Kaposi sarcoma in HIV-seronegative children presenting to the paediatric oncology ward in The Queen Elizabeth Central Hospital,Blantyre,Malawi during 2002

Abstract

One of the most common malignancies in HIV-endemic, resource-poor countries is Kaposi sarcoma (KS). It is an AIDS-defining disease and as Malawi’s incidence and prevalence of HIV is high, KS is now the most common cancer in adult male Malawians and the second most common in women and children. Most attention has focused on HIV-seropositive adults as their number far outweighs those of children. This audit concerns the presentation and outcome of HIV-seronegative children with KS who presented in a 12-year period (2002–2014) to The Queen Elizabeth Central Hospital. Twenty (10.5%) of the 191 children with KS presenting to the paediatric oncology ward during 2002–2014 were HIV-seronegative. They were usually younger than seropositive children and 62% had severe anaemia. The main presenting complaints in the HIV-seronegative group were woody oedema, commonly of a limb, and lymphadenopathy. Woody oedema was common in children with or without HIV infection. Seronegative children with KS were less likely to have oral KS than HIV infected children. Of 11 children who completed courses of chemotherapy, seven (63%) had complete cure sustained over a 1-year follow-up period. KS is potentially curable in this group of children. Chemotherapy regimens are equally effective in HIV-seropositive and HIV-seronegative children. The presentation of HIV-seronegative children with KS differs from adults and HIV-seropositive children. Further research is necessary to determine possible triggers for developing KS in HIV-seronegative children.

Keywords

HIV-seronegative Kaposi sarcoma (KS)children Malawi

Introduction

Kaposi sarcoma (KS) is an angio-proliferative cancer associated with AIDS. It is one of the most common malignancies in resource-limited settings where access to antiretroviral therapy has improved in recent years but is still not available to every patient at the point of diagnosis.^1–4 The rise in KS numbers reflects the increase in HIV infections in HIV-epidemic areas and KS is an AIDS-defining disease.⁵ KS is one of the most common causes of cancer in sub-Saharan Africa and the second most common malignancy in children aged under 15 years in Malawi.^5,6 As most patients who present with KS are HIV-seropositive, research has focused on the seropositive patients.^7,8 Nevertheless, during an observational period of 12 years we saw a significant number of HIV-seronegative KS patients and will describe their presentations and response to treatment.

Background

Malawi is a landlocked country in southern Africa with a population of about 16 million. Malaria is seasonal and hyperendemic; HIV infection is endemic and affects about 10% of the population,⁹ in children the prevalence of HIV is less, and according to UNAIDS approximately 170,000 children aged less than 14 years are affected.¹⁰

The Queen Elizabeth Central Hospital (QECH) is a 1100-bed public government tertiary hospital that is also the teaching hospital for the medical school and serves as the district hospital for Blantyre district. The paediatric department admits 28,000 children a year and 90,000 are seen annually in the emergency and outpatient departments. The children’s oncology ward has 21 beds and admits 340 new cases a year.

Methodology

This is a descriptive, retrospective analysis of patient records of HIV-seronegative children presenting with KS at QECH paediatric oncology ward during 2002–2014. Demographic, clinical, laboratory, treatment and outcome details were extracted from the medical records and entered into a Word Excel file with all personal identifiers removed. Data were analysed using the same programme, categorical variables were analysed using chi-squared test, paired T-test was used to compare means and descriptive statistics were used to describe other variables using ‘StatsDirect’.

Results

In the 12 study years, 191 patients with KS presented to the paediatric oncology ward, of whom, 89.5% (n = 171), were HIV-seropositive and 20 (10.5%) were HIV-seronegative. The 20 HIV-seronegative patients presented at a median age of 4 years (range, 1.9–15 years); 80% were boys. Half the children were of fair or good nutritional status (between >3rd and >75th centile of weight for age), the other half had nutritional deficits ranging from –1 Z standard deviations (SD) to >–3 Z SD (Figure 1). Most patients (n = 13; 65%) presented during the hot, wet season.

Figure 1.

