Stage Kaposi's Sarcoma Research Articles

Divergent clinical presentations and outcomes among children and adolescents with Kaposi sarcoma in Malawi and Tanzania.

The Kaposi sarcoma (KS) T0 versus T1 staging classification does not address the unique clinical features of paediatric KS in human gammaherpesvirus 8 (HHV-8) endemic regions of Africa. This study seeks to define patterns of childhood KS using a paediatric-specific approach. The Lilongwe paediatric KS staging classification categorizes disease based on clinical phenotype: stage 1=mild/moderate KS limited to cutaneous/oral involvement, stage 2=primarily lymphadenopathic disease, stage 3=woody edema KS, stage 4=visceral and/or severe/disseminated mucocutaneous disease. Characteristics and outcomes were evaluated from paediatric referral centres in Lilongwe, Malawi, and Mbeya, Tanzania. Among 171 patients, the median age was 9.3 years, 37% (n=63) were female, and 87% (n=149) had HIV. Breakdown by stage was as follows: 18% (n=31) stage 1, 33% (n=56) stage 2, 19% (n=33) stage 3, and 30% (n=51) stage 4. Age (younger stage 2 and older stage 3), severe CD4 count suppression (lower CD4 for stages 1 and 4), and presence of severe anaemia and thrombocytopenia (worse for stages 2 and 4) differed across stages. Estimated 2-year event-free survival/progression-free survival/overall survival by stage was as follows: stage 1, 81%/81%/87%; stage 2, 50%/50%/63%; stage 3, 24%/49%/81%; and stage 4, 29%/34%/54%. Sub-analysis of stage 2 lymphadenopathic KS demonstrated superior long-term 6-year event-free survival of 70% (95% confidence interval [CI] 49-83) for younger children (aged <7 years) versus 27% (95% CI 8-51) for older children. This paediatric-specific staging classification categorizes patients with distinct characteristics and patterns of treatment response. This platform may guide clinicians to provide risk-stratified treatment with the hope of improving survival among children with KS.

A prospective study of clinical outcomes of HIV-associated and HIV-negative Kaposi sarcoma in Uganda.

Improved understanding of the effect of HIV infection on Kaposi sarcoma (KS) presentation and outcomes will guide development of more effective KS staging and therapeutic approaches. We enrolled a prospective cohort of epidemic (HIV-positive; HIV + KS) and endemic (HIV-negative; HIV - KS) KS patients in Uganda to identify factors associated with survival and response. Adults with newly diagnosed KS presenting for care at the Uganda Cancer Institute (UCI) in Kampala, Uganda, between October 2012 and December 2019 were evaluated. Participants received chemotherapy per standard guidelines and were followed over 1 year to assess overall survival (OS) and treatment response. Two hundred participants were enrolled; 166 (83%) had HIV + KS, and 176 (88%) were poor-risk tumor (T1) stage. One-year OS was 64% (95% confidence interval [CI] 57-71%), with the hazard of death nearly threefold higher for HIV + KS (hazard ratio [HR] = 2.93; P = 0.023). Among HIV + KS, abnormal chest X-ray (HR = 2.81; P = 0.007), lower CD4 + T-cell count (HR = 0.68 per 100 cells/μl; P = 0.027), higher HIV viral load (HR = 2.22 per log 10 copies/ml; P = 0.026), and higher plasma Kaposi sarcoma-associated herpesvirus (KSHV) copy number (HR = 1.79 per log 10 copies/ml; P = 0.028) were associated with increased mortality. Among HIV - KS, factors associated with mortality included Karnofsky score <70 (HR = 9.17; P = 0.045), abnormal chest X-ray (HR = 8.41; P = 0.025), and higher plasma KSHV copy number (HR = 6.21 per log 10 copies/ml; P < 0.001). Although survival rates were better for HIV - KS than HIV + KS, the high mortality rate seen in both groups underscores the urgent need to identify new staging and therapeutic approaches. Factors associated with mortality, including high plasma KSHV, may serve as important targets of therapy.

Yield of FDG PET/CT for Defining the Extent of Disease in Patients with Kaposi Sarcoma.

