Taxonomic reclassification of Kaposi Sarcoma identifies disease entities with distinct immunopathogenesis.

BACKGROUND: The taxonomy of Kaposi Sarcoma (KS) is based on a classification system focused on the description of clinicopathological features of KS in geographically and clinically diverse populations. The classification includes classic, endemic, epidemic/HIV associated and iatrogenic KS, and KS in men who have sex with men (MSM). We assessed the medical relevance of the current classification of KS and sought clinically useful improvements in KS taxonomy. METHODS: We reviewed the demographic and clinicopathological features of 676 patients with KS, who were referred to the national centre for HIV oncology at Chelsea Westminster hospital between 2000 and 2021. RESULTS: Demographic differences between the different subtypes of KS exist as tautological findings of the current classification system. However, no definitive differences in clinicopathological, virological or immunological parameters at presentation could be demonstrated between the classic, endemic or MSM KS patients. Reclassifying patients as either immunosuppressed or non-immunosuppressed, showed that the immunosuppressed group had a significantly higher proportion of adverse disease features at presentation including visceral disease and extensive oral involvement, classified together as advanced disease (chi2 P = 0.0012*) and disseminated skin involvement (chi2 P < 0.0001*). Immunosuppressed patients had lower CD4 counts, higher CD8 counts and a trend towards higher HHV8 levels compared to non-immunosuppressed patients, however overall survival and disease specific (KS) survival was similar across groups. CONCLUSION: The current system of KS classification does not reflect meaningful differences in clinicopathological presentation or disease pathogenesis. Reclassification of patients based on the presence or absence of immunosuppression is a more clinically meaningful system that may influence therapeutic approaches to KS.

Prevention of Oncogenic Gammaherpesvirinae (EBV and HHV8) Associated Disease in Solid Organ Transplant Recipients.

Long-term risk for malignancy is higher among solid organ transplant (SOT) recipients compared to the general population. Four non-hepatitis viruses have been recognized as oncogenic in SOT recipients-EBV, cause of EBV-associated lymphoproliferative diseases; human herpes virus 8 (HHV8), cause of Kaposi sarcoma, primary effusion lymphoma and multicentric Castleman disease; human papilloma virus, cause of squamous cell skin cancers, and Merkel cell polyomavirus, cause of Merkel cell carcinoma. Two of these viruses (EBV and HHV8) belong to the human herpes virus family. In this review, we will discuss key aspects regarding the clinical presentation, diagnosis, treatment, and prevention of diseases in SOT recipients associated with the two herpesviruses.

Kaposi sarcoma in three pediatric liver transplantation recipients.

BACKGROUND: Kaposi sarcoma (KS) is an endothelial cell tumor, rare in children. It is 200 times more frequent after solid organ transplantation than in the general population. METHODS: We report three cases of pediatric patients who developed KS after liver transplantation (LT). RESULTS: Case 1, a 4-year-old boy undergoing LT due to familial intrahepatic cholestasis. Five months after LT, he presented with fever, dyspnea, and cough with enlarged lymph nodes and splenomegaly, anemia, thrombocytopenia, elevated liver enzymes, and positive EBV viral load. Lymph node biopsy diagnosed KS with an elevated HHV8 viral load. Case 2, a 4-year-old boy who underwent LT due to secondary biliary cirrhosis resulting from extrahepatic biliary atresia. Two years later, graft dysfunction was noticed with positive EBV viral load, thrombocytopenia, massive cervical lymph node enlargement, and splenomegaly. Lymph node biopsy diagnosed KS, Castleman's disease, and plasmablastic lymphoma related to HHV8 infection. Case 3, a 15-month-old girl, who received two LT due to biliary cirrhosis. Six months later, she presented with diarrhea, abdominal distension, anemia, thrombocytopenia, enlarged lymph nodes, splenomegaly, and positive CMV viral load. Axillary lymph node biopsy diagnosed KS and HHV8 infection was confirmed. In all three cases, tacrolimus was discontinued and, after diagnosis, sirolimus was started. All recovered without relapse and have a good graft function. CONCLUSIONS: Kaposi sarcoma is a rare disease post-LT in children. Recognizing keywords and early diagnosis is crucial for timely treatment and survival.