Nutritional status on presentation of HIV-seronegative children with KS.^a

Thirteen (60%) patients presented with lymphadenopathy, 14 (70%) with oedema, eight (40%) had localised skin lesions, two (10%) had oral lesions, a further four (20%) had sub-conjunctival haemorrhages and two had a history of nose bleeds. Four (20%) children had received tuberculosis treatment prior to referral because of the presence of large cervical lymph nodes.

Six patients who had a chest X-ray were found to have various problems such as a widened mediastinum, pleural effusion, hilar lymphadenopathy and opacity in the right upper lung zone.

Prior to treatment, all patients had a Lansky score (Table 1) done to assess quality of life: 60% (n = 12) had a post-treatment Lansky score measured. The Lansky score prior to treatment was 80.5% (range, 50–100%) and after treatment was 97.5% (range, 80–100%).

Table 1.

Lansky score and performance.

Lansky score	Performance
100	Fully active, normal
90	Minor restrictions to strenuous physical activity
80	Active but tires more quickly
70	Both greater restriction of and less time spent in play activity
60	Up and around but minimal active play; keeps busy with quieter activities
50	Gets dressed but lies around much of the day; no active play but able to participate in all quiet activities and play
40	Mostly in bed; participates in quiet activities
30	In bed; needs assistance even for quiet play
20	Often sleeping; play limited entirely limited to very passive activities
10	No play; does not get out of bed
0	Unresponsive

On admission all patients, after obtaining consent, had a repeat HIV Elisa test (Determine HIV Rapid Test and if positive to be followed by a second rapid HIV test Uni-Gold™ Recombigen® HIV) which confirmed that they were negative. Thirteen patients had blood packed cell volume (PCV) measured: the median was 25% (range, 11.9–37.8%). Twelve patients had white cell counts (WCC) measured – the median was 9650/µL (range, 3400–24,500/µL); they also had platelets measured – the median was 94,500/µL (range, 13,000–268,000/µL). Following World Health Organization (WHO) guidelines to assess the severity of anaemia five children had moderate anaemia and eight had severe anaemia.¹¹ Six received blood transfusions.

The same chemotherapy was offered to HIV-seropositive and HIV-seronegative patients. The regimens changed over the years but were six courses of various combinations of etoposide, bleomycin, vincristine and thalidomide. Thalidomide is an immunomodulatory and anti-angiogenic drug which was given to two patients as a single drug treatment;¹² six other patients received thalidomide over a period where clinical symptoms persisted from 6 weeks to 9 months.

Of the 20 patients, 11 (55%) completed treatment. Of these 11, seven (64%) were completely cured, three (27%) were partially cured and one (9%) was transferred to another hospital closer to his home. Of the 20 patients, two (10%) were unresponsive to treatment and absconded. A further four (20%) failed to complete treatment, and three (15%) patients died (Figure 2).

Figure 2.

Outcome of treatment.

Four (20%) patients relapsed. Most patients were followed up for a period of 12 months.

Discussion

Malawi has a high incidence and prevalence of HIV infection.¹⁰ In 2013 an estimated 170,000 children (range, 150,000–190,000) were living with HIV in Malawi.¹⁰

The presentation of KS in HIV-seropositive and HIV-seronegative children is reported to differ significantly.⁷ Children, whatever their HIV status, appear to present less commonly with isolated cutaneous KS lesions than adults and have more frequent lymph node involvement.^1,7,13 A previous retrospective audit from Malawi described cutaneous manifestations in only 21% of seropositive children.⁷ Another descriptive study of 81 HIV infected children with KS attending antiretroviral clinics in Malawi and Botswana found that 82% primarily presented with skin manifestations of whom 52% had lymph node involvement and 41% had oral cavity findings.^7,14

In our audit of HIV-seronegative children they had non-significantly less skin involvement than seropositive children: 40% had localised skin manifestations but 60% had lymph node involvements. In a Ugandan study of 73 seropositive children, 48% had cutaneous lesions and 60% lymphadenopathy.¹ We found only 10% of seronegative children had oral cavity involvement. In the descriptive study of seropositive Malawian and Batswana children attending antiretroviral clinics, 41% of patients had oral cavity findings; and in 73 Ugandan children with KS, 21% had evidence of oral KS involvement.^1,14