Simple SummaryThe potential role of positron emission tomography/computed tomography with fluorodeoxyglucose (FDG PET/CT) for assessing the extent of Kaposi sarcoma is not well studied. We analyzed FDG PET/CTs performed on 75 patients referred to our department for Kaposi sarcoma staging or restaging. FDG PET/CTs detected most lymph nodes, bone, and muscle lesions, whereas digestive and mucous lesions could be missed. Most cutaneous lesions can be identified when whole-body FDG PET/CT (including lower limbs) is performed. Thus, a true whole-body FDG PET/CT can be recommended for staging purposes in patients with active Kaposi sarcoma and, if positive, be useful for therapeutic evaluation and follow-up.Background: Positron emission tomography/computed tomography with fluorodeoxyglucose (F-18) (FDG PET/CT) is increasingly used in Kaposi sarcoma (KS), but its value has not been assessed. Objectives: In this study, we aimed to evaluate the diagnostic accuracy of FDG PET/CT to define the extent of disease in KS. Methods: Consecutive patients with KS referred to our department for FDG PET/CT were included. The diagnostic accuracy of FDG PET/CT for cutaneous and extra-cutaneous KS staging was assessed on a per lesion basis compared to staging obtained from clinical examination, standard imaging, endoscopy, histological analyses, and follow-up. Results: From 2007 to 2017, 75 patients with FDG PET/CT were analyzed. The sensitivity and specificity of FDG PET/CT for the overall detection of KS lesions were 71 and 98%, respectively. Sensitivity and specificity were 100 and 85% for lymph nodes, 87 and 98% for bone, 87 and 100% for lungs, and 100 and 100% for muscle involvement, whereas sensitivity was only 17% to detect KS digestive involvement. The sensitivity of the diagnostic for KS cutaneous involvement increased from 73 to 88% when using a whole-body examination. Conclusion: FDG PET/CT showed good sensitivity and specificity for KS staging (digestive involvement excepted) and could be used for staging patients with active KS.

Beyond T Staging in the "Treat-All" Era: Severity and Heterogeneity of Kaposi Sarcoma in East Africa.

Although many patients with Kaposi sarcoma (KS) in sub-Saharan Africa are diagnosed with AIDS Clinical Trials Group (ACTG) T1 disease, T1 staging insufficiently captures clinical heterogeneity of advanced KS. Using a representative community-based sample, we detailed disease severity at diagnosis to inform KS staging and treatment in sub-Saharan Africa. We performed rapid case ascertainment on people living with HIV, aged 18 years or older, newly diagnosed with KS from 2016 to 2019 at 3 clinic sites in Kenya and Uganda to ascertain disease stage as close as possible to diagnosis. We reported KS severity using ACTG and WHO staging criteria and detailed measurements that are not captured in the current staging systems. We performed rapid case ascertainment within 1 month for 241 adults newly diagnosed with KS out of 389 adult patients with suspected KS. The study was 68% men with median age 35 years and median CD4 count 239. Most of the patients had advanced disease, with 82% qualifying as ACTG T1 and 64% as WHO severe/symptomatic KS. The most common ACTG T1 qualifiers were edema (79%), tumor-associated ulceration (24%), extensive oral KS (9%), pulmonary KS (7%), and gastrointestinal KS (4%). There was marked heterogeneity within T1 KS, with 25% of patients having 2 T1 qualifying symptoms and 3% having 3 or more. Most of the patients newly diagnosed with KS had advanced stage disease, even in the current antiretroviral therapy "treat-all" era. We observed great clinical heterogeneity among advanced stage patients, leading to questions about whether all patients with advanced KS require the same treatment strategy.

Classic Kaposi's sarcoma: A review of 156 cases

Abstract Background Kaposi's sarcoma (KS) is a reactive, multifocal, multicentric, angiogenic neoplastic proliferation that is thought to originate from endothelial cells that are infected with human herpesvirus-8 (HHV-8). This report examines a cohort of patients with classic Kaposi's sarcoma (KS) evaluated at the national institute of oncology over the 13-year period. Methods A retrospective analysis of 156 patients with classic KS, between January 2000 and November 2013, was performed. This study focused on the clinical presentation, staging, diagnosis, and treatment of classic KS. Results One hundred fifty-six patients (median age 69 and 115 male) were enrolled into the study. Median age at diagnosis was 69 (range: 32–95 years). Male/female ratio was 2.80. The most common location was the lower limbs. There were 75 stage I patients (48.1%), 8 stage II patients (22.4%), 31 stage III patients (19.9%) and 15 stage IV patients (9.6%). Surgery was the most common local treatment method (43%). 44 patients (28.2%) received radiotherapy (RT) at diagnosis. Cytotoxic treatment with chemotherapy or interferon-α was administered in 57 patients. Visceral involvement was observed in 10 patients (lung: nine patients, liver: one patient) and bone metastasis occurred in two patients at relapse. Conclusion This study is one of the largest reported series. Further studies are required and it will be important to standardize the assessment of disease activity and clinical response.

Coexistence of Kaposi's sarcoma and psoriasis: is there a hidden relationship?

