Stenotrophomonas maltophilia skin infection in an immunocompetent patient: Primary cutaneous CD30+ T-cell lymphoproliferative disorder or pseudolymphoma?

Cutaneous pseudolymphomas are a wide group of diseases mimicking cutaneous lymphoma. They comprise several skin conditions with different etiopathogenesis, clinical-pathological features, and prognosis, which may occur in the absence of an identifiable trigger factor or after administration of medications or vaccinations, tattoos, infections, or arthropod bites. They present with different manifestations: from solitary to regionally clustered lesions, up to generalized distribution and, in rare cases, erythroderma. They persist variably, from weeks to years, and resolve spontaneously or after antibiotics, but may recur in some cases. CD30+ T-cell pseudolymphomas are characterized by the presence of large, activated lymphoid cells, generally in response to viral infections, arthropod assault reactions, and drug eruptions. Stenotrophomonas maltophilia is a ubiquitous Gram-negative bacillus responsible for opportunistic infections in immunocompromised patients. Infection of intact skin in immunocompetent patients is particularly rare. Here, we report a case of a man presenting an isolated nodule histopathologically mimicking a primary cutaneous CD30+ T-cell lymphoproliferative disorder.

Co-infection of Pneumocystis jirovecii pneumonia and pulmonary CMV in a infant with X-linked severe combined immunodeficiency.

We herein report a rare case of co-infection of Pneumocystis jirovecii pneumonia and pulmonary CMV in a 3-month-old infant with X-linked severe combined immunodeficiency, in which diagnostic clues were obtained from the bronchoalveolar lavage fluid. We focus on the value of cytological diagnosis of P. jirovecii pneumonia and pulmonary CMV in the bronchoalveolar lavage fluid. Recognizing morphological characteristics of these pathogenic microorganisms is important to get timely diagnosis and treatment for the patients. Furthermore, repeated severe infections in infants should remind us to screen for immunosuppressed states.

Infections in patients with lymphoproliferative diseases treated with targeted agents: SEIFEM multicentric retrospective study.

We describe the opportunistic infections occurring in 362 patients with lymphoproliferative disorders treated with ibrutinib and idelalisib in clinical practice. Overall, 108 of 362 patients (29·8%) developed infections, for a total of 152 events. Clinically defined infections (CDI) were 49·3% (75/152) and microbiologically defined infections (MDI) were 50·7% (77/152). Among 250 patients treated with ibrutinib, 28·8% (72/250) experienced one or more infections, for a total of 104 episodes. MDI were 49% (51/104). Bacterial infections were 66·7% (34/51), viral 19·6% (10/51) and invasive fungal diseases (IFD) 13·7% (7/51). Among the 112 patients treated with idelalisib, 32·1% (36/112) experienced one or more infections, for a total of 48 episodes. MDI were 54·2% (26/48). Bacterial infections were 34·6% (9/26), viral 61·5% (16/26) and IFD 3·8% (1/26). With ibrutinib, the rate of bacterial infections was significantly higher compared to idelalisib (66·7% vs. 34·6%; P = 0·007), while viral infections were most frequent in idelalisib (61·5% vs. 19·6%; P < 0·001). Although a higher rate of IFD was observed in patients treated with ibrutinib, the difference was not statistically significant (13·7% vs. 3·8% respectively; P = 0·18). Bacteria are the most frequent infections with ibrutinib, while viruses are most frequently involved with idelalisib.

The Possible Role of Gut Microbiota and Microbial Translocation Profiling During Chemo-Free Treatment of Lymphoid Malignancies.

The crosstalk between gut microbiota (GM) and the immune system is intense and complex. When dysbiosis occurs, the resulting pro-inflammatory environment can lead to bacterial translocation, systemic immune activation, tissue damage, and cancerogenesis. GM composition seems to impact both the therapeutic activity and the side effects of anticancer treatment; in particular, robust evidence has shown that the GM modulates the response to immunotherapy in patients affected by metastatic melanoma. Despite accumulating knowledge supporting the role of GM composition in lymphomagenesis, unexplored areas still remain. No studies have been designed to investigate GM alteration in patients diagnosed with lymphoproliferative disorders and treated with chemo-free therapies, and the potential association between GM, therapy outcome, and immune-related adverse events has never been analyzed. Additional studies should be considered to create opportunities for a more tailored approach in this set of patients. In this review, we describe the possible role of the GM during chemo-free treatment of lymphoid malignancies.

Association between CMV and Invasive Fungal Infections After Autologous Stem Cell Transplant in Lymphoproliferative Malignancies: Opportunistic Partnership or Cause-Effect Relationship?