International survey of human herpes virus 8 screening and management in solid organ transplantation.

BACKGROUND: HHV-8/Kaposi Sarcoma herpesvirus has been associated with a broad spectrum of diseases in solid organ transplant (SOT) recipients. Primary donor-derived infection can be associated with severe and rapidly fatal non-neoplastic disease, and diagnosis is made with high HHV-8 DNAemia. METHODS: We carried out an international survey to investigate the current approach to HHV-8 screening, and management in SOT since a protocol has not been established by international guidelines. RESULTS: A total of 51 transplant centers from 15 countries filled out the survey. HHV-8-associated diseases in SOT have been diagnosed during the previous 5 years in 67% of centers. Pretransplant serological screening is performed in 17 centers (33%), and posttransplant HHV-8 nucleic acid testing (NAT) monitoring is performed in 21 centers (41%). Performing HHV-8 NAT monitoring and serological screening were found associated with having diagnosed in the previous 5 years a non-malignant HHV-8-associated disease. CONCLUSIONS: Serological pretransplant screening of donors and recipients and post-transplant HHV-8 NAT monitoring recommendations should be standardized. Even though serological assays are not optimal, they could contribute to increasing knowledge on epidemiology and management of HHV-8-associated diseases after SOT.

Donor-derived human herpesvirus 8 infection with Kaposi sarcoma and Kaposi sarcoma inflammatory cytokine syndrome in a heart transplant recipient: A case report.

Human herpesvirus-8 (HHV-8) infection is associated with neoplastic and non-neoplastic diseases in immunocompromised patients. Kaposi sarcoma (KS) is a common malignancy reported in solid organ transplant recipients (SOTR). Kaposi sarcoma inflammatory cytokine syndrome (KICS), initially described in HIV patients, is characterized by high viral loads, elevated levels of cytokines, cytopenia, high fever, organ failure, and poor outcome. We report the case of a 54-year-old patient who developed simultaneous occurrence of KS of lymph nodes and KICS as a complication of primary donor-transmitted HHV-8 infection, after heart transplantation (HT). The diagnosis, management, and prognosis of this condition are unclear and needs a multidisciplinary approach.

Recurrence and Occurrence of Kaposi's Sarcoma in Patients Living With Human Immunodeficiency Virus (HIV) and on Antiretroviral Therapy, Despite Suppressed HIV Viremia.

In 21 cutaneous and/or visceral Kaposi's sarcoma cases, occurring in patients living with human immunodeficiency virus (HIV) who were on antiretroviral therapy with suppressed HIV viremia and high CD4 T cell counts, the efficacy of conventional chemotherapies was limited due to cumulative toxicities, comedications, and a lack of immune improvement.

The spectrum of the cytopathological features of primary effusion lymphoma and human herpes virus 8-related lymphoproliferative disorders.

INTRODUCTION: Human herpes virus 8-related lymphoproliferative disorders are a complex and heterogeneous group of entities and some of them are eminently diagnosed by cytopathology. In a routine laboratory, these lesions account for less than 1% of the effusion fluids samples. However, they represent up to 30% of all the lymphoma diagnosis from effusion cytological samples and their consideration in the diagnostic flow chart is mandatory, especially in human immunodeficiency virus-positive patients. METHODS: A retrospective series of cytological specimens from cavity effusions (n = 605) were analysed. Five human herpes virus 8-related lymphoproliferative processes were recruited. A combination of morphological criteria (enhanced with May-Grünwald Giemsa staining), cell block-based immunocytochemistry and flow cytometry were undertaken for final characterisation. RESULTS: The identification of malignant cells may be difficult. Some specimens are particularly rich, easily leading to suspect a lymphoproliferative process, whereas in other cases, the presence of abundant reactive mesothelial cells, histiocytes, neutrophils, small reactive T and B lymphocytes may obscure the neoplastic process. The biological behaviour may be very heterogeneous and a standardised therapy for these cases is still lacking, although some patients may benefit from antiretroviral therapy in a human immunodeficiency virus setting. CONCLUSIONS: The present case series highlights some characteristic findings of these entities to reaffirm useful cytopathological diagnostic criteria, stressing the crucial role of the appropriate technical processing of effusion fluids to obtain the best performances.