The relationship between Kaposi's sarcoma (KS) and psoriasis is still controversial. To analyse the association between KS and psoriasis, address the hypothesis of a reciprocal influence between the two conditions relative to clinical presentation and evolution, and consider the best therapeutic approach to be used for the treatment of psoriasis in KS patients in order to avoid the typical induction or worsening of KS during immunosuppression. We retrospectively reviewed clinical records of 37 patients with KS and psoriasis. Fisher's exact test was performed in order to compare epidemiological and clinical data between subsets of patients. The prevalence of psoriasis in our KS population (n=1407) was 2.6%. There were no statistically significant differences in terms of stage or rate of progression between KS patients with and without psoriasis, except for a higher frequency of patients with KS Stage IIB among patients with KS and psoriasis (p=0.001). Patients with psoriasis have a risk of KS comparable to that of the general population. Psoriasis and KS do not appear to influence each other. For the treatment of psoriasis in KS patients, one should take into account the KS-inducing potential of certain anti-psoriatic drugs.

Survival of patients with Kaposi's sarcoma in the South African antiretroviral treatment era: A retrospective cohort study.

When South Africa (SA) implemented its antiretroviral therapy (ART) programme in 2004, the model for treating HIV-positive Kaposi's sarcoma (KS) patients shifted from symptomatic palliation to potential cure. To evaluate survival and changes over time in AIDS-KS patients treated at a tertiary academic hospital oncology unit (the Steve Biko Academic Hospital medical oncology unit) in Pretoria, SA, in the context of ART availability in SA. We conducted a retrospective review of electronic and paper records of KS patients who accessed cancer care between May 2004 and September 2012. We used Kaplan-Meier survival functions to estimate 1- and 2-year survival, and Cox regression models to identify changes over time and prognostic factors. Our study included 357 AIDS-KS patients, almost all of whom were black Africans (n=353, 98.9%); 224 (62.7%) were men. The median age at cancer diagnosis was 37 (interquartile range (IQR) 30 - 43) years, and the median baseline CD4+ count was 242 (IQR 130 - 403)cells/µL. Most patients received ART (n=332, 93.0%) before or after KS diagnosis; 169 (47.3%) were treated with chemotherapy and 209 (58.6%) with radiation therapy. Mortality was 62.7% lower (adjusted hazard ratio (HR) 0.37, 95% confidence interval (CI) 0.19 - 0.73) in the late (2009 - 2012) than in the early (2004 - 2008) ART period. Receiving chemotherapy (adjusted HR 0.3, 95% CI 0.15 - 0.61) and poor-risk AIDS Clinical Trials Group KS stage (adjusted HR 2.88, 95% CI 1.36 - 6.09) predicted mortality. Our results show that large national ART roll-out programmes can successfully reduce KS-related mortality at the individual patient level. If ART coverage is extended, KS-associated morbidity and mortality are likely to drop.

Role of HHV-8 and mTOR pathway in post-transplant Kaposi sarcoma staging.

Kaposi's sarcoma (KS) is one of the most frequent transplant related tumors. Several pathways are involved; however, the impact of the molecular phenotype associated to the tumor stage and the behavior-depending resultant therapy is still unknown. The aim of our study was to analyze the role of HHV-8 and mTOR pathway in tumor stages of skin KS after renal transplantation. Twelve renal transplant recipients with cutaneous KS from five transplant centers (1980-2007) under reduction of immunosuppression or conversion to mTOR inhibitor were included. The expression of HHV-8, PTEN, TGFβ, VEGF, phospho-mTOR, and phospho-P70S6K in tumoral tissue was analyzed. KS lesions were classified as patch, plaque, and nodule state. HHV-8 infection was found in all tissue samples. KS lesions showed high activation of VEGF, p-mTOR and p-P70S6K, low PTEN, and null TGFβ expression. The only pathway activated in a staging-dependent manner was mTOR with higher p-mTOR and p-P70S6K expression in nodule versus patch stage. KS lesions disappeared after 5.24 months in all converted patients without any recurrence in 14.05 years of mean follow-up. The activation of mTOR pathway according to KS stages supports the rational of the mTOR inhibitor in post-transplant Kaposi.

