Organizing pneumonia associated with Richter transformation in chronic lymphocytic leukemia: a case report and review of the literature.

Organizing pneumonia (OP) is defined histologically by the presence of granulation tissue within alveolar ducts and alveoli. Recently, several lymphoid neoplasms have been implicated as a risk factor for OP, however, OP as a primary manifestation of malignancy transformation has not been widely reported in the literature. Here, we report a case of a patient with a history of chronic lymphocytic leukemia (CLL) who presented with weight loss, low-grade fever, lymphadenopathy, and bilateral pulmonary infiltrates revealed in imaging studies. Video-assisted thoracoscopic lung biopsy showed CLL cells within the pulmonary vessels and areas of OP in the lung parenchyma. Subsequent lymph nodes biopsies were consistent with CLL transformation to diffuse large B-cell lymphoma (DLBCL). To our knowledge, this is the first reported case of OP associated with CLL transformation into DLBCL. This case suggests that OP could represent a form of immunological reaction to ongoing Richter transformation.

Advances in the understanding of molecular genetics and therapy of Richter transformation in chronic lymphocytic leukemia.

Richter's transformation (RT) is defined as the evolution of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma. This complication is rare and aggressive, with poor prognosis and dismal survival. Clonal relationship with the underlying CLL/SLL, observed in ∼80% of cases, represents one of the main factors affecting prognosis. Treatment has been historically based on chemoimmunotherapy, but frequent mutations in genes involved in cell survival and proliferation-such as TP53, NOTCH1, MYC, CDKN2A-confer resistance to standard treatments. During the last years, advances in the knowledge of the biological mechanisms underlying RT allowed to identify genetic and molecular lesions that can potentially be targeted by novel selective agents. Pathway and checkpoint inhibitors, bispecific antibodies and CAR T-cell therapy are currently under investigation and represent promising treatment options. This review summarizes current biological evidence and available data on novel therapeutic agents.

Contemporary Standard of Care Therapy for Richter's Transformation and Future Directions.

Richter's transformation (RT) is a life-threatening evolution of chronic lymphocytic leukemia (CLL) into a more aggressive lymphoma, typically diffuse large B-cell lymphoma (DLBCL), marking a challenging juncture in CLL management due to the associated poor prognosis and limited treatment options. This review delves into the current therapeutic landscape for RT. Despite the modest efficacy of traditional chemoimmunotherapy (CIT) regimens such as R-CHOP and its variations, this regimen remains the most commonly recommended standard of care. Multiple therapeutic strategies are under investigation, including targeted kinase inhibitors, checkpoint inhibitors, bispecific antibodies, and CAR T therapy. Given the complex nature of RT and the evolving therapeutic paradigms, ongoing research is imperative to refine treatment strategies and integrate novel therapeutic agents to enhance survival and quality of life for people with RT. Given the lack of a clear standard of approach in the management of RT, patients with RT should be prioritized to enroll on clinical trials where feasible.

Lymphocytic Lymphoma Transforming into Hodgkin Lymphoma in Sub-Saharan Africa: Case Report and Literature Review.

The Hodgkin variant Richter syndrome (HvRS) is an infrequent complication occurring in 1% of lymphocytic lymphoma/chronic lymphocytic leukemia patients. We report a case of HvRS diagnosed in Sub-Saharan Africa. A 63-year-old patient was consulted for the investigation of an abdominal mass that had been evolving for 5 years prior to admission. His history revealed night sweats, 13% weight loss in 3 months and persistent pruritis. Examination revealed bilateral cervical axillary and inguinal macroadenopathies, painless abdominal distension, pruritic lesions and WHO 2 PS. The blood count showed anemia at 9.5 g/dL. Histology revealed a lymphomatous proliferation of diffuse architecture, nodular in places, with Hodgkin and Sternberg cells associated with small lymphocytes, histiocytes and eosinophilic polymorphs. Immunohistochemistry showed CD20, PAX5, BCL2, CD5, CD23 and MYC positivity; Ki67 at 10% and cyclin D1, BCL6 and CD10 negativity; CD30 positivity on Hodgkin and Sternberg cells that remained CD20 negative; difficulty interpreting CD15; EBV positivity (EBERs); and CD3 and CD5 positivity on reactive T cells. CD138 and kappa and lambda light chains were non-contributory. The extension work-up classified the patient as Ann Arbor stage III B with a Hasenclever score of 3/7. This case illustrates the difficulties in diagnosing HvRS in our countries, where the number of haematopathologists is insufficient and the technical facilities are limited.