Unlike allogeneic transplant, autologous stem cell transplantation (ASCT) represents a procedure with a low-risk of cytomegalovirus (CMV) symptomatic reactivation-infection/end-organ disease (CMV complications) and invasive fungal disease (IFD). However, novel drugs for the treatment of lymphoproliferative malignancies could cause an increase of such opportunistic infections, even after ASCT. To the best of our knowledge, there are no published data demonstrating an association between CMV and IFD in the autologous setting, while this association has been widely reported in allogeneic transplantation. We have reviewed our series of 347 ASCT in myeloma and lymphoma patients performed over a period of 14 years with the aim of investigating the descriptive and analytical epidemiology of bacterial, CMV and IFD complications, focusing on the association between CMV and IFD. Patients with myeloma have significantly fewer bacterial infections and IFD than patients with lymphoma, but a similar rate of CMV complications. Descriptive epidemiological data are consistent with the literature, indicating an overall incidence of 36%, 3.5% and 15.5% for bacterial infections, IFD and CMV complications, with a case mortality rate of 4%, 16.7% and 3.7%, respectively. A strong correlation between CMV and IFD exists, with 8 cases of IFD out of a total of 12 presenting a CMV complication. At multivariate analysis, a diagnosis of lymphoma, ≥3 previous treatment lines and age ≥60 years were found to be independent risk factors for IFD. Duration of neutropenia (ANC < 500/mm³) ≥7 days represents an independent risk factor for CMV complications, where neutropenia most likely represents a crude surrogate biomarker indicating a deeper and longer state of overall immunosuppression. From our data we conclude that (1) myeloma patients are at lower risk of bacterial infections and IFD as compared with lymphoma patients but are at equal risk of CMV complications, most likely as a consequence of a selective impact of bortezomib on Herpes Viruses infection control; (2) a significant association exists between CMV and IFD, although a possible cause-effect relationship remains to be determined; (3) IFD is a rare complication after ASCT but burdened by a mortality rate of about 17%, with peak rates in older lymphoma patients who underwent more intensive therapeutic regimens.

A Reactive Peripheral Gamma-Delta T-cell Lymphoid Proliferation After a Tick Bite.

Peripheral gamma-delta T-cell proliferations are encountered in reaction to certain infections and in primary malignancies. Identifying sources of benign reactions is key in avoiding unnecessary workup and surveillance of these aggressive malignancies. Borrelia infections have been implicated in a number of lymphoproliferative disorders, but rarely, if ever, in this setting. While gamma-delta T-cells are known to play a prominent role in the immune response to Borrelia infection, B-cell differentiation is encountered in the majority of Borrelia-associated proliferations. We present here a unique case of benign-appearing peripheral gamma-delta T-cell lymphoid proliferation in the setting of a tick-bite with subsequent erythema migrans-like skin findings.

Comprehensive polymerase chain reaction assay for detection of pathogenic DNA in lymphoproliferative disorders of the ocular adnexa.

Infectious agents have been identified as a major cause of specific types of human cancers worldwide. Several microorganisms have been identified as potential aggravators of ocular adnexal neoplasms; however, given the rarity of these neoplasms, large epidemiological studies are difficult to coordinate. This study aimed to conduct an exhaustive search for pathogenic DNA in lymphoproliferative disorders (LPD) of the ocular adnexa in a total of 70 patients who were diagnosed with LPD of the ocular adnexa between 2008 and 2013. Specimens were screened for bacterial, viral, fungal, and parasitic DNA by multiplex polymerase chain reaction (PCR) and quantitative real-time PCR. Among cases of conjunctival mucosa-associated lymphoid tissue lymphoma, human herpes virus (HHV)-6, HHV-7, chlamydia, Epstein-Barr virus (EBV) and bacterial 16S ribosomal DNA were detected. In cases of IgG4-related ocular disease, similar pathogens were detected but in a larger number of patients. Our PCR assays detected DNAs of various infectious agents in tumor specimens, especially HHV6, HHV7, and EBV, with different positive rates in various types of LPD. Chronic inflammatory stimulation or activation of oncogenes from these infectious agents might be involved in the pathogenesis of LPD of the ocular adnexa.

Endobronchial ultrasound-guided transbronchial needle aspiration for the diagnosis of central lung parenchymal lesions.