Children, whether HIV-seropositive or HIV-seronegative, with lymphadenopathy as their main presenting complaint tend to present at a young age.¹ We found that in children with lymphadenopathy the mean age was 4.1 years, (median, 3.05 years; range, 1.11–10 years) compared with 5.7 years, that is on average 3.7 years younger than HIV-seropositive without lymphadenopathy.¹

Children presented with woody oedema (70%) and lymphadenopathy (60%) which are not common in HIV-positive adults though more often seen in young children.¹

It is reported that HIV-seronegative children are younger than HIV-seropositive children on first presentation.^7,15 HIV-seronegative children with KS presented to us at a median age of 4 years (range, 1.11–15 years). In five other KS studies in African HIV-seropositive children, the median age at presentation was higher. One retrospective group from South Africa presented at a median age of 6.2 years while three other studies (two retrospective and one open, randomised trial) reported median ages of 8 years and 10 years, respectively.² It has been suggested that HIV-seropositive children who present with KS at a younger age may have high levels of circulating Human Herpes Virus 8 (HHV8).¹ It is unknown if similar findings apply for HIV-seronegative children in our audit as we were unable to test for HHV8 during this observational period during 2002–2014.

HHV8 or Kaposi sarcoma herpes virus (KSHV) together with other co-factors is seen as causative in the development of KS. HHV8 genomic sequences are found in >90% of all types of KS lesions.¹⁶

On admission eight patients (62%) were severely anaemic and five (38%) were moderately anaemic. By comparison in a retrospective audit of 81 seropositive children from Malawi and Botswana, severe anaemia was only found in 29%.

The nutritional status of children in Malawi using the WHO grading shows that 47% of children aged <5 years in the general population are stunted which makes the interpretation of weight for age very difficult.¹⁷ In Malawi paediatric oncology patients with malignancies other than KS, malnutrition has been described in about 50% of all patients on admission.¹⁸ One-third of the children admitted to the oncology unit with KS were malnourished (SD ≤ 2).

Patients who were HIV-seropositive received antiretroviral therapy (ART) according to national guidelines and a combination of chemotherapy as the outcome of a combined treatment has been described as better than a single drug regimen.⁴

In summary we found, as reported from other studies in Malawi (cutaneous manifestations 21%), Malawi and Botswana (skin presentations 82%) and Uganda (cutaneous lesions 48%), that HIV-seronegative children have less isolated KS cutaneous manifestations than all studies of HIV-seropositive children.^1,2,13,14

The median age of our study population was significantly younger (median age, 4 years) than in other studies from countries in sub-Saharan Africa (median age, 6.2, 8 and 10 years), however, all other studies included mainly HIV-seropositive children.^2,7

As one other study also looked at anaemia they had only 29% of patients being HIV-seropositive who presented with severe anaemia while we identified 62%.¹⁴

Conclusion

About 10% of the total number of children with KS are HIV-seronegative.

KS is potentially life-threatening but can be cured in this group of children.

Chemotherapy regimens are equally effective in HIV-seropositive and HIV-seronegative children.

Children who are HIV-seronegative are usually younger than HIV-seropositive children at the time they develop KS.¹⁹

We found 62% of HIV-seronegative children had severe anaemia.

Children presenting with lymphadenopathy are young and the incidence of lymphadenopathy in both seropositive and seronegative children is high.

The main presenting complaints in our study group were woody oedema and lymphadenopathy.

The presentation of woody oedema in children with KS with or without HIV infection is similar.

HIV-seronegative children with KS are less likely to have oral KS than HIV-infected children.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

^aNutritional status definition: good: > 15^th-75^th Percentile; fair: 3^rd–15^th Percentile; poor: -1 Z SD; wasted: -2 Z SD; severely wasted: -3 Z SD

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Kaposi sarcoma in HIV-seronegative children presenting to the paediatric oncology ward in The Queen Elizabeth Central Hospital,Blantyre,Malawi during 2002–2014

Abstract

Keywords

Introduction

Background

Methodology

Results

Discussion

Conclusion

Footnotes

Declaration of conflicting interests

Funding

References