Expressions of Kaposi's sarcoma-associated herpesvirus type 8-associated microRNAs k12-1 and k12-12 in Kaposi's sarcoma and their significance

Objective To measure the expressions of Kaposi's sarcoma-associated herpesvirus type 8 associated-microRNAs k12-1 (kshv-miR-k12-1) and k12-12 (kshv-miR-k12-12) in Kaposi's sarcoma tissue, and to assess their relationship with pathological stage and lesion area of Kaposi's sarcoma, HIV infection, and human herpesvirus type 8 (HPV-8) infection. Methods Totally, 18 paired tissue specimens stored in liquid nitrogen from Kaposi's sarcoma lesions and paralesional skin were collected. Total RNAs were extracted from these specimens by using Trizol reagent, and reversely transcribed into cDNA. SYBR Green real-time fluorescence-based quantitative PCR was performed to measure the expressions of kshv-miR-k12-1 and kshv-miR-k12-12 in these specimens. The relationship of kshv-miR-k12-1 and kshv-miR-k12-12 expressions with the pathological stage and lesion area of Kaposi's sarcoma, HIV and HPV-8 infections was analyzed. Results Compared with paralesional normal skin, Kaposi's sarcoma lesions showed significantly increased expressions of kshv-miR-k12-1 (2-ΔΔCt: 1.016 ± 1.645 vs. 0.029 ± 0.019, t= 2.542, P= 0.016) and kshv-miR-k12-12 (2-ΔΔCt: 2.104 ± 1.973 vs. 0.102 ± 0.093, t= 4.301, P= 0.000). There were no significant differences in the expressions of kshv-miR-k12-1 or kshv-miR-k12-12 between patients with HIV or HPV-8 infection and those without, among patients with different pathological stages of Kaposi's sarcoma, or among patients with different lesion areas (all P> 0.05). Conclusion Both kshv-miR-k12-1 and kshv-miR-k12-12 are highly expressed in Kaposi's sarcoma, but neither of their expressions is related to HIV or HPV-8 infection, pathological stage or lesion area of Kaposi's sarcoma. Key words: Sarcoma, Kaposi; Herpesvirus 8, human; kshv-miR-k12-1; kshv-miR-k12-12

Variability of HHV8 LNA-1 Immunohistochemical Staining Across the 3 Histologic Stages of HIV-Associated Mucocutaneous Kaposi Sarcoma: Is There a Relationship to Patients' CD4 Counts?

The histologic diagnosis of Kaposi sarcoma (KS) can be confirmed with human herpes virus 8 (HHV8) latency-associated nuclear antigen (LNA)-1 immunohistochemistry, which may show variability in distribution and intensity. This retrospective study was aimed at addressing the factors that may contribute to this variability. All cases of mucocutaneous KS diagnosed in a 5-year period at the histopathology department at a tertiary hospital in South Africa with available patients' CD4 counts and HHV8 LNA-1 immunohistochemically stained slides were reviewed, and the biopsy stages of KS (patch/plaque/nodular), CD4 counts, immunohistochemistry staining method (manual vs. automated), and distribution (diffuse/focal) and intensity (strong/weak) of HHV8 LNA-1 staining were recorded. A total of 127 cases were reviewed. No relationship was demonstrated between the median CD4 count and the histologic stages of KS (P = 0.701) or the intensity and distribution of HHV8 immunohistochemical staining using either staining method. Multivariate analysis showed that method of immunohistochemical staining was a significant predictor of distribution (P = 0.006) and intensity (P = 0.044) of staining, and that stage was a significant predictor of distribution of staining (P = 0.033).

Human herpesvirus 8 (HHV-8) detected by nested polymerase chain reaction (PCR) in HIV patients with or without Kaposi's sarcoma. An analytic cross-sectional study.

Kaposi's sarcoma (KS) is a common neoplastic disease in AIDS patients. The aim of this study was to evaluate the frequency of human herpesvirus 8 (HHV-8) infection in human immunodeficiency virus (HIV)-infected patients, with or without KS manifestations and correlate HHV-8 detection with KS staging. Analytic cross-sectional study conducted in a public tertiary-level university hospital in Ribeirão Preto, São Paulo, Brazil. Antibodies against HHV-8 lytic-phase antigens were detected by means of the immunofluorescence assay. HHV-8 DNA was detected in the patient samples through a nested polymerase chain reaction (nested PCR) that amplified a region of open reading frame (ORF)-26 of HHV-8. Anti-HHV-8 antibodies were detected in 30% of non-KS patients and 100% of patients with KS. Furthermore, the HHV-8 DNA detection rates observed in HIV-positive patients with KS were 42.8% in serum, 95.4% in blood samples and 100% in skin biopsies; and in patients without KS, the detection rate was 4% in serum. Out of the 16 serum samples from patients with KS-AIDS who were classified as stage II, two were positive (12.5%); and out of the 33 samples from patients in stage IV, 19 (57.6%) were positive. We observed an association between HHV-8 detection and disease staging, which was higher in the serum of patients in stage IV. This suggests that detection of HHV-8 DNA in serum could be very useful for clinical assessment of patients with KS and for monitoring disease progression.

