Questions

Kaposi's sarcoma-associated herpesvirus — Questions

Study questions about Kaposi's sarcoma-associated herpesvirus — exam-style, clinical-scenario and FAQ.

Mock Exam mode

Sit this set one question at a time. Multiple-choice questions mark themselves; written questions reveal a tickable mark scheme so you can score your own answer. You get a combined score at the end.

15 questions: 10 MCQ, 5 written.

High-priority (past-paper) questions only

Why B

Kaposi sarcoma is driven by human herpesvirus 8 under failing immune control, and antiretroviral therapy is first-line for limited cutaneous disease: restoring immunity often causes the lesions to regress without specific cancer treatment.

Systemic chemotherapy such as liposomal doxorubicin or paclitaxel is reserved for advanced, visceral or rapidly progressive disease, given alongside antiretroviral therapy. Surgery and radiotherapy have only local roles, and antivirals such as ganciclovir are of unproven benefit.

A complete answer covers the three viral drivers, the tumours each causes, and the central role of antiretroviral therapy.

Kaposi sarcoma (HHV-8)

Human herpesvirus 8 causes Kaposi sarcoma, violaceous skin and mucosal lesions (characteristically the palate and gingiva) that can involve the gut and lungs, and also primary effusion lymphoma and multicentric Castleman disease. Antiretroviral therapy is first-line for limited disease, with chemotherapy for advanced or visceral disease.

The AIDS lymphomas (EBV)

Epstein-Barr virus drives the AIDS-defining lymphomas: systemic non-Hodgkin lymphoma (diffuse large B-cell, Burkitt and plasmablastic types) and primary central nervous system lymphoma, which is almost always EBV-positive and is distinguished from cerebral toxoplasmosis by EBV DNA in the cerebrospinal fluid and by metabolic imaging. Treatment combines chemotherapy, often with rituximab for systemic disease and high-dose methotrexate for central nervous system disease, with antiretroviral therapy.

Cervical and anal cancer (HPV)

Human papillomavirus causes accelerated cervical and anal intraepithelial neoplasia and a several-fold higher risk of invasive cervical cancer (an AIDS-defining condition) and anal cancer, which is why regular cervical and anal screening is essential.

The common thread

All three are controlled by cell-mediated immunity, so antiretroviral therapy underpins management of each, with tumour-specific treatment added according to the malignancy.

In endemic areas KSHV spreads chiefly through saliva, horizontally and within families from early childhood.

In low-prevalence Western settings it spreads mainly sexually, efficiently among men who have sex with men; transfusion, faecal-oral and vector routes are not the endemic pattern.

KICS is a severe systemic inflammatory illness with high interleukin-6 and interleukin-10 and a high KSHV blood viral load, often with Kaposi sarcoma but without the lymph-node pathology of multicentric Castleman disease.

It is neither a discrete tumour nor a congenital, inherited or vaccine-related condition.

Epstein-Barr virus, a lymphocryptovirus, is the only other human gammaherpesvirus; like KSHV it establishes latency in lymphocytes and can cause B-cell lymphoma.

Cytomegalovirus and human herpesvirus 6 are betaherpesviruses; herpes simplex virus and varicella-zoster virus are alphaherpesviruses.

Both host interleukin-6 and the KSHV-encoded viral homologue drive the polyclonal lymphoproliferation of multicentric Castleman disease, which is the rationale for rituximab and for anti-interleukin-6 agents such as siltuximab.

The other cytokines listed are not the principal driver of this disorder.

Primary effusion lymphoma is a KSHV-positive lymphoma arising from monoclonal plasmablastic B cells, often co-infected with Epstein-Barr virus, that presents as malignant effusions in body cavities without a solid mass.

It is usually HIV-positive, is not human-papillomavirus-driven, forms no solid nodal mass, and is of B-cell rather than T-cell origin.

The epidemic, AIDS-associated form became the commonest cancer of the HIV epidemic and is frequently aggressive and visceral.

The classic, endemic and iatrogenic forms arise in other settings, and primary effusion lymphoma is a separate KSHV-associated malignancy, not a form of Kaposi sarcoma.