Prevascular Richter's hernia a rare and challenging presentation of a potentially life-threatening condition: A rare case report.

INTRODUCTION: Richter's hernia is a relatively uncommon type of hernia that can lead to severe clinical consequences if left unaddressed. The definitive treatment involves the reduction and repair of the hernia defect, with various surgical approaches available, including open transabdominal, inguinal, obturator, and laparoscopic techniques, depending on the size of the defect and the viability of the involved bowel. CASE PRESENTATION: A 29-year-old female patient presented with Richter's hernia, a rare type of hernia, and underwent surgical intervention to release the incarcerated bowel loop and resect the necrotic segment. The case emphasizes the need to consider Richter's hernia in atypical hernia presentations to prevent severe complications. DISCUSSION: Richter's hernia is a distinct type of hernia characterized by the entrapment of a portion of the intestinal circumference, often leading to rapid onset of gangrene without causing intestinal obstruction. The diverse anatomical locations of Richter's hernias, including the rare prevascular variant, emphasize the importance of maintaining a high index of suspicion for this condition, particularly in the context of laparoscopic interventions and atypical hernia presentations. CONCLUSION: Early recognition and prompt referral for appropriate imaging investigations are essential to prevent the significant morbidity and mortality associated with this notoriously challenging-to-diagnose condition, and a heightened awareness and a comprehensive diagnostic approach are crucial to effectively identify and address this rare but potentially life-threatening surgical emergency.

Applications of 18F-Fluorodesoxyglucose PET Imaging in Leukemia.

The main finding that 18F-FDG PET imaging can reveal in patients with leukemias is the presence of bone marrow (BM) infiltration in both acute or chronic forms. This ability can influence and guide the use of BM biopsy but also assess to therapy response. Additionally 18F-FDG PET imaging has been reported as particularly useful for the diagnosis of leukemias in patients with non specific symptoms. In the case of acute leukemias it revealed also a role for the evaluation of extramedullary forms while in the case of chronic forms a role for the assessment of Richter transformation has been reported.

Molecular Subtypes and the Role of TP53 in Diffuse Large B-Cell Lymphoma and Richter Syndrome.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy and a heterogeneous entity comprised of several biologically distinct subtypes. Recently, novel genetic classifications of DLBCL have been resolved based on common mutational patterns indicative of distinct pathways of transformation. However, the complicated and costly nature of the novel classifiers has precluded their inclusion into routine practice. In view of this, the status of the TP53 gene, which is mutated or deleted in 20-30% of the cases, has emerged as an important prognostic factor for DLBCL patients, setting itself apart from other predictors. TP53 genetic lesions are particularly enriched in a genetic subtype of DLBCL that shares genomic features with Richter Syndrome, highlighting the possibility of a subset of DLBCL arising from the transformation of an occult chronic lymphocytic leukemia-like malignancy, such as monoclonal B-cell lymphocytosis. Patients with TP53-mutated DLBCL, including those with Richter Syndrome, have a particularly poor prognosis and display inferior responses to standard chemoimmunotherapy regimens. The data presented in this manuscript argue for the need for improved and more practical risk-stratification models for patients with DLBCL and show the potential for the use of TP53 mutational status for prognostication and, in prospect, treatment stratification in DLBCL.

Mouse models of chronic lymphocytic leukemia and Richter transformation: what we have learnt and what we are missing.