Prognosis and delay of diagnosis among Kaposi's sarcoma patients in Uganda: a cross-sectional study.

BackgroundIn low- and middle-income countries, the association between delay to treatment and prognosis for Kaposi’s sarcoma (KS) patients is yet to be studied.MethodsThis is a prospective study of HIV-infected adults with histologically-confirmed KS treated at the Uganda Cancer Institute (UCI). Standardized interviews were conducted in English or Luganda. Medical records were abstracted for KS stage at admission to UCI. Multivariable logistic regression assessed relationships between diagnostic delay and stage at diagnosis.ResultsOf 161 patients (90% response rate), 69% were men, and the mean age was 34.0 years (SD 7.7). 26% had been seen in an HIV clinic within 3 months, 72% were on antiretroviral therapy, and 26% had visited a traditional healer prior to diagnosis. 45% delayed seeking care at UCI for ≥3 months from symptom onset. Among those who delayed, 36% waited 6 months, and 25% waited 12 months. Common reasons for delay were lack of pain (48%), no money (32%), and distance to UCI (8%). In adjusted analysis patients who experienced diagnostic delay were more likely than those who did not delay to have poor-risk KS stage (OR 3.41, p = 0.002, 95% CI: 1.46-7.45). In adjusted analyses visiting a traditional healer was the only variable associated with greater likelihood of delay (OR 2.69, p = 0.020, 95% CI: 1.17-6.17).ConclusionsDiagnostic delay was associated with poor-risk stage at diagnosis, and visiting a traditional healer was associated with higher odds of delay. The relationship between traditional and Western medicine presents a critical intervention point to improve KS-related outcomes in Uganda.

Prospective Stage-Stratified Approach to AIDS-Related Kaposi's Sarcoma

Combination antiretroviral therapy (cART) is standard of care for patients with HIV diagnosed with Kaposi's sarcoma (KS), but the current role of systemic chemotherapy is undefined. Since 1998, a prospective stage-stratified approach has been adopted for 469 patients with HIV with KS. Patients with early-stage (T0) KS are treated with cART alone; patients with advanced-stage (T1) KS receive cART plus liposomal anthracycline chemotherapy. Clinical characteristics, overall survival, and KS progression-free survival were analyzed according to stage at presentation and treatment received. A total of 303 patients presented with T0 stage KS, including 237 who were not receiving cART, and 166 patients had T1 stage KS. Patients with T0 KS had higher CD4 cell counts (P < .001); 90% of patients with T0 KS who were not receiving cART and 84% of those with T1 KS were treated in accordance with the stage-stratified approach. Median follow-up was 4.6 years, and 5-year overall survival was 89%; 54 patients have died, 15 as a result of KS. Overall 5-year survival was 92% for T0 KS and 83% to T1 KS (P = .0024). On-treatment analysis of 213 cART-naive patients with T0 KS treated with cART alone revealed 5-year overall survival of 95% and progression-free survival of 77%. For 140 patients with T1 disease treated with cART and liposomal anthracycline chemotherapy, 5-year overall survival was 85%. This stage-stratified approach to the management of KS achieves high survival in patients with advanced KS and reduces exposure to chemotherapy in patients with early-stage KS.

Abstract B180: Molecular pathology in cancer medicine: Our experience in Cameroon.

Abstract Background: Cameroon, located in Central Africa, is a developing country with a population of approximately 20,000,000 millions.Cameroon's Public Health Care System includes: • 1 University teaching hospital established 40 years ago; • 7 new faculties for medical studies established in the last 5 years, with few resources; • The Ministry of Public Health, for all of Cameroon, has an annual budget of approximately $7 millions; • HIV, malaria, and tuberculosis are the most common infectious diseases. Almost the entire budget is devoted to these three diseases, leaving very little to use for cancer care, which has a higher mortality rate than these three diseases combined. Cancer Facts in Cameroon: • Liver cancer is the most common cancer in Cameroon, with virtually a 100% mortality rate. • Cervical cancer and breast cancer each represent 11% of the total cancer cases in the population. • Only 10% of all cancer cases are confirmed through microscopy. 90% of cancer cases go undiagnosed either due to a lack of money or, in rural areas, as pathology facilities are not available. • There are fewer than 10 pathologists and 10 oncologists for the whole population of Cameroon. • A hospital based cancer registry was established in 1987. Since 2000, Cameroon has been working to include population based cancer statistics in the registry. • Radiology, ultrasonography, and endoscopy are only performed in the two main cities, Douala and Yaoundé, which have only 20% of the general population. • Thoracic surgery, neurosurgery and radiotherapy are not readily available. Thus, very little can be offered for inoperable tumors. • Medical oncology/haematology services have just been introduced, but only a restricted spectrum of cancer chemotherapy drugs are available and the patient must pay for them. • 80% of undiagnosed cancer patients end up with late-stage cancer, with no palliative care available. These people resort to treatment by Marabout, who provide home grown “cures”. The result: death! In developed countries, molecular pathology techniques such as immunohistochemical staining is widely used in the diagnosis of abnormal cells such as those found in cancerous tumors and is now introduced in the new WHO classification of diseases. Most of these techniques can be used on paraffin-embedded specimens. Materials and Methods: In Cameroon, the above techniques are not available. We established a collaboration with few laboratories in developed countries including National Cancer Institutes, USA, Switzerland, and France. Paraffin blocks of diagnosed cancers have been sent abroad since January 2000. Immunohistochemistry has been performed free of charge. Results: A series of 130 cancer patients was included in this study. There were 47 malignant lymphomas, 20 cases of early stage Kaposi's sarcoma, 20 soft tissue tumours, 15 breast cancers, 5 brain tumours, 3 urethral cancers and 20 cases of colon cancers. The delay of sending specimens and receiving results via the Internet was one month. Apart from classifying and clarifying their diagnosis, none of these patients received TARGET treatment after the immunohistochemistry result to date as drugs are either expensive or not available. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B180. Citation Format: Nkegoum Blaise, Mboumtou Liliane. Molecular pathology in cancer medicine: Our experience in Cameroon. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B180.