PURPOSE: The purpose of this study was to evaluate the usefulness of convex probe endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for detecting malignancy in parenchymal pulmonary lesions located adjacent to the central airways. MATERIALS AND METHODS: We retrospectively reviewed the diagnostic performance of EBUS-TBNA in consecutive patients with high clinical suspicion of a centrally located primary lung cancer who had undergone EBUS-TBNA at the Samsung Medical Center between May 2009 and June 2011. RESULTS: Thirty-seven patients underwent EBUS-TBNA for intrapulmonary lesions adjacent to the central airways. Seven lesions were located adjacent to the trachea and 30 lesions were located adjacent to the bronchi. Cytologic and histologic samples obtained via EBUS-TBNA were diagnostic in 32 of 37 (86.4%) of patients. The final diagnosis was lung cancer in 30 patients (7 small cell lung cancer, 23 non-small cell lung cancer), lymphoma in one and malignant fibrous histiocytoma in one patient. The diagnostic sensitivity of EBUS-TBNA in detecting malignancy and detecting both malignancy and benignity was 91.4% and 86.5%, respectively. Two patients experienced minor complications. CONCLUSION: EBUS-TBNA is an effective and safe method for tissue diagnosis of parenchymal lesions that lie centrally close to the airways. EBUS-TBNA should be considered the procedure of choice for patients with centrally located lesions without endobronchial involvement.

Increased risk for invasive aspergillosis in patients with lymphoproliferative diseases after autologous hematopoietic SCT.

The risk of invasive aspergillosis (IA) is considered to be low among autologous HSCT recipients, but an increase in the incidence has been observed recently in this setting. The aim of the study was to assess the influence of immunosuppressive drugs (steroids, rituximab, fludarabine, thalidomide), used in treatment of lymphoid malignancies during 6 months of pretransplant period, on IA incidence after autologous HSCT. A total of 109 patients with non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD) and multiple myeloma (MM), conditioned with carmustine, etoposide, cytarabine, melphalan or melphalan and transplanted with PBSC, were analyzed prospectively. Patients were monitored with twice-weekly galactomannan test. High-resolution computed tomograhy of the chest and bronchoscopy were performed in case of positive galactomanan test, persistent fever or pulmonary infiltrates. Documented IA was diagnosed in nine (8%) patients (three proven, six probable). The incidence of IA was comparable in NHL, HD and MM patients and not influenced by age, advanced disease or conditioning regimen. Factors significant for development of documented IA by univariate analysis were treatment with fludarabine (P=0.008) or rituximab (P=0.039). The only factor predicting documented IA by multivariate analysis was treatment with fludarabine (P=0.008). Patients treated with fludarabine or rituximab in pretransplant period are at risk of IA and require close monitoring and/or anti-mould prophylaxis.

Mutation in the Fas pathway impairs CD8+ T cell memory.

Fas death pathway is important for lymphocyte homeostasis, but the role of Fas pathway in T cell memory development is not clear. We show that whereas the expansion and contraction of CD8+ T cell response against Listeria monocytogenes were similar for wild-type (WT) and Fas ligand (FasL) mutant mice, the majority of memory CD8+ T cells in FasL mutant mice displayed an effector memory phenotype in the long-term in comparison with the mainly central memory phenotype displayed by memory CD8+ T cells in WT mice. Memory CD8+ T cells in FasL mutant mice expressed reduced levels of IFN-gamma and displayed poor homeostatic and Ag-induced proliferation. Impairment in CD8+ T cell memory in FasL mutant hosts was not due to defective programming or the expression of mutant FasL on CD8+ T cells, but was caused by perturbed cytokine environment in FasL mutant mice. Although adoptively transferred WT memory CD8+ T cells mediated protection against L. monocytogenes in either the WT or FasL mutant hosts, FasL mutant memory CD8+ T cells failed to mediate protection even in WT hosts. Thus, in individuals with mutation in Fas pathway, impairment in the function of the memory CD8+ T cells may increase their susceptibility to recurrent/latent infections.

Chlamydiae and Mycoplasma infections in pulmonary MALT lymphoma.

Chlamydia pneumoniae, Chlamydia trachomatis and Chlamydia psittaci were detected at low frequencies (<20%) among 69 pulmonary mucosa-associated lymphoid tissue (MALT) lymphomas, 30 other lymphoproliferative disorders (LPD) and 44 non-LPD. The incidence of individual Chlamydiae was generally higher in MALT lymphoma than non-LPD, although not reaching statistical significance. Mycoplasma pneumoniae DNA was not detected.

Rothia dentocariosa sepsis in a pediatric renal transplant recipient having post-transplant lymphoproliferative disorders.