An unusual case of Kaposi sarcoma masquerading as cystitis in a kidney transplant recipient.

Human Herpes Virus-8 (HHV-8) may reactivate in immunocompromised patients including recipients of solid organ transplants. Reactivation of HHV-8 may result in Kaposi sarcoma (KS). KS typically occurs with dermatologic involvement but can affect virtually any other organ; most commonly the gastrointestinal tract. We present a diagnostically challenging case of KS in a South American woman 7 months after kidney transplant. She presented with recurrent urinary tract infection manifested by pelvic pain and dysuria. Imaging studies revealed bladder thickening with pelvic lymphadenopathy. Findings on tissue biopsied from the bladder and lymph nodes were consistent with KS. Her skin was not affected. This case illustrates that KS and other HHV-8-related diseases should be on the differential diagnosis as a cause of mass lesions as well as lymphadenopathy in transplant recipients. The case exemplifies the need to pursue a tissue diagnosis in immunocompromised patients when a diagnosis is uncertain.

[Human herpes virus 8-negative primary effusion lymphoma-like lymphoma recurring as a tumor adjacent to the left atrium].

Primary effusion lymphoma (PEL) is a rare type of non-Hodgkin lymphoma, usually presenting as serous effusions without detectable tumor masses, and it is universally associated with the human herpesvirus 8 (HHV8). In contrast, cases of HHV8-negative effusion lymphoma have been reported and termed as HHV8-negative PEL-like lymphoma. Here, we have reported a rare case of HHV8-negative PEL-like lymphoma that developed in the left atrium tumor 4 years after the pericardial drainage. A 74-year-old female was admitted due to cardiac tamponade caused by massive pericardial effusion. Pericardial drainage was performed, and cytopathologic examination of the fluid revealed atypical lymphoid cells consistent with an effusion lymphoma of B-cell lineage. The pericardial effusion was completely drained, and complete remission was achieved. After 4 years of the drainage, she developed syncope caused by arrhythmia. A computed tomography scan revealed a large tumor in the left atrium and multiple swollen mediastinal lymph nodes. Biopsy of one of the lymph nodes was performed, and its histology was consistent with diffuse large B-cell lymphoma. She was treated with chemotherapy, including rituximab, and complete remission was achieved again. Thus, our experience suggests that careful follow-up may be required in patients with HHV8-negative PEL-like lymphoma after complete remission has been achieved by the drainage.

Clinical characteristics and outcomes of Castleman disease: A multicenter study of 185 Chinese patients.

Castleman disease (CD) is a rare lymphoproliferative disorder. To assess the clinical features, outcomes, and prognostic factors of this disease, we retrospectively analyzed 185 HIV-negative CD patients from four medical centers in southern China. The median age was 37 years. One hundred and twenty-one patients (65.4%) were classified as unicentric CD (UCD) and 64 patients (34.6%) were classified as multicentric CD (MCD). The histology subtype was hyaline-vascular for 132 patients (71.4%), plasma cell for 50 patients (27%), and mixed type for 3 patients (1.6%). The 5-year overall survival (OS) of 185 CD cases was 80.3%. All UCD patients underwent surgical excision, whereas the treatment strategies of MCD patients were heterogeneous. The outcome for UCD patients was better than MCD patients, with 5-year OS rates of 93.6% and 51.2%, respectively. In further analysis of the MCD subgroup, a multivariate analysis using a Cox regression model revealed that age, splenomegaly and pretreatment serum albumin level were independent prognostic factors for OS. This multicenter study comprising the largest sample size to date suggested that MCD is a distinct entity from UCD with a significantly worse outcome. Older age (≥40 years), splenomegaly, and hypoalbuminemia were risk factors for poorer MCD prognosis.