Prognosis, diagnostic delay, and patient characteristics associated with diagnostic delay among Kaposi sarcoma (KS) patients in Uganda.

6578 Background: The incidence and mortality of KS remain high in sub-Saharan Africa. Delaying treatment might explain poor outcomes, but no study has measured the association between delay, characteristics associated with delay, and prognosis for KS patients in low- and middle-income countries. Methods: This is a prospective, cross-sectional study conducted from June-October 2012 at the Uganda Cancer Institute (UCI) in Kampala, Uganda among HIV-infected adults with histologically confirmed KS. The aim was to measure the association between delay and overall KS stage risk at diagnosis. Standardized interviews were conducted in English or Luganda to measure delay, and medical records were abstracted to obtain KS stage at admission to UCI. Multivariable logistic regression was used to assess the relationship between diagnostic delay and poor-risk stage at diagnosis. Results: 161 patients were enrolled; 68.9% were men, mean age was 34.0 years (SD 7.7), 58.1% had income &lt; $2 per day, and 49.4% had ≥primary education. 25.8% had been seen in an HIV clinic within 3 months, 71.6% were on antiretroviral therapy (ART), and 25.5% had visited a traditional healer prior to being seen at UCI. 45.3% delayed seeking care at UCI for ≥3 months from onset of symptoms. Among those who delayed, 35.6% waited 6 months, and 24.7% waited 12 months. The most common reasons for delay were lack of pain (47.9%), no money (31.5%), and distance to UCI (8.2%). In adjusted analysis patients who experienced diagnostic delay were more likely to have poor-risk stage compared to those who did not delay (OR 3.41, p=0.002, 95%CI: 1.46-7.45). After adjusting for patient characteristics, HIV clinic attendance, and ability to pay out-of-pocket costs, visiting a traditional healer was the only characteristic associated with greater likelihood of delay (OR 2.69, p=0.020, 95%CI: 1.17-6.17). Conclusions: Diagnostic delay was independently associated with poor-risk stage at diagnosis, and visiting a traditional healer was the only patient characteristic independently associated with delay. The relationship between traditional and Western medicine presents a critical point of intervention to improve KS outcomes in Uganda.

Non-AIDS-related Kaposi's sarcoma: A single-institution experience

To evaluate the outcomes and potential prognostic factors in patients with non-acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma (KS). Patients with histologically proven non-AIDS-related KS treated with systemic chemotherapy were included in this retrospective analysis. In some cases, the human herpes virus 8 status was assessed by immunohistochemistry. The patients were staged according to the Mediterranean KS staging system. A multivariable model was constructed using a forward stepwise selection procedure. A P value < 0.05 was considered statistically significant, and all tests were two-sided. Thirty-two cases were included in this analysis. The average age at diagnosis was 70 years, with a male/female ratio of approximately 2:1. Eighty-four percent of the cases had classic KS. All patients received systemic chemotherapy containing one of the following agents: vinca alkaloid, taxane, and pegylated liposomal doxorubicin. Ten patients (31.5%) experienced a partial response, and a complete response was achieved in four patients (12.4%) and stable disease in sixteen cases (50%). Two patients (6.2%) were refractory to the systemic treatment. The median progression-free survival (PFS) was 11.7 mo, whereas the median overall survival was 28.5 mo. At multivariate analysis, the presence of nodular lesions (vs macular lesions only) was significantly related to a lower PFS (hazard ratio: 3.09; 95%CI: 1.18-8.13, P = 0.0133). Non-AIDS-related KS appears mostly limited to the skin and is well-responsive to systemic therapies. Our data show that nodular lesions may be associated with a shorter PFS in patients receiving chemotherapy.