Although the chronic lymphocytic leukemia (CLL) treatment landscape has changed dramatically, unmet clinical needs are emerging, as CLL in many patients does not respond, becomes resistant to treatment, relapses during treatment, or transforms into Richter. In the majority of cases, transformation evolves the original leukemia clone into a diffuse large B-cell lymphoma (DLBCL). Richter transformation (RT) represents a dreadful clinical challenge with limited therapeutic opportunities and scarce preclinical tools. CLL cells are well known to highly depend on survival signals provided by the tumor microenvironment (TME). These signals enhance the frequency of immunosuppressive cells with protumor function, including regulatory CD4+ T cells and tumor-associated macrophages. T cells, on the other hand, exhibit features of exhaustion and profound functional defects. Overall immune dysfunction and immunosuppression are common features of patients with CLL. The interaction between malignant cells and TME cells can occur during different phases of CLL development and transformation. A better understanding of in vivo CLL and RT biology and the availability of adequate mouse models that faithfully recapitulate the progression of CLL and RT within their microenvironments are "conditio sine qua non" to develop successful therapeutic strategies. In this review, we describe the xenograft and genetic-engineered mouse models of CLL and RT, how they helped to elucidate the pathophysiology of the disease progression and transformation, and how they have been and might be instrumental in developing innovative therapeutic approaches to finally eradicate these malignancies.

A rare case of Richter transformation with breast involvement: A case report and literature review.

Richter transformation (RT) represents the development of intrusive lymphoma in individuals previously or concurrently diagnosed with chronic lymphocytic leukemia (CLL) and is characterized by lymph node enlargement. However, cases involving extra-nodal organ involvement as the first symptom are rare. There are no reports of RT with breast lesions as the first symptom. Nonspecific and atypical clinical manifestations represent key challenges in the accurate diagnosis and appropriate treatment of RT. This case report describes an elderly female patient who presented with breast lesions as the first RT symptom. The patient was admitted with a painless mass in the left breast. Examination revealed multiple lymphadenopathies and abnormally high white blood cell levels. The patient was diagnosed with CLL after hematological tests, assessments of bone marrow morphology, and tissue biopsy. Mammography and B-ultrasonography showed solid space-occupying lesions (BI-RADS category 5) in the left breast. Initially, the patient declined a breast biopsy and was therefore prescribed ibrupotinib treatment, which showed limited efficacy. A needle biopsy of the affected breast indicated the presence of diffuse large B-cell lymphoma. Based on auxiliary and pathological examinations and medical history, the final diagnosis was RT with breast involvement. Zanubrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone treatment provided initial control; however, the treatment strategy required adjustment because of the patient's fluctuating condition. The current status of the patient is marked as stable, showing an overall achievement of partial alleviation. The patient is in the process of receiving follow-up treatment. We also performed a comprehensive literature review on RT, with particular emphasis on its biological paradigm, prognosis implications, existing therapeutic approaches, and emerging directions in treatment modalities.

Edvard Munch's crisis in 1908 and French medicine: His doctors, treatments, and sources of information.

In 1908, Norwegian artist Edvard Munch-already famous for The Scream and other paintings showing sickness, despair, and suffering-put himself under the care of Dr. Daniel Jacobson, a nerve doctor in Copenhagen. Jacobson had previously attended some of Jean-Martin Charcot's lectures in Paris, as had Knud Pontoppidan, his mentor. Munch, in turn, had long been showing signs and symptoms of an anxiety disorder and what might have been viewed as neurasthenia or hysteria. Now, he also seemed to be suffering from acute alcoholic toxicity. In this article, we explore Scandinavian psychiatry at the turn of the century; Jacobson and Pontoppidan's connections to Paris; and how some of Munch's treatments, most notably his electrotherapy sessions, related to therapeutics at La Salpêtrière. Additionally, various ways in which Munch learned about French medicine are examined. This material reveals how well-known and influential Charcot and his ideas about disorders of the brain and mind had become at the turn of the century, affecting not just the French physicians but also a world-famous artist and his nerve doctor in Scandinavia.

Mouse models of CLL: In vivo modeling of disease initiation, progression, and transformation.