BACKGROUND: Rothia dentocariosa (RD) is a Gram-positive rod that colonizes the human oral cavity and can cause infective endocarditis. RESULT: We report on a six-yr-old boy who underwent renal transplantation for polycystic kidney disease at the age of eight months. He developed post-transplant lymphoproliferative disorders after four yr and progressive graft failure. Following chemotherapy, the patient presented with neutropenia and sepsis. RD was isolated from blood and treatment with piperacillin/tazobactam was initiated; however, the child died because of multiorgan failure. DISCUSSION: To the best of our knowledge, this is the first case of RD sepsis in a pediatric solid organ transplant recipient.

Cutaneous lymphoid hyperplasia and other lymphoid infiltrates of the breast nipple: a retrospective clinicopathologic study of fifty-six patients.

This study characterizes the clinicopathological spectrum of lymphoproliferations involving the breast nipple and/or areola. Morphologic, immunohistochemical, molecular-genetic, and clinical features of 58 specimens from 56 patients were analyzed. They were re-diagnosed as cutaneous lymphoid hyperplasia (CLH, n = 44); other benign lymphoid infiltrates (OBLI, n = 8); peripheral T-cell lymphoma, not otherwise specified (n = 1); cases with overlapping features of CLH and B-cell lymphoma (n = 3), one of them composed of spindle cells. Cutaneous lymphoid hyperplasia infiltrates were dense, composed mainly of B cells forming follicles with germinal centers (GC). Cutaneous lymphoid hyperplasia frequently showed features suggesting a malignancy as coalescing follicles with non-polarized germinal centers lacking mantle zones, and smudged infiltrates of lymphoid cells spreading into collagen (often as "Indian files"), smooth muscle, vessel walls, and nerve sheaths. Only two cutaneous lymphoid hyperplasias recurred; otherwise all patients are without disease (mean follow-up 62 months). Monoclonal rearrangement of immunoglobulin heavy chain gene was detected in five, and of T-cell receptor gamma gene in two cutaneous lymphoid hyperplasias using polymerase chain reaction (PCR), but the patients fared well too. In 47% of cases Borrelia burgdorferi was detected by polymerase chain reaction and/or serology, of which one was monoclonal. We conclude that cutaneous lymphoid hyperplasia is the most common lymphoproliferation of the breast nipple, rarely recognized clinically, and often overdiagnosed histologically as lymphoma.

Leaving previously implanted central venous catheters (ports) in place does not increase morbidity in patients undergoing autologous peripheral stem cell transplantation.

We sought to assess if leaving in place a previously inserted noncolonized or infected implantable catheter (IC) is associated with an increase in morbidity in patients undergoing autologous peripheral stem cell transplantation (APSCT). Medical records from all patients between March 1997 and January 2002 undergoing APSCT with an IC in place were reviewed. Case group (IC in place) was compared with a control group (no IC) from 6 days prior to 60 days after APSCT. In all, 43 cases were matched with 43 controls by underlying disease, age and sex. In both groups, duration of neutropenia and use of antimicrobial prophylaxis were comparable. Underlying malignancies were lymphoma (22/24), multiple myeloma (14/12), leukemia (3/3), and others (7/7) in case and control groups. Cases and controls had comparable rates of risk for fever, bloodstream infection, use of vancomycin and amphotericin B, and death, as well as comparable lengths of stay and readmissions. ICs were used in 20 of 43 patients. Using the IC did not significantly increase the risk of fever, bloodstream infection, length of stay, and/or readmissions after APSCT but was associated with increased use of antibacterial and antifungal agents. Leaving in place a previously inserted, noncolonized or infected IC did not increase morbidity in patients undergoing APSCT.

Fatal disseminated paracoccidioidomycosis in a two-year-old child.

A two year-old female child was admitted at the Pediatric Intensive Care Unit in a septic shock associated with a lymphoproliferative syndrome, with history of fever, adynamia and weight loss during the last two months. On admission, the main clinical and laboratory manifestations were: pallor, jaundice, disseminated enlarged lymph nodes, hepatosplenomegaly, crusted warts on face, anemia, eosinophilia, thrombocytopenia, increased direct and indirect bilirubin, alkaline phosphatase, and gammaglutamyl transpeptidase. A parenteral administration of fluids, dobutamine and mechanical ventilation was started, without improvement of the clinical conditions. A direct examination of exsudate collected from cervical lymph node revealed numerous oval-to-around cells with multiple budding, like a "pilot wheel" cell, suggesting Paracoccidioides brasiliensis. Even though treatment with intravenous sulfamethoxazole-trimethoprine was soon started, the child died 36 hours after hospital admission. Disseminated paracoccidioidomycosis was confirmed in the autopsy. This is the youngest case of paracoccidioidomycosis in children reported in the literature.