Disseminated bone lesions in AIDS‐associated Kaposi sarcoma, a bad prognosis? About four cases

Kaposi sarcoma (KS) can present with a wide range of clinical features ranging from minimal cutaneous disease to a rapidly progressing neoplasm. Bone lesions are most often discovered accidently in the context of radiological investigations done for the screening of KS‐visceral involvement [1]. Little is known on clinical outcome and response to antiretroviral therapy (ART) and/or chemotherapy of these lytic osseous lesions. We report four cases with bone involvement in the context of systemic KS and aim at describing the long‐term clinical outcome in two of these patients. Cases of AIDS‐associated KS with disseminated bone lesions were collected in the HIV Unit, University Hospital Geneva, Switzerland. Patients were compared on clinical, biological and radiological features and therapeutic responses. Between 2002 and 2012, four HIV1‐infected patients with T1 stage of KS presented disseminated osseous lesions (Table 1). Mean age was 43 years (range 39 ‐ 47 years), mean time of follow up until our analysis was 48.5 months (SD 53.8), and mean CD4 count at KS diagnosis was 190.5 c/mL (SD 202.8). All patients showed hypodense bone lesions predominating the axial skeleton (figure 1), but no radiological imaging was performed to search for peripheral bone lesions.No patient reported pain or experienced pathological fractures. In one patient a dual‐energy X‐ray absorptiometry (DXA) showed a bone mineral density within normal range after 10 years of KS diagnosis with disseminated bone lesions. No radiological change was observed in that patient despite stable KS disease after 13 cycles of liposomal doxorubicin and ART (figure 1). We describe a well‐documented long‐term follow up of disseminated osseous AIDS‐associated KS disease. In our four cases, lytic bone lesions were asymptomatic and were not associated with bone fragility. We even could confirm the KS nature of the lesions by bone biopsy in patient B (3 months after KS diagnosis), as the differential diagnosis is wide, and include bacillary angiomatosis, cancers or metastasis. Chemotherapy and antiretroviral treatment did not affect bone lesions using CT scan despite a good response on other KS‐affected sites. Prognostic factors are well established in AIDS‐associated KS [2]; however disseminated bone disease does not seem to have an impact on disease evolution. A larger sample size is needed to confirm this hypothesis.Patient with 10yr follow up, lumbar vertebre after 6 (2002) and 13 (2012) sycles of chemotherapy with Liposomal Doxorubicin.image Baseline characteristics for all four patients with AIDS‐related KS and osseous lesions. Staging classification is based on Known SE et al. J Clin Oncol 1989; 7: 1201–7 and includes the following parameters: T for Tumor (T0 = KS confined to skin and minimal oral disease, T1 = all other manifestations), I for Immune system (I0 = CD4 cells &gt;200/ µL and I1 = CD4 cells &lt;200 µL) and S for systemic illness (S0 = no history of opportunistic infections, S1 = history of opportunistic infections and thrush) Patient Sex Age Ethnicity Kaposi stage (TIS) Follow‐up time since KS diagnosis Visceral involvement Bone lesion (imaging) HHV8 viremia at KS diagnosis (full blood c/mL) Chemotherapy (first line, number of cycles, time period) Last HIV‐RNA (c/µL) ART including PI (y/n) Special comment A M 47 (1965) CAU 1/1/1 10 years yes Axial skeleton, disseminated, hypodense (CT scan) n.a. Liposomal Doxorubicin (13, 1999–2004) &lt; 20 yes DXA‐scan BMD within normal range B M 45 (1969) SSA 1/1/1 8 months Yes Axial skeleton, disseminated, hypodense (CT scan) 2200 Paclitaxel (4, 2012–ongoing) 45 yes KS confirmation by bone biopsy C M 41 (1971) SSA 1/0/1 5 years Yes Axial skeleton, disseminated, hypodense (CT scan) Not done none 94 no D M 39 (1973) SSA 1/1/1 6 months Yes Axial skeleton, single lesions, hypodense (CT scan) 62200 Paclitaxel (3, 2012–ongoing) &lt; 20 yes (but stop May 2012) (Abbreviations: SSA = Sub Saharan Africa; CAU = Caucasian; n.a.=not available DXA = Dual‐energy X‐ray absorptiometry; BMD = bone mineral density)

