E30 Kaposi’s sarcoma and HHV8 infections

Introduction

Moritz Kaposi initially described the clinical manifestations of classic Kaposi’s sarcoma (KS) as a disease with skin lesions and enlarged lymph nodes in 1872. He named it an “idiopathic multiple pigmented sarcoma”. However, the disease really came into the limelight in 1981 when 26 homosexual men in the United States were diagnosed with a more aggressive form of KS with disseminated lesions. Several of these patients had other concomitant opportunistic infections. These patients were later identified to have HIV infection and AIDS as the cause of immune suppression leading to fulminant KS. (MMWR 1981 http://img.thebody.com/cdc/pdfs/mmwr28aug81.pdf)

Patients with KS typically present with raised purplish skin nodules, sometimes associated with mucosal lesions, lymphadenopathy and oedema, and rarely systemic disease. KS is an angioproliferative disease characterised microscopically by the presence of spindle shaped tumour cells in a background of vascular endothelial proliferation. Investigation into the causality of KS in HIV patients resulted in identification of DNA sequences of a herpes-like virus in the KS lesions which was not found in normal tissue.[1] This virus was named the Kaposi’s sarcoma related herpes virus (KSHV) or Human Herpes virus 8 (HHV8). Further extensive work firmly established HHV8 to be pathogenic in KS.

In the United States a steady decrease in KS incidence has been noted after the introduction of antiretroviral therapy and improvement in immune status of patients with HIV.[2] A similar change in trend has also been noted in Hong Kong. In Hong Kong, between 1985 and 1994, KS accounted for 8% of the primary AIDS defining illnesses (ADI).[3] The incidence has since declined and during the period of 1997 to 2016 KS only contributed to 2% of ADI in Hong Kong. (HIV Surveillance report – 2016 update. https://www.aids.gov.hk/english/surveillance/sur_report/hiv16.pdf)

This chapter describes the role of HHV8 in pathogenesis of KS, the clinical manifestations of KS in patients with HIV and its management.[Algorithm 30]

Role of HHV8 in KS pathogenesis

Following the identification of HHV8 in the KS lesions of HIV patients, work was done by several groups to establish its role in oncogenesis. Initial studies looked at seroprevalence of HHV8 in different populations with and without HIV and KS. One study utilised the San Francisco men’s health study cohort where participants were compared for baseline seroprevalence of HHV8 infection between homosexual and heterosexual men using the anti-latency associated nuclear antigen test (anti-LANA). Anti-LANA antibodies were identified in 37.6% of patients who reported any homosexual activity versus none of the patients who were exclusively heterosexual suggesting a sexual mode of transmission of this virus.[4] Studies were then done comparing serum samples of homosexual men with AIDS with and without KS. One of these studies showed that patients with HIV related KS had an 80% prevalence of seropositivity for HHV8 antibodies compared to 18% in HIV patients without KS.[5] These studies based on seropositivity strongly suggested a role for HHV8 latency in KS pathogenesis. Several groups were able to then independently demonstrate the presence of HHV8 viral fragments localised to the endothelial cells and spindle cells in the KS lesions.

However, HHV8 infection, while necessary for KS pathogenesis in HIV, is not sufficient for development of the tumour. In areas endemic for KS such as sub-Saharan Africa, the seroprevalence of HHV8 approaches 50%, however not all seropositive individuals develop KS.[6] The incidence of KS in patients with HIV was found to be about 20,000 times higher than in the general population, suggesting that host immune factors may play a role. One hypothesis suggested that after initial infection, usually by orogenital transmission, HHV8 may remain latent in KS cell progenitors, B cells and monocytes. When these cells are exposed to inflammatory cytokines they may differentiate into KS-like spindle cells. The lytic gene expression pathway may also be activated by these cytokines resulting in release of various pro angiogenic factors and active angiogenesis. (reviewed in ref [7])

Pathological features of KS

KS lesions are microscopically characterised by the presence of spindle shaped tumour cells surrounded by brisk angiogenesis with leaky blood vessels, extravasated red blood cells and an inflammatory infiltrate. The exact cell of origin of the spindle shaped tumour cells is unclear. While a majority of the tumour cells express endothelial markers, many also express lymphatic markers, dendritic cell and smooth muscle markers.[7] Studies suggested that transcriptional reprogramming of HHV8 infected endothelial cells may explain the expression of lymphatic endothelial genes in the tumour cells.[8]