Immunohistochemistry for the latency-associated nuclear antigen (LANA) shows a characteristic stippled nuclear pattern and is the confirmatory test across all KSHV diseases.

p16 marks high-risk human papillomavirus disease, CD20 is a pan-B-cell marker, Ki-67 measures proliferation, and no glycoprotein B stain is used for this purpose.

RTA, encoded by ORF50, is sufficient on its own to initiate lytic replication; in latency the latency-associated nuclear antigen (LANA) represses its promoter to keep the virus quiescent.

LANA, viral cyclin and viral FLIP are latent proteins, and K8.1 is a lytic glycoprotein rather than the switch itself.

A minority of cells in a lesion express lytic and paracrine genes whose secreted angiogenic factors (viral G-protein-coupled-receptor-driven VEGF, viral interleukin-6) drive proliferation in neighbouring cells, so the lesion is polyclonal and regresses when immune control returns.

Kaposi sarcoma is therefore not a monoclonal, single-oncogene or integration-driven malignancy, and it is unequivocally KSHV-associated.

KSHV underlies all three; they separate cleanly on cell of origin, clonality and clinical behaviour.

Disease	Cell of origin	Clonality	Clinical behaviour
Kaposi sarcoma	Endothelial-derived spindle cells	Non-monoclonal	Angioproliferative, paracrine-driven; patch to plaque to nodular; regresses when immune control is restored
Primary effusion lymphoma	Postgerminal-centre plasmablastic B cells	Monoclonal	Malignant pleural, peritoneal or pericardial effusions without a solid mass; aggressive, poor prognosis
Multicentric Castleman disease	Plasmablastic B cells of the lymph-node mantle zone	Polyclonal	Interleukin-6-driven relapsing fever, lymphadenopathy, hepatosplenomegaly and cytopenias; treated with rituximab

Kaposi sarcoma occurs in four epidemiological forms (classic, endemic African, iatrogenic, AIDS-associated). Primary effusion lymphoma is universally KSHV-positive and usually co-infected with Epstein-Barr virus. Multicentric Castleman disease is KSHV-associated in essentially all HIV-positive cases, with the blood KSHV viral load tracking activity.

A complete answer links seroprevalence and transmission to the four clinical forms.

Seroprevalence and transmission. KSHV seroprevalence is low in the West (a few %), intermediate around the Mediterranean, and very high in sub-Saharan Africa (approaching half of adults in places). It spreads mainly by saliva in childhood in endemic areas and sexually (notably among men who have sex with men) in low-prevalence settings, with inefficient transplant and transfusion transmission.

The four forms of Kaposi sarcoma. Classic (indolent, elderly Mediterranean men); endemic African (adults and children, pre-AIDS, sometimes aggressive); iatrogenic (transplant immunosuppression, regresses when it is reduced); and epidemic, AIDS-associated (advanced HIV, aggressive and often visceral, the defining cancer of the epidemic).

A complete answer explains both the persistence and the oncogenic roles.

Latency programme. In the host KSHV is overwhelmingly latent. The genome circularises into a multicopy episome, is copied once per cell cycle by host machinery, and expresses only a small set of latent genes, with no virion production but full lytic potential retained.

LANA. LANA tethers the episome to host mitotic chromosomes so it segregates to daughter cells, maintaining the infection. It also drives transformation: it inactivates p53 and the retinoblastoma protein, stabilises beta-catenin and Myc, and represses the lytic switch RTA to keep the virus latent.

A complete answer covers the virus and its tumours, the seroprevalence-driven epidemiology, and the management.

The virus and its tumours

HHV-8 (Kaposi sarcoma-associated herpesvirus) causes Kaposi sarcoma, and also primary effusion lymphoma and multicentric Castleman disease. In transplant recipients Kaposi sarcoma is typically the earliest post-transplant malignancy, arising either from reactivation of the recipient’s own latent virus or, less often, from a donor-derived infection transmitted in the graft.

