinogenic to humans by the International Agency for Research on Cancer. Lymphomas represent one of the most frequent malignancies among individuals infected by HIV. Diffuse large B-cell lymphoma remains a leading cancer after the introduction of combined antiretroviral therapy (cART). The incidence of other lymphomas including Burkitt lymphoma, primary effusion lymphomas, and plasmablastic lymphoma of the oral cavity remain stable, whereas the incidence of Hodgkin lymphoma and Kaposi sarcoma-associated herpesvirus (KSHV)-associated multicentric Castleman disease has increased. The heterogeneity of lymphomas in individuals infected by HIV likely depends on the complexity of involved pathogenetic mechanisms (ie, HIV-induced immunosuppression, genetic abnormalities, cytokine dysregulation, and coinfection with the gammaherpesviruses Epstein-Barr virus and KSHV) and the dysregulation of the immune responses controlling these viruses. In the modern cART era, standard treatments for HIV-associated lymphoma including stem cell transplantation in relapsed/refractory disease mirror that of the general population. The combination of cART and antineoplastic treatments has resulted in remarkable prolongation of long-term survival. However, oncolytic and immunotherapic strategies and therapies targeting specific viral oncogenes will need to be developed.

Castleman disease.

Castleman disease (CD), a heterogeneous group of disorders that share morphological features, is divided into unicentric CD and multicentric CD (MCD) according to the clinical presentation and disease course. Unicentric CD involves a solitary enlarged lymph node and mild symptoms and excision surgery is often curative. MCD includes a form associated with Kaposi sarcoma herpesvirus (KSHV) (also known as human herpesvirus 8) and a KSHV-negative idiopathic form (iMCD). iMCD can present in association with severe syndromes such as TAFRO (thrombocytopenia, ascites, fever, reticulin fibrosis and organomegaly) or POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder and skin changes). KSHV-MCD often occurs in the setting of HIV infection or another cause of immune deficiency. The interplay between KSHV and HIV elevates the risk for the development of KSHV-induced disorders, including KSHV-MCD, KSHV-lymphoproliferation, KSHV inflammatory cytokine syndrome, primary effusion lymphoma and Kaposi sarcoma. A CD diagnosis requires a multidimensional approach, including clinical presentation and imaging, pathological features, and molecular virology. B cell-directed monoclonal antibody therapy is the standard of care in KSHV-MCD, and anti-IL-6 therapy is the recommended first-line therapy and only treatment of iMCD approved by the US FDA and EMA.

Immunodeficiency-associated Hodgkin lymphoma.

Introduction: Hodgkin lymphoma (HL) can occur in different host conditions, i.e. in the general population and immunocompromised individuals, either during HIV infection or solid organ/hematopoietic transplantation and immunosuppressive drug treatment.Areas covered: Areas covered include multidimensional characteristics of tumor cells and cellular composition of tumor microenvironment of HL. Current conventional treatments and new treatment strategies for HL in immunosuppressed patients, especially in persons living with HIV (PLWH), are also discussed.PubMed and MEDLINE were used for database searches to identify articles in English published from 1989 to 2020.Expert opinion: For people with post-transplant HL or for those with HIV/AIDS-associated HL, standard treatments mirror those in the general population. In the last decade, the combination of cART with anti-neoplastic treatments, alongside with current anti-rejection therapies, has increased long-term survival of people with HL and acquired immune deficiencies. High-dose chemotherapy and autologous stem cell transplantation have been favorably proven as salvage therapy in PLWH with relapsed and refractory HL. Immune checkpoint inhibitors emerged as an area of clinical investigation for relapsed and refractory HL in the general population. Pembrolizumab, an anti-programmed cell death protein 1 (PD-1) drug, resulted safe in PLWH indicating that PD-1 ligand assessment should be advisable in HIV-associated HL.

Hodgkin lymphoma.

Hodgkin lymphoma (HL) is a B cell lymphoma characterized by few malignant cells and numerous immune effector cells in the tumour microenvironment. The incidence of HL is highest in adolescents and young adults, although HL can affect elderly individuals. Diagnosis is based on histological and immunohistochemical analyses of tissue from a lymph node biopsy; the tissue morphology and antigen expression profile enable classification into one of the four types of classic HL (nodular sclerosis, mixed cellularity, lymphocyte-depleted or lymphocyte-rich HL), which account for the majority of cases, or nodular lymphocyte-predominant HL. Although uncommon, HL remains a crucial test case for progress in cancer treatment. HL was among the first systemic neoplasms shown to be curable with radiation therapy and multiagent chemotherapy. The goal of multimodality therapy is to minimize lifelong residual treatment-associated toxicity while maintaining high levels of effectiveness. Recurrent or refractory disease can be effectively treated or cured with high-dose chemotherapy followed by autologous haematopoietic stem cell transplantation, and prospective trials have demonstrated the potency of immunotherapeutic approaches with antibody-drug conjugates and immune checkpoint inhibitors. This Primer explores the wealth of information that has been assembled to understand HL; these updated observations verify that HL investigation and treatment remain at the leading edge of oncological research.