Chronic lymphocytic leukemia (CLL) is a highly complex disease characterized by the proliferation of CD5+ B cells in lymphoid tissues. Current modern treatments have brought significant clinical benefits to CLL patients. However, there are still unmet needs. Patients relapse on Bruton's tyrosine kinase inhibitors and BCL2 inhibitors and often develop more aggressive diseases including Richter transformation (RT), an incurable complication of up to ∼10% patients. This evidence underscores the need for improved immunotherapies, combination treatment strategies, and predictive biomarkers. A mouse model that can recapitulate human CLL disease and certain components of the tumor immune microenvironment represents a promising preclinical tool for such purposes. In this review, we provide an overview of CRISPR-engineered and xenograft mouse models utilizing either cell lines, or primary CLL cells suitable for studies of key events driving the disease onset, progression and transformation of CLL. We also review how CRISPR/Cas9 established mouse models carrying loss-of-function lesions allow one to study key mutations driving disease progression. Finally, we discuss how next generation humanized mice might improve to generation of faithful xenograft mouse models of human CLL.

Clinicopathologic findings of splenic marginal zone lymphoma with gallbladder involvement that progressed to diffuse large B-cell lymphoma in a dog.

A 12-year-old spayed female Dalmatian presented with acute vomiting and anorexia. The clinicopathological and imaging abnormalities included icterus, biliary obstruction, and multiple diffuse splenic hypoechogenic nodules. Cholecystectomy was performed to remove the obstruction, followed by liver biopsy and splenectomy. Histopathological and immunohistology evaluation of the spleen, liver, and gallbladder revealed splenic marginal zone lymphoma (MZL) with gallbladder and hepatic infiltration of neoplastic CD20/CD79α-positive cells. Moreover, we observed clonal rearrangements of the immunoglobulin heavy-chain (IgH) gene in all three tissues. The dog was in good condition without chemotherapy. However, there was progressive elevation of liver enzymes, which could be attributed to neoplastic hepatic infiltration. Chlorambucil and prednisolone were administered until day 108, when the liver enzyme levels normalized. On day 156, the dog developed diffuse large B-cell lymphoma (DLBCL) of the peripheral lymph nodes. Sequence analysis of the clonally rearranged IgH gene revealed that all neoplastic cells in the spleen, gallbladder, and liver at initial presentation, as well as lymph nodes on day 156, possessed the same sequence identity of the amplified IgH fragments. This demonstrated that all neoplastic cells were derived from the same B-lymphocyte clone. The DLBCL was considered to have transformed from the splenic MZL, with gallbladder involvement. In cases of splenic MZL, it is important to consider gallbladder involvement and transformation to DLBCL. Moreover, gallbladder lymphoma should be included in the differential diagnosis of dogs with gallbladder abnormalities. Further studies are warranted to investigate the prognosis of splenic MZL.

Anisolymphocytosis: A clue for Richter transformation.

When chronic lymphocytic leukemia progressed to Richter syndrome, the coexistence of small and large lymphocytes was observed as a bone marrow finding. We consider this finding to be a clue for the progression of chronic lymphocytic leukemia to Richter syndrome.

The Diagnostic Performance of 2-[18F]FDG PET/CT in Identifying Richter Transformation in Chronic Lymphocytic Leukemia: An Updated Systematic Review and Bivariate Meta-Analysis.

Richter transformation is a rare phenomenon characterized by the transformation of cell chronic lymphocytic leukemia (CLL) into a more aggressive lymphoma variant. The early identification of CLLs with a high risk of RT is fundamental. In this field, 2-deoxy-2-[18F]-fluoro-D-glucose positron emission tomography/computed tomography (2-[18F]FDG PET/CT) has been shown to be a non-invasive and promising tool, but apparently, unclear data seem to be present in the literature. This systematic review and bivariate meta-analysis aimed to investigate the diagnostic performance of 2-[18F]FDG PET/CT and its parameters in predicting RT. Between 2006 and 2024, 15 studies were published on this topic, including 1593 CLL patients. Among semiquantitative variables, SUVmax was the most investigated, and the best threshold derived for detecting RT was five. With this cut-off value, a pooled sensitivity of 86.8% (95% CI: 78.5-93.3), a pooled specificity of 48.1% (95% CI: 27-69.9), a pooled negative predictive value of 90.5% (95% CI: 88.4-92.4), a pooled negative likelihood ratio of 0.35 (95% CI: 0.17-0.70), a pooled positive likelihood ratio of 1.8 (95% CI: 1.3-2.4), and a pooled diagnostic odds ratio of 6.7 (3.5-12.5) were obtained. With a higher cut-off (SUVmax = 10), the specificity increased while the sensitivity reduced. The other metabolic features, like metabolic tumor volume, total lesion glycolysis, and radiomic features, were only marginally investigated with controversial evidence.