A comprehensive analysis of Lymphoma-associated haemophagocytic syndrome in a large French multicentre cohort detects some clues to improve prognosis.

Lymphoma-associated haemophagocytic syndrome (LAHS) accounts for most cases of secondary haemophagocytic syndrome (HS) and has been extensively described in Asian populations. However, little is known about the epidemiology of LAHS in Western countries. We herein report a case series of 71 LAHS patients in which the lymphomas were mainly of the aggressive type. Diagnoses included non-Hodgkin B cell lymphoma (46·5%) including human herpes virus 8-associated non-Hodgkin lymphoma (12·7%), T cell lymphoma (28·2%) and Hodgkin lymphoma (23·9%). An underlying immunodeficiency was described in 30 patients (42·3%). Early mortality within the 30 days following HS diagnosis was observed in 26·8% of cases. The overall survival was estimated at 45·7% [95% confidence interval, CI (35·4-59·0)] at 6 months, and 34·3% [95% CI (24·8-47·4)] at 2 years. Concurrent infection, age over 50 years, ethnicity and etoposide treatment were independently associated with mortality. While it appears that certain types of lymphomas were more prone to trigger HS, LAHS were not restricted to a few types of lymphoma. The overall prognosis was poor, with a particularly high rate of early mortality, highlighting the importance of both early recognition and choice of initial therapeutic management.

Kaposi sarcoma, oral malformations, mitral dysplasia, and scoliosis associated with 7q34-q36.3 heterozygous terminal deletion.

Chromosome 7 germline macrodeletions have been implicated in human congenital malformations and developmental delays. We herein report a novel heterozygous macrodeletion of 7q34-q36.3 in a 16-year-old girl originally from West Indies. Similar to previously reported cases of germline chromosome 7q terminal deletions, our patient has dental malposition, and developmental (growth and intellectual) delay. Novel phenotypic features include endemic Kaposi sarcoma (KS), furrowed tongue, thoracolumbar scoliosis, and mild mitral valve dysplasia. The occurrence of human herpes virus 8-driven KS, in a child otherwise normally resistant to other infectious agents and without any other tumoral lesion, points to a very selective immunodeficiency. While defects in organogenesis have been described with such macrodeletions, this is the first report of immunodeficiency and cancer predisposition.

Calcium spirulan derived from Spirulina platensis inhibits herpes simplex virus 1 attachment to human keratinocytes and protects against herpes labialis.

BACKGROUND: Chronic infections with herpes simplex virus (HSV) type 1 are highly prevalent in populations worldwide and cause recurrent oral lesions in up to 40% of infected subjects. OBJECTIVE: We investigated the antiviral activity of a defined Spirulina platensis microalga extract and of purified calcium spirulan (Ca-SP), a sulfated polysaccharide contained therein. METHODS: The inhibitory effects of HSV-1 were assessed by using a plaque reduction assay and quantitative PCR in a susceptible mammalian epithelial cell line and confirmed in human keratinocytes. Time-of-addition and attachment experiments and fluorescence detection of the HSV-1 tegument protein VP16 were used to analyze the mechanism of HSV-1 inhibition. Effects of Ca-SP on Kaposi sarcoma-associated herpesvirus/human herpes virus 8 replication and uptake of the ORF45 tegument protein were tested in human retinal pigment epithelial cells. In an observational trial the prophylactic effects of topically applied Ca-SP were compared with those of systemic and topical nucleoside analogues in 198 volunteers with recurrent herpes labialis receiving permanent lip makeup. RESULTS: Ca-SP inhibited HSV-1 infection in vitro with a potency at least comparable to that of acyclovir by blocking viral attachment and penetration into host cells. Ca-SP also inhibited entry of Kaposi sarcoma-associated herpesvirus/human herpes virus 8. In the clinical model of herpes exacerbation, the prophylactic effect of a Ca-SP and microalgae extract containing cream was superior to that of acyclovir cream. CONCLUSION: These data indicate a potential clinical use of Ca-SP containing Spirulina species extract for the prophylactic treatment of herpes labialis and suggest possible activity of Ca-SP against infections caused by other herpesviruses.