Considerable debate still exists on whether KS is a true neoplasm. Transplanted KS-like spindle cells were unable to generate a neoplasm in nude mice unless treated with suitable inflammatory cytokines.[9] Based on observations that oncogenic mutations occur in late stages of the disease, it is postulated that in initial stages KS develops as a polyclonal lesion in response to inflammatory cytokines and immune suppression and in later stages it may evolve into a truly monoclonal neoplastic process.

Clinical manifestations and diagnosis of KS

Mucocutaneous KS

KS typically presents with multifocal dark blue or purple coloured skin macules, papules, plaques or nodules. Locally aggressive lesions may fungate and ulcerate whereas the more indolent lesions may present with subtle bruise like macules or small patches. The sites of predilection are the extremities, often the feet and occasionally the hands, ears or nose. Despite its vascular nature, most of the KS lesions are not completely blanchable. Oedema of the associated limb may be present when the involvement by KS of the affected limbs is relatively more extensive. In that case, regional lymphadenopathy may also be present.

KS of the oral mucosa may occur independently and sometimes be the first manifestation of HIV infection. The most common site of involvement of the oral cavity is the hard palate, followed by the gingival mucosa. Other potential sites of involvement are soft palate, tongue, tonsils, floor of the mouth and pharynx. While most oral cavity disease is asymptomatic, sometimes it may be bulky or ulcerated and affect oral intake or speech. Oral mucosal KS may herald visceral involvement. Thence, examination of the oral mucosae is the simplest bedside examination to pick up early visceral KS

The differential diagnoses of cutaneous KS include other vascular diseases of the integument such as lobular capillary haemangioma (also known as pyogenic granuloma), bacillary angiomatosis, and melanocytic lesions like blue naevus. Skin biopsy is required to confirm the diagnosis before initiation of specific therapy for KS.

Visceral KS

Systemic involvement is rare but may occur in KS. Bulky lymphadenopathy may sometimes be seen. Musculoskeletal involvement has been reported. The most frequent sites of involvement are the gastrointestinal tract and respiratory system. With the advent of highly active antiretroviral therapy (HAART) the incidence of visceral KS has been decreasing.

Evaluation for systemic disease in KS is done using stool occult blood testing for gastrointestinal involvement and chest X-ray for pulmonary involvement. Patients with positive findings will then go on to have a colonoscopy or bronchoscopy as indicated. Routine imaging with CT scans in asymptomatic patients is not recommended for staging workup.

Staging and prognostication of KS

Unlike most solid tumours which are staged using the T (tumour), N (node), M (metastasis) staging, KS staging system in the context of AIDS was originally developed by the AIDS Clinical Trials Group (ACTG) in the pre-HAART era includes T (tumour characteristics), I (host immune status) and S (the presence of systemic illness). Box 30.1 illustrates the details of the TIS staging system. This TIS system was also validated in the post HAART-era and was found to correlate with survival.[10] In principle, HAART alone may be enough to treat those with T0 disease whereas combination of HAART and chemotherapy may be used in those with T1 disease.

In the post-HAART era a prognostic score for predicting HIV KS related mortality was developed based on 326 HIV KS patients in a London based cohort. Having KS as the ADI and an increasing CD4 count were both good prognostic factors, while age over 50 years and having other HIV related comorbidities were poor prognostic factors.[11] Calculation of a prognostic score based on values assigned to these variables was predictive of mortality.