Richter supraumbilical hernia managed with invagination: a case report.

Introduction and importance: Richter's hernia is an incarceration of the anti-mesenteric border of a segment of bowel through an abdominal wall defect. It primarily affects elderly individuals but can occur at any age, with a slightly increased incidence in females. The increase in laparoscopic and robotic-assisted procedures has led to a rise in Richter's hernias. Case presentation: A 40-year-old male with a history of laparoscopic cholecystectomy and kidney transplantation presented with a 4-day history of supraumbilical swelling and abdominal pain. The swelling was irreducible and accompanied by mild tenderness, and local signs of inflammation were exhibited. Intraoperatively, a 1.5 cm hernia defect was found, with the sac containing omentum and a portion of bowel segment for which invagination with serosal closure with the Mayo double-breasting technique was done. Clinical discussion: Richter's hernia presents with abdominal discomfort, bloating, nausea, and vomiting, with a notable feature being the delayed onset of symptoms due to its partial involvement of the bowel wall. Diagnosis can be achieved through a computed tomography (CT) scan or intraoperative exploration. Management of Richter hernia is contingent upon the patient's clinical condition, physical examination, and suspicion of strangulation. Conclusion: Diagnosis of Richter's hernia demands higher suspicion, particularly in patients with predisposing factors like a history of minimally invasive surgery. Prompt surgical intervention is crucial for reducing mortality and enhancing prognosis, with invagination alone being adequate if ischaemia is confined and mesh placement is unnecessary.

Case report: 'Atypical Richter transformation from CLL-type monoclonal B-cell lymphocytosis into Burkitt lymphoma in a treatment naïve patient'.

Background: Richter transformation refers to the progression of an initially slow-growing small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) into an aggressive lymphoma, typically diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma. Case presentation: The patient presented with a rapid onset of localized cervical swelling, accompanied by monoclonal B-cell lymphocytosis displaying a CLL immunophenotype. The histopathological analysis identified a Burkitt lymphoma (BL) located in the submandibular gland and adjacent lymph node. The patient's bone marrow displayed a minor infiltration of monoclonal B-cells with a CLL immunophenotype (< 10%). Molecular analysis demonstrated the presence of the same monoclonal rearrangement in the framework region (FR3 region) of the immunoglobulin heavy chain (IGH) locus. High-throughput sequencing of the immunoglobulin heavy and light chains also confirmed the presence of the same rearrangement in SLL/CLL and in the Burkitt lymphoma sample, but also highlighted the presence of a second rearrangement in the Burkitt lymphoma cells, not shared with the SLL/CLL cells in the bone marrow. The patient was treated with DA-EPOCH-R, which lead to a complete metabolic response. Conclusion: This report provides an exceptionally rare description of a CLL-type monoclonal B-cell lymphocytosis transforming into a very aggressive Burkitt lymphoma in a treatment naïve patient.

Are we closer to a standard of care for Richter's syndrome? Novel treatments on the horizon.

INTRODUCTION: The therapeutic landscape for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has significantly evolved over the past decade with dramatically improved outcomes with the introduction of targeted therapies. This unfortunately has not been the case for Richter transformation (RT), the histologic transformation to a more aggressive lymphoma, most typically diffuse large B-cell lymphoma (DLBCL). As such, RT continues to be one of the most challenging complications of CLL/SLL. Historically, RT has a poor response to treatment, with a minority reaching complete remission (CR) and overall survival (OS) being less than a year. AREAS COVERED: The focus of this review is to discuss the effectiveness of commonly used regimens, and review existing data for emerging regimens being examined in ongoing clinical trials to improve prognosis and outcomes in patients with RT. Despite extensive efforts to optimize therapies for RT, there is still no generalized consensus on either first-line treatment regimens or regimens in the relapsed/refractory setting. RT continues to carry a high mortality rate without durable response to current therapeutic agents. EXPERT OPINION: Ongoing and future research may identify novel treatment approaches that will eventually improve outcomes for patients with RT. The optimal care for RT patients is a clinical trial, when feasible.