Epidemiology

Risk tracks HHV-8 seroprevalence, which is geographically very uneven: under 5 per cent in Northern European blood donors but up to around 80 per cent in parts of sub-Saharan Africa. Post-transplant Kaposi sarcoma is therefore rare (under 1 per cent) in low-prevalence regions but reaches several per cent in high-prevalence populations, where it makes up the majority of all post-transplant cancers.

Clinical and management

Kaposi sarcoma presents as violaceous cutaneous nodules, but visceral involvement (gastrointestinal, pulmonary) occurs in up to 40 per cent and may bleed or obstruct. The mainstay of treatment is reduction of immunosuppression and a switch to an mTOR inhibitor (sirolimus), which is both immunosuppressive and antitumour and can drive regression. Visceral or refractory disease needs chemotherapy. Antivirals are of unproven benefit.

High priorityMCQ
What is the first-line treatment for limited cutaneous Kaposi sarcoma in a patient with HIV?
- A. Liposomal doxorubicin
- B. Antiretroviral therapy
- C. Wide surgical excision
- D. Radiotherapy to each lesion
- E. Ganciclovir
Show answer
Correct answer: B
Why B

Kaposi sarcoma is driven by human herpesvirus 8 under failing immune control, and antiretroviral therapy is first-line for limited cutaneous disease: restoring immunity often causes the lesions to regress without specific cancer treatment.

Systemic chemotherapy such as liposomal doxorubicin or paclitaxel is reserved for advanced, visceral or rapidly progressive disease, given alongside antiretroviral therapy. Surgery and radiotherapy have only local roles, and antivirals such as ganciclovir are of unproven benefit.
High priorityExam-styleDiscuss the virus-associated malignancies seen in AIDS. [8]
Model answer
A complete answer covers the three viral drivers, the tumours each causes, and the central role of antiretroviral therapy.

Kaposi sarcoma (HHV-8)

Human herpesvirus 8 causes Kaposi sarcoma, violaceous skin and mucosal lesions (characteristically the palate and gingiva) that can involve the gut and lungs, and also primary effusion lymphoma and multicentric Castleman disease. Antiretroviral therapy is first-line for limited disease, with chemotherapy for advanced or visceral disease.

The AIDS lymphomas (EBV)

Epstein-Barr virus drives the AIDS-defining lymphomas: systemic non-Hodgkin lymphoma (diffuse large B-cell, Burkitt and plasmablastic types) and primary central nervous system lymphoma, which is almost always EBV-positive and is distinguished from cerebral toxoplasmosis by EBV DNA in the cerebrospinal fluid and by metabolic imaging. Treatment combines chemotherapy, often with rituximab for systemic disease and high-dose methotrexate for central nervous system disease, with antiretroviral therapy.

Cervical and anal cancer (HPV)

Human papillomavirus causes accelerated cervical and anal intraepithelial neoplasia and a several-fold higher risk of invasive cervical cancer (an AIDS-defining condition) and anal cancer, which is why regular cervical and anal screening is essential.

The common thread

All three are controlled by cell-mediated immunity, so antiretroviral therapy underpins management of each, with tumour-specific treatment added according to the malignancy.
MCQ
In high-seroprevalence regions such as sub-Saharan Africa, what is the main route of KSHV transmission?
- A. Saliva
- B. Blood transfusion
- C. Respiratory droplets
- D. Faecal-oral spread
- E. Mosquito bite
Show answer
Correct answer: A
In endemic areas KSHV spreads chiefly through saliva, horizontally and within families from early childhood.

In low-prevalence Western settings it spreads mainly sexually, efficiently among men who have sex with men; transfusion, faecal-oral and vector routes are not the endemic pattern.
MCQ
KSHV inflammatory cytokine syndrome (KICS) is which of the following?
- A. A systemic inflammatory illness
- B. A localised cutaneous tumour
- C. A congenital infection syndrome
- D. An inherited immunodeficiency
- E. A vaccine adverse event
Show answer
Correct answer: A
KICS is a severe systemic inflammatory illness with high interleukin-6 and interleukin-10 and a high KSHV blood viral load, often with Kaposi sarcoma but without the lymph-node pathology of multicentric Castleman disease.