Gene Expression Profiling Associated with the Progression of Classic Kaposi's Sarcoma

Although Kaposi's sarcoma (KS) gene expression profile is closer to lymphatic (LEC) rather than blood vascular endothelial cells (BEC), uncertainty still surrounds the cellular origin of KS. To follow KS progression from early to late (nodular) stage, and characterize the molecular fingerprinting associated with each stage, gene arrays were used to compare gene expression profile of 9 skin samples of classic KS (4 Early, 2 Mixed, and 3 Nodular CKS samples) to 4 normal samples. Results for selected genes were validated by Real-time (RT) PCR and immunohistochemistry. Genes regulating immune and defense responses, angiogenesis, apoptosis and proliferation were differentially expressed in different KS stages compared to normal skin. Hierarchical clustering separated normal skin from KS with a clear gradient from early to nodular KS lesions. The gene expression level of endothelium markers, metalloproteinases, angiogenic factors and chemokines, gradually increased from normal through all KS stages. The expression of LEC genes highly increased from early to nodular KS. In the initiation phase we noticed a higher expression of growth factors, as compared to progressive stages. LEC and BEC markers co-exist in “KS expression signature”, although the LEC signature prevailed. Our results also show a complex environment of inflammatory cells and chemokines during KS evolution. A pathogenic hypothesis where cellular hyperproliferation is driven by local expression of chemokines and growth factors without clonal expansion of cells is suggested.

Utility of Immunohistochemical Staining With FLI1, D2-40, CD31, and CD34 in the Diagnosis of Acquired Immunodeficiency Syndrome–Related and Non–Acquired Immunodeficiency Syndrome-Related Kaposi Sarcoma

Kaposi sarcoma (KS) is a vascular tumor frequently associated with advanced human immunodeficiency virus infection, advanced age, or iatrogenic immunosuppression. Immunohistochemistry for CD31 and CD34, and more recently for FLI1 and D2-40, has been used as ancillary diagnostic tests for KS, despite little information regarding the sensitivities and differential staining patterns of the latter 2 markers in the major clinical subtypes and histologic stages of KS. This retrospective study aims to assess the prevalence of the vascular markers D2-40 and FLI1 in the main clinical subgroups and tumor stages of KS. Twenty-four cases of KS (12 acquired immunodeficiency syndrome [AIDS]-related cases and 12 non-AIDS-related cases; 11 nodular-stage and 13 patch/plaque-stage KS) were stained for CD34, CD31, D2-40, and FLI1 by immunohistochemistry. The distribution of immunoreactivity was compared between the clinical subtypes and tumor stages of KS using the Mann-Whitney test. CD31, CD34, D2-40, and FLI1 strongly and diffusely stained tumor cells in 75%, 92%, 67%, and 92% of AIDS-related cases and 58%, 92%, 67%, and 75% of non-AIDS-related cases, respectively. Differences in the proportions of positive cases between AIDS-related and non-AIDS-related cases did not reach statistical significance. No significant staining differences were observed between nodular- and patch/plaque-stage KS either. There are no differences in the distribution of immunohistochemical reactivity for CD31, CD34, D2-40, or FLI1 between AIDS-related and non-AIDS-related KS or between nodular- and patch/plaque-stage KS. All of the markers studied demonstrated high sensitivity in both clinical settings and both stages of tumor progression.

Lymphatic Differentiation in Classic Kaposi’s Sarcoma: Patterns of D2-40 Immunoexpression in the Course of Tumor Progression

The recent development of lymphatic endothelium-specific immuno-indicators has given rise to research on the histogenesis of Kaposi sarcoma (KS), specifically focusing on its lymphatic root and differentiation. D2-40 is a new lymphatic marker that recognizes podoplanin and is easily applied to formalin-fixed paraffin-embedded human tissues. This study examined D2-40 immunoexpression in 178 classical KS lesions using immunohistochemical methods. D2-40 immunoexpression was also examined in 63 non-KS soft tissue lesions to test the reliability of D2-40 monoclonal antibody in the pathological diagnosis of KS. D2-40 immunoreactivity was detected at all of the KS lesions and in lymphangioma and nonneoplastic lymphatic endothelium. There was no significant relationship between the extent of D2-40 staining and histopathological stage; however, there was a positive correlation between the staining intensity and histopathological stage in KS cases. D2-40 immunoreactivity was detected at all histopathological stages of KS and may be added to the routine immunohistochemical panel used for the differential diagnosis of KS. Widespread D2-40 protein expression is evidence of a lymphatic origin or the differentiation of neoplastic cells in KS, and D2-40 expression increases with tumor progression.