Fatal disseminated paracoccidioidomycosis in a two-year-old child

Uma menina de dois anos foi internada em Unidade de Terapia Intensiva com o diagnóstico de choque séptico associado a sindrome linfoproliferativa febril, adinamia e perda de peso nos últimos dois meses. Na admissão, as principais manifestações clínicas e laboratoriais eram: palidez, icterícia, aumento ganglionar em todas as cadeias superficiais, hepatoesplenomegalia, lesões crostosas em face, anemia, eosinofilia, plaquetopenia, elevação de bilirrubina indireta e direta, de fosfatase alcalina e de gama glutamil transferase. A terapêutica instituída foi infusão de fluidos, dobutamina e ventilação mecânica, sem melhora das condições clínicas, seguido da introdução de sulfametoxazol-trimetoprina. O exame direto do linfonodo revelou numerosas estruturas ovaladas, com múltiplos brotamentos, como "roda de leme" sugerindo Paracoccidioides brasiliensis. A paciente evoluiu para o óbito 36 horas após a internação. Paracoccidioidomicose disseminada foi confirmada na necropsia. Trata-se do caso mais jovem de paracoccidioidomicose reportado na literatura consultada.

Systemic Tropheryma whippleii infection associated with monoclonal B-cell proliferation: a Helicobacter pylori-type pathogenesis?

We report a case of Whipple disease in a 55-year-old woman who presented with arthralgia, weight loss, and lymphadenopathy. Tropheryma whippleii bacilli were identified in the mesenteric lymph nodes by diastase-resistant periodic acid-Schiff stain and confirmed by electron microscopy. Retrospectively, previous biopsy specimens from the duodenum and right axillary lymph node of this patient, which were initially considered to demonstrate reactive changes, also showed features consistent with involvement by Whipple disease. At the time of presentation, a large kappa-restricted monoclonal B-cell population with the phenotype CD20+CD19+CD5-CD10- was identified in the patient's peripheral blood, lymph nodes, and bone marrow by flow cytometry study. The monoclonality of the mesenteric lymph node B cells was confirmed by immunohistochemical stain for kappa chain after antigen retrieval and also by polymerase chain reaction with the primer set targeting FR2-V(H). Routine cytogenetic study failed to reveal any chromosomal abnormalities, and polymerase chain reaction for Bcl-2 major and minor breakpoint cluster of t(14:18) was not detected. The monoclonal B cells have persisted in blood for the entire follow-up period (10 months). The possibility of reactive monoclonal B-cell proliferation versus Whipple disease-related B-cell lymphoma is discussed.

Post-transplant lymphoproliferative disorders: improved outcome after clinico-pathologically tailored treatment.

BACKGROUND AND OBJECTIVES: Clinical and pathologic variability of post-transplant lymphoproliferative disorders (PTLDs), their aggressive behavior and the recognized therapy-related toxicity make management of patients with these disorders difficult. Assessment of first-line treatment and identification of prognostic factors need to be better defined. DESIGN AND METHODS: Data on 40 PTLDs which developed in adult solid organ recipients were analyzed in order to evaluate clinical and pathologic features, response to treatment and prognostic factors. Data were collected retrospectively between 1989 and 1996; since 1997 a prospective study has been activated. RESULTS: The median time from transplant to PTLD was 56 months. Regarding histologic features, plasmacytic hyperplasia was diagnosed in 5 patients (12.5%), polymorphic lymphoproliferative disorders in 3 (7.5%), malignant lymphoma in 32 (80%). The diagnosis was made at autopsy in eight patients (20%). Late-onset PTLDs (>12 months from transplant) occurred in 33 patients (83%), EBV-negative forms in 12 (31%). Relevant differences have been observed between EBV-positive and EBV-negative forms. Twenty-nine patients completed their scheduled treatment and are evaluable for outcome. The cumulative probability of survival at 1 year is 57% (CI 37.6-73.4) and the median survival time of the entire group has not been reached at 54 months. Clinical stage, performance status, lactate dehydrogenase and number of sites are predictive factors for survival. The International Prognostic Index and the PTLD index are able to identify different risk groups. INTERPRETATION AND CONCLUSIONS: Although rare, PTLDs are a significant cause of mortality in allograft recipients. Therapy tailored on histologic and clinical features of PTLD is feasible and is able to give long-lasting complete responses.