Iatrogenic enterocutaneous fistula following an incarcerated Richter's femoral hernia misdiagnosed for an inguinal abscess: A case report.

INTRODUCTION AND IMPORTANCE: As the Richter's hernia contains anti-mesenteric intestinal wall, patients usually do not present with obstructive symptoms. Consequently, this leads to delays in diagnosis and increased morbidity and mortality. Early detection and surgical treatment are therefore paramount to improving outcomes. CASE PRESENTATION: A 51-year-old female presented with an incarcerated Richter's femoral hernia misdiagnosed as inguinal abscess that underwent incision and drainage. This developed into an enterocutaneous fistula (EC Fistula) and was eventually complicated by peritonitis, requiring laparotomy and herniorrhaphy. Post-operative recovery was uneventful. CLINICAL DISCUSSION: In advanced stages, Richter's femoral hernia may present with obstructive symptoms as in other incarcerated hernias. Richter's hernias may eventually present with obstructive symptoms in their advanced stages. Their relatively asymptomatic nature increases the risk of complications, such as enterocutaneous fistula. CONCLUSION: This case highlights how an incarcerated Richter's femoral hernia in a female misdiagnosed as an abscess delayed treatment, increased patient morbidity with development of an enterocutaneous fistula and peritonitis, and mandated surgical exploration to control sepsis and repair the hernia.

2-[18F]-FDG PET/CT Semiquantitative and Radiomics Predictive Parameters of Richter's Transformation in CLL Patients.

Background and Objectives: Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in developed countries, which can evolve into aggressive lymphoma variants, a process called Richter transformation (RT). The aim of this retrospective study was to analyze the role of 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography (2-[18F]-FDG PET/CT) and its semiquantitative and radiomics features in detecting RT and evaluate the impact on overall survival (OS). Materials and Methods: One hundred and thirty-seven patients with histologically proven CLL were retrospectively recruited. PET/CT images were qualitatively and semiquantitatively examined by estimating the main metabolic parameters (the maximum standardized uptake value body weight (SUVbw), lean body mass (SUVlbm), body surface area (SUVbsa), lesion-to-blood-pool SUV ratio (L-BP SUV R), lesion-to-liver SUV ratio (L-L SUV R), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) and radiomics first- and second- order variables of the lesion with highest uptake. The role of these parameters in predicting RT and OS was analyzed. Results: One hundred and thirty (95%) PET/CT scans were positive, showing an increased tracer uptake at the site of disease, whereas the remaining 7 (5%) scans were negative. SUVbw, SUVlbm, SUVbsa, L-L SUV ratio, and L-BP SUV ratio were significantly higher in the RT group (p < 0.001 in all cases). Radiomics first- and second-order features were not significantly associated with RT. After a median follow-up of 44 months, 56 patients died; OS was significantly shorter in patients with RT than patients without RT (28 vs. 34 months; p = 0.002). Binet-stage, RT, and L-BP SUV R were shown to be independent prognostic features. Conclusions: Semiquantitative PET/CT parameters such as SUVbw, SUVlbm, SUVbsa, L-L SUV ratio and L-BP SUV ratio may be useful in discriminating patients with a high risk of developing RT, whereas Binet-stage, RT, and L-BP SUV R are also significant in predicting OS.

Long-term remission in a patient with relapsed Richter's transformation treated with CD19-directed chimeric antigen-receptor T-cells after allogeneic stem cell transplantation.

Patients with Richter's transformation of chronic lymphocytic leukemia (CLL) to diffuse large B-cell lymphoma (DLBCL-RT) face a dismal prognosis. A 51-year-old female patient diagnosed with CLL with deletion (17p) in 2009. CLL treatment included chemoimmunotherapy and targeted substances. DLBCL-RT was diagnosed in November 2016. After receiving an allogeneic hematopoietic stem cell transplantation, she relapsed in September 2019 and tisagenlecleucel was infused in December 2019. Cytokine release syndrome grade 2 was treated with two doses of tocilizumab and the patient was started on 140 mg ibrutinib in February 2020. Our patient remains in remission up to 4 years after CAR T-cell treatment.