Treatment of KS

WHO consensus guidelines suggest that mild to moderate HIV related KS should be treated with HAART alone while severe symptomatic KS should be treated with HAART in combination with chemotherapy.[Further Reading B] The KS prognostic score is another modality used to drive treatment decisions. Patients having good risk and a prognostic score <5 are usually chosen to receive HAART while those with poor prognosis and a score >12 receive HAART with chemotherapy.[12]

Mild to moderate KS is defined as disease confined to skin and lymph nodes and is treated with HAART upfront. In about 50-60% of patients, control of the HIV viraemia and improvement in the T cell immune response results in regression of the cutaneous KS lesions. However, this regression takes time as T cell recovery occurs in two phases after HAART introduction. In the first phase there is a redistribution of memory T cells and in the second phase there is development of naive T cells. KS response typically occurs in the second phase of immune recovery, about 2 to 3 months after HAART initiation, when there is development of naive T cells (reviewed in ref [12]). A proportion of patients may require other local treatments in addition to HAART either if they develop KS while on HAART or have progressive lesions despite HAART. Options of local treatments are summarised in Box 30.2.

In about 6 to 10% of HIV patients with KS treated with HAART alone, improvement in the immune system results in a clinical syndrome called immune reconstitution inflammatory syndrome (IRIS).[Chapter C17][13] IRIS in KS usually manifests within 3 months after initiation of HAART, is associated with HIV viral suppression of >1 Log10 and clinically manifests with significant progression of KS lesions in the absence of other aetiology for the progression. These patients usually need systemic chemotherapy in addition to the HAART. Systemic chemotherapy is also indicated upfront in patients with severe disseminated disease such as widespread cutaneous involvement with >25 lesions, symptomatic visceral involvement, severe tumour related oedema or ulceration, extensive oral lesions and life threatening or disabling disease.

Chemotherapy options for KS

In patients with KS who have indications for systemic treatment including those with disseminated disease, progression on HAART or development of IRIS, the recommended first line chemotherapy options include pegylated liposomal doxorubicin (PLD) or liposomal daunorubicin (All systemic therapy options are reviewed in ref [14]) PLD is given at 20mg/m² IV every 3 weeks and liposomal daunorubicin is given at 40mg/m² IV every 2 weeks. An overall response rate of 30-60% has been reported with these agents in different studies.

Single agent PLD was compared to combination chemotherapy in different studies and superior response rates were seen with the use of single agent PLD compared to combinations of either doxorubicin, bleomycin and vincristine or bleomycin and vincristine alone. In another randomised study, use of single agent liposomal daunorubicin was comparable to use of combination chemotherapy in terms of response rates, progression free and overall survival. A small double blind study comparing PLD (n=60) to liposomal daunorubicin (n=19) suggested better response rates to PLD, although the numbers in both arms were small and imbalanced and insufficient to make meaningful conclusions. Liposomal anthracyclines have less severe side effects compared to combination chemotherapy. Myelosuppression is often seen with the liposomal anthracyclines. Hand foot syndrome may occur. Cardiotoxicity is significantly lesser with the liposomal formulation compared to conventional anthracyclines.

Paclitaxel is typically used in the second line setting in patients who have failed or progressed after initial response to liposomal anthracyclines. Caution must be exercised in the use of paclitaxel in this patient population given the need for steroid premedication which is associated with additional immune suppression and the metabolism of paclitaxel by the cytochrome p450 system which also metabolises other antiretrovirals.[15] In a randomised controlled study evaluating 73 patients with advanced KS comparing liposomal doxorubicin at 20mg/m² IV every 3 weeks versus paclitaxel 100mg/m² IV every 2 weeks, no significant difference in response rate, progression free or overall survival was seen. Paclitaxel resulted in higher grade 3-5 toxicities, although the risk of increased toxicity did not reach statistical significance.

Several other systemic therapies in KS remain under investigation including the angiogenesis inhibitor bevacizumab, mTOR inhibitor sirolimus and imatinib, a tyrosine kinase inhibitor.

Despite these systemic therapy options, patients in the poor prognostic group with disseminated disease and severely compromised immune status respond poorly to treatment and often KS in these patients can cause life threatening complications.

Conclusion

KS may herald the diagnosis of HIV. The incidence and severity of KS has decreased overall since the introduction of HAART. However, a proportion of patients still present with disseminated KS in the setting of hitherto undiagnosed advanced HIV. The prognosis of these patients with disseminated disease remains poor despite treatment with HAART and concurrent chemotherapy. More research is needed in this area to identify better treatments for patients with disseminated disease.

References

Further reading