Cancer Classification at the Crossroads.

Internationally accepted classifications of malignant tumors, developed by the World Health Organization (WHO) and the Union for International Cancer Control (UICC), are based on the histotype, site of origin, morphologic grade, and spread of cancer throughout the body. The WHO classifications are the foundation of cancer diagnosis and the starting point for cancer management. Starting in 2000, the WHO classifications began to include biologic and molecular-genetic features. These developments are having a strong impact on cancer diagnosis and treatment, and this impact is amplifying, given the advances in cancer genomics. Molecular-genetic profiling can be used to refine existing classifications of tumors and, for a small but increasing number of cancers, even determine the treatment irrespective of histotype. Here I discuss how cancer classifications may change in the era of cancer genomics.

Follicular lymphoma.

Follicular lymphoma (FL) is a systemic neoplasm of the lymphoid tissue displaying germinal centre (GC) B cell differentiation. FL represents ~5% of all haematological neoplasms and ~20-25% of all new non-Hodgkin lymphoma diagnoses in western countries. Tumorigenesis starts in precursor B cells and becomes full-blown tumour when the cells reach the GC maturation step. FL is preceded by an asymptomatic preclinical phase in which premalignant B cells carrying a t(14;18) chromosomal translocation accumulate additional genetic alterations, although not all of these cells progress to the tumour phase. FL is an indolent lymphoma with largely favourable outcomes, although a fraction of patients is at risk of disease progression and adverse outcomes. Outcomes for FL in the rituximab era are encouraging, with ~80% of patients having an overall survival of >10 years. Patients with relapsed FL have a wide range of treatment options, including several chemoimmunotherapy regimens, phosphoinositide 3-kinase inhibitors, and lenalidomide plus rituximab. Promising new treatment approaches include epigenetic therapeutics and immune approaches such as chimeric antigen receptor T cell therapy. The identification of patients at high risk who require alternative therapies to the current standard of care is a growing need that will help direct clinical trial research. This Primer discusses the epidemiology of FL, its molecular and cellular pathogenesis and its diagnosis, classification and treatment.

Optimizing checkpoint inhibitors therapy for relapsed or progressive classic Hodgkin lymphoma by multiplex immunohistochemistry of the tumor microenvironment.

Immune checkpoint-blocking antibodies have therapeutic activity against relapsed or progressive classic Hodgkin lymphoma (cHL), but Hodgkin Reed-Sternberg cells can develop resistance to this therapy via multiple mechanisms. To improve the efficacy of immune checkpoint blockade, we need a more precise understanding of the immune escape mechanisms active in individual cHL patients, and this requires a detailed characterization of immune cell populations in the tumor microenvironment. These cell-cell interactions can now be studied by multiplex immunohistochemistry coupled to digital image analysis. This method should allow the identification of actionable target molecules mediating resistance to immune checkpoint inhibitors in individual cHL patients, thereby favoring the implementation of personalized therapies.

Epstein Barr Virus-Associated Hodgkin Lymphoma.

Abstract: Classical Hodgkin lymphoma (cHL) is a distinct clinical and pathological entity with heterogeneous genetic and virological features, with regards to Epstein⁻Barr virus (EBV) infection. The variable association of cHL with EBV infection is probably related to the different levels of patient immunosuppression, both locally in the tumour tissue and at the systemic level. This review paper focuses on EBV-related cHL highlighting pathogenetic and pathological features that may impact pathobiology-driven treatment for the affected patients.

Are EBV-related and EBV-unrelated Hodgkin lymphomas different with regard to susceptibility to checkpoint blockade?

Epstein-Barr virus (EBV)-related and EBV-unrelated classical Hodgkin lymphomas (cHLs) are morphologically and phenotypically indistinguishable. However, the tumor microenvironment of EBV-related cHLs contains higher numbers of macrophages and higher expression levels of PD-L1 than that of EBV-unrelated cHLs. Moreover, viral oncoprotein LMP1 may sustain an immunosuppressive microenvironment by inducing/enhancing production of immunosuppressive cytokines and the expression of PD-1. The presence of enhanced immunosuppressive features in EBV-related cHL should make EBV-related cHL patients more susceptible to checkpoint blockade.