[Prevalence of DNA viruses in maxillofacial area of HIV-infected]. / Porazhennost' DNK-virusami cheliustno-litsevoi oblasti bol'nykh s VICh-infektsiei.

DNA viruses have high oncogenic risk viruses; they cause emergence of Kaposi sarcoma, Lymphoma, Squamous cell carcinoma. HIV immunodeficiency promotes increase in frequency of such tumors. Etiotropic therapy of HIV patients considerably reduces prevalence of DNA viruses and a viral malignization.

Genetic diversity of HHV8 subtypes in South Africa: A5 subtype is associated with extensive disease in AIDS-KS.

Human herpes virus 8 (HHV8) is the etiological agent of all forms of Kaposi's sarcoma (KS). Six major subtypes (A-F), based on genetic variability of open reading frame (ORF)-K1, have been identified. Numerous studies point to differing tumorigenic and pathogenic properties of the HHV8 subtypes. The study objectives were to determine the HHV8 subtypes and their prevalence in a cohort of clinical and histologically confirmed KS in Cape Town, South Africa, and analyze associations between the different subtypes and clinical presentation of KS. Clinical records were prospectively reviewed to extract clinical presentation; demographic data were retrospectively collected and tissue biopsies were taken for ORF-K1 subtyping. Eighty six patients were subtyped; 81 AIDS (acquired immune deficiency syndrome)-KS and 5 African endemic-KS. Subtype A5 (42/86) and B2 (16/86) predominated. B1, B3, A1 and A4 subtypes were identified in 10/86, 9/86, 4/86 and 1/86 patients, respectively. A5 and B subtypes were found in African blacks and individuals of mixed ancestry, while subtypes A1 and A4 were found only in whites and individuals of mixed ancestry. Subtype A5 was associated with >10 KS lesions at presentation in the AIDS cohort (adjusted OR: 3.13; CI: 1.02-9.58). Subtypes A1 and A4 combined were less likely to be associated with poor risk tumor extension (P = 0.031) and A1 was associated with lower likelihood of lower limb involvement (P = 0.019). In conclusion, these results indicate that subtype A5 and B predominate in South Africa and A5 may be associated with more extensive disease.

Kaposi Sarcoma of Childhood: Inborn or Acquired Immunodeficiency to Oncogenic HHV-8.

Kaposi sarcoma (KS) is an endothelial malignancy caused by human herpes virus-8 (HHV-8) infection. The epidemic and iatrogenic forms of childhood KS result from a profound and acquired T cell deficiency. Recent studies have shown that classic KS of childhood can result from rare single-gene inborn errors of immunity, with mutations in WAS, IFNGR1, STIM1, and TNFRSF4. The pathogenesis of the endemic form of childhood KS has remained elusive. We review childhood KS pathogenesis and its relationship to inherited and acquired immunodeficiency to oncogenic HHV-8.

A HHV-8 positive, HIV negative multicentric Castleman disease treated with R-CEOP chemotherapy and valganciclovir combination.