It is neither a discrete tumour nor a congenital, inherited or vaccine-related condition.
MCQ
KSHV's only human relative within the gammaherpesvirus subfamily is which virus?
- A. Cytomegalovirus
- B. Herpes simplex virus
- C. Varicella-zoster virus
- D. Epstein-Barr virus
- E. Human herpesvirus 6
Show answer
Correct answer: D
Epstein-Barr virus, a lymphocryptovirus, is the only other human gammaherpesvirus; like KSHV it establishes latency in lymphocytes and can cause B-cell lymphoma.

Cytomegalovirus and human herpesvirus 6 are betaherpesviruses; herpes simplex virus and varicella-zoster virus are alphaherpesviruses.
MCQ
Multicentric Castleman disease is driven principally by excess activity of which cytokine?
- A. Interferon gamma
- B. Tumour necrosis factor alpha
- C. Interleukin-2
- D. Interleukin-10
- E. Interleukin-6
Show answer
Correct answer: E
Both host interleukin-6 and the KSHV-encoded viral homologue drive the polyclonal lymphoproliferation of multicentric Castleman disease, which is the rationale for rituximab and for anti-interleukin-6 agents such as siltuximab.

The other cytokines listed are not the principal driver of this disorder.
MCQ
Primary effusion lymphoma is best characterised as which of the following?
- A. A solid nodal mass
- B. An HPV-driven tumour
- C. A T-cell effusion lymphoma
- D. A KSHV-positive lymphoma
- E. Typically HIV-negative
Show answer
Correct answer: D
Primary effusion lymphoma is a KSHV-positive lymphoma arising from monoclonal plasmablastic B cells, often co-infected with Epstein-Barr virus, that presents as malignant effusions in body cavities without a solid mass.

It is usually HIV-positive, is not human-papillomavirus-driven, forms no solid nodal mass, and is of B-cell rather than T-cell origin.
MCQ
Which form of Kaposi sarcoma is the defining cancer of advanced HIV?
- A. Classic
- B. Epidemic
- C. Endemic African
- D. Iatrogenic
- E. Primary effusion lymphoma
Show answer
Correct answer: B
The epidemic, AIDS-associated form became the commonest cancer of the HIV epidemic and is frequently aggressive and visceral.

The classic, endemic and iatrogenic forms arise in other settings, and primary effusion lymphoma is a separate KSHV-associated malignancy, not a form of Kaposi sarcoma.
MCQ
Which immunohistochemical marker confirms KSHV in a spindle-cell or lymphoid lesion?
- A. p16
- B. LANA
- C. CD20
- D. Ki-67
- E. HHV-8 glycoprotein B
Show answer
Correct answer: B
Immunohistochemistry for the latency-associated nuclear antigen (LANA) shows a characteristic stippled nuclear pattern and is the confirmatory test across all KSHV diseases.

p16 marks high-risk human papillomavirus disease, CD20 is a pan-B-cell marker, Ki-67 measures proliferation, and no glycoprotein B stain is used for this purpose.
MCQ
Which KSHV protein is the master switch that triggers the lytic cycle?
- A. LANA
- B. Viral cyclin
- C. RTA (ORF50)
- D. Viral FLIP
- E. K8.1
Show answer
Correct answer: C
RTA, encoded by ORF50, is sufficient on its own to initiate lytic replication; in latency the latency-associated nuclear antigen (LANA) represses its promoter to keep the virus quiescent.

LANA, viral cyclin and viral FLIP are latent proteins, and K8.1 is a lytic glycoprotein rather than the switch itself.
MCQ
Why is Kaposi sarcoma angioproliferative, non-monoclonal and reversible rather than a classical clonal cancer?
- A. Monoclonal outgrowth of one cell
- B. A single driving oncogene
- C. Paracrine cytokine signalling
- D. Integration of the viral genome
- E. Unrelated to KSHV
Show answer
Correct answer: C
A minority of cells in a lesion express lytic and paracrine genes whose secreted angiogenic factors (viral G-protein-coupled-receptor-driven VEGF, viral interleukin-6) drive proliferation in neighbouring cells, so the lesion is polyclonal and regresses when immune control returns.