Multicentric Castleman disease (MCD) is a lymphoproliferative disorder characterized by systemic symptoms like recurrent lymphadenopathy, fever and hepatosplenomegaly. Human herpes virus 8 (HHV-8) can be associated with MCD whether the patient is infected with human immunodeficiency virus (HIV) or not. A 59-year-old male patient presented with fatigue, drowsiness and enlarged lymph nodes. Thoracic and abdominal computed tomography showed enlarged mediastinal, axillary, paracardiac, paraaortic, celiac, mesenteric, obturator and inguinal lymph nodes concomitant with enlarged liver and spleen. Cervical lymph node biopsy revealed HHV-8 positive plasma cell MCD. The patient's tests were negative for HIV. R-CEOP (rituximab, cyclophosphamide, etoposide, vincristin, prednisolone) and valganciclovir treatments were started simultaneously. After sixth cycle of R-CEOP, the patient achieved unconfirmed complete remission. Rituximab combined with CEOP protocol and antiviral therapy against HHV-8 might be an effective therapeutic approach without a considerable side effect for HHV-8-positive HIV-negative MCD patients.

Human Herpesvirus 8-Related Primary Effusion Lymphoma After Liver Transplantation.

Primary effusion lymphoma is a rare subclass of non-Hodgkin lymphoma associated with human herpesvirus 8 infection and principally seen in human immunodeficiency virus-positive patients. We report on the case of a 72-year-old human immunodeficiency virus-negative male with a hepatic transplant 10 years prior, who presented with a symptomatic right-sided pleural effusion and was found to have primary effusion lymphoma by flow cytometric and cytopathologic examination. Immunohistochemistry of his lymphoma cells was positive for human herpesvirus 8. Both he and his donor had no identifiable risk factors for human herpesvirus 8 infection. The patient was intolerant of antiviral therapy and chemotherapy, dying 7 months after diagnosis. Posttransplant primary effusion lymphoma is exceedingly rare and carries a very poor prognosis. Individualized treatment strategies are necessary given the scant body of published literature with guidance based solely on case reports.

Macrophage polarization at the crossroad between HIV-1 infection and cancer development.

Mononuclear phagocytes play a fundamental role in the tissue homeostasis and innate defenses against viruses and other microbial pathogens. In addition, they are likely involved in several steps of cancer development. Circulating monocytes and tissue macrophages are target cells of viral infections, including human cytomegalovirus, human herpes virus 8, and the HIV, and alterations of their functional and phenotypic properties are likely involved in many tissue-degenerative diseases, including atherosclerosis and cancer. Different tissue microenvironments as well as their pathological alterations can profoundly affect the polarization state of macrophages toward the extreme phenotypes conventionally termed M1 and M2. Thus, targeting disease-associated macrophages is considered a potential approach particularly in the context of cancer-associated tumor-associated macrophages, supporting malignant cell growth and progression toward a metastatic phenotype. Of note is the fact that tumor-associated macrophages isolated from established tumors display phenotypic and functional features similar to those of in vitro-derived M2-polarized cells. Concerning HIV-1 infection, viral eradication strategies in the context of combination antiretroviral therapy should also consider the possibility to deplete, at least transiently, certain mononuclear phagocytes subsets, although the possibility of distinguishing those that are either infected or pathogenically altered remains a goal of future research. In the present review, we will focus on the recent literature concerning the role of human macrophage polarization in viral infections and cancer.

Human herpes virus 8-unrelated primary effusion lymphoma-like lymphoma in a patient with hepatitis B virus-related liver cirrhosis: A case report.

This study describes a rare case of Human Immunodeficiency Virus and Human Herpes Virus 8 (HHV-8) negative primary effusion lymphoma (PEL)-like lymphoma in a patient with hepatitis B virus-related liver cirrhosis, diagnosed in a 66-year-old male who rapidly progressed to a sense of abdominal fullness. Cytological analysis of the pleural effusion demonstrated large atypical lymphoid cells with rounded nuclei, prominent nucleoli, and abundant cytoplasm. Immunocytochemistry of the pleural effusion detected atypical CD20(+) lymphoid cells. The patient was hospitalized, and died following sepsis and multi-organ failure. Our case highlights that HHV-8-unrelated PEL-like lymphoma patients have different pathogenetic mechanisms of causality at the biological level, immunophenotype, clinical behavior, and prognosis.