Kaposi sarcoma is therefore not a monoclonal, single-oncogene or integration-driven malignancy, and it is unequivocally KSHV-associated.

Exam-styleCompare Kaposi sarcoma, primary effusion lymphoma and multicentric Castleman disease as KSHV-associated diseases, addressing cell of origin, clonality and clinical behaviour. [6]

Model answer

KSHV underlies all three; they separate cleanly on cell of origin, clonality and clinical behaviour.

Disease	Cell of origin	Clonality	Clinical behaviour
Kaposi sarcoma	Endothelial-derived spindle cells	Non-monoclonal	Angioproliferative, paracrine-driven; patch to plaque to nodular; regresses when immune control is restored
Primary effusion lymphoma	Postgerminal-centre plasmablastic B cells	Monoclonal	Malignant pleural, peritoneal or pericardial effusions without a solid mass; aggressive, poor prognosis
Multicentric Castleman disease	Plasmablastic B cells of the lymph-node mantle zone	Polyclonal	Interleukin-6-driven relapsing fever, lymphadenopathy, hepatosplenomegaly and cytopenias; treated with rituximab

Exam-styleDescribe the epidemiology of KSHV and the four epidemiological forms of Kaposi sarcoma. [6]
Model answer
A complete answer links seroprevalence and transmission to the four clinical forms.

Seroprevalence and transmission. KSHV seroprevalence is low in the West (a few %), intermediate around the Mediterranean, and very high in sub-Saharan Africa (approaching half of adults in places). It spreads mainly by saliva in childhood in endemic areas and sexually (notably among men who have sex with men) in low-prevalence settings, with inefficient transplant and transfusion transmission.

The four forms of Kaposi sarcoma. Classic (indolent, elderly Mediterranean men); endemic African (adults and children, pre-AIDS, sometimes aggressive); iatrogenic (transplant immunosuppression, regresses when it is reduced); and epidemic, AIDS-associated (advanced HIV, aggressive and often visceral, the defining cancer of the epidemic).
Exam-styleOutline the latency programme of KSHV and the roles of the latency-associated nuclear antigen (LANA). [5]
Model answer
A complete answer explains both the persistence and the oncogenic roles.

Latency programme. In the host KSHV is overwhelmingly latent. The genome circularises into a multicopy episome, is copied once per cell cycle by host machinery, and expresses only a small set of latent genes, with no virion production but full lytic potential retained.

LANA. LANA tethers the episome to host mitotic chromosomes so it segregates to daughter cells, maintaining the infection. It also drives transformation: it inactivates p53 and the retinoblastoma protein, stabilises beta-catenin and Myc, and represses the lytic switch RTA to keep the virus latent.
Exam-styleWrite short notes on human herpesvirus 8 (HHV-8) and Kaposi sarcoma in the transplant recipient. [6]
Model answer
A complete answer covers the virus and its tumours, the seroprevalence-driven epidemiology, and the management.

The virus and its tumours

HHV-8 (Kaposi sarcoma-associated herpesvirus) causes Kaposi sarcoma, and also primary effusion lymphoma and multicentric Castleman disease. In transplant recipients Kaposi sarcoma is typically the earliest post-transplant malignancy, arising either from reactivation of the recipient’s own latent virus or, less often, from a donor-derived infection transmitted in the graft.

Epidemiology

Risk tracks HHV-8 seroprevalence, which is geographically very uneven: under 5 per cent in Northern European blood donors but up to around 80 per cent in parts of sub-Saharan Africa. Post-transplant Kaposi sarcoma is therefore rare (under 1 per cent) in low-prevalence regions but reaches several per cent in high-prevalence populations, where it makes up the majority of all post-transplant cancers.

Clinical and management

Kaposi sarcoma presents as violaceous cutaneous nodules, but visceral involvement (gastrointestinal, pulmonary) occurs in up to 40 per cent and may bleed or obstruct. The mainstay of treatment is reduction of immunosuppression and a switch to an mTOR inhibitor (sirolimus), which is both immunosuppressive and antitumour and can drive regression. Visceral or refractory disease needs chemotherapy. Antivirals are of unproven benefit.