HHV8 Associated Lymphoproliferative Disorders

Question 1

What are the diseases that are caused by HHV8 (Kaposi-sarcoma associated herpesvirus) ?

Answer 1

• Kaposi sarcoma (which can involve the lymph nodes)*
• HHV8 + multi centric Castleman disease*
• HHV8 + DLBCL, NOS (often arises from Castelman’s disease)*
• Germinotropic lymphoproliferative disorder (GLPD)
• Primary effusion lymphoma or extracavitary PEL *

* denotes association with HIV infection or in HHV8 endemic areas, also can be seen in immunocompromised states such as transplantation

Question 2

What are general considerations in HHV8 associated disorders?

Answer 2

• cases have been reported where there are overlapping features
• GLPD tends not to progress but there is a reported case of evolution to HG HHV8+, EBV+ Lymphoma
• D/D between HHV8 DLBCL and PEL may be problematic but most cases of PEL are EBV+
  * they lack cytoplasmic Ig and are positive for plasma cell markers

Question 3

Review the table on page 325

Answer 3

Review table

Question 4

What is the definition of Multicentric Castleman Disease (MCD) ?

Answer 4

• clinicopathological entity composed of systemic polyclonal disorders
• proliferation of morphologically benign lymphocytes, plasma cells and vessels
• reaction to excessive cytokine production, particularly IL-6
  * IL6 R is activated
• in HIV patients, MCD is always HHV8 related
  * in HIV - patients 50% of cases are associated with HHV8, but usually occur in endemic areas

Question 5

MCD is idiopathic in HHV8 negative, HIV negative patients, true or false ?

Answer 5

• true
• it is a systemic disease with constitutional symptoms, laboratory abnormalities, and multicentric lymphadenopathy
• there is polytypic plasmacytosis
• variably prominent hyper vascular or regressed germinal centers
• must exclude other etiologies to make this diagnosis
  * infection (other viruses), autoimmunity, paraneoplastic syndromes are all able to increase cytokines

Question 6

What is the epidemiology of HHV8 + MCD ?

Answer 6

• immunosuppressed, usually associated with HIV/AIDS or immunocompetent patients in HHV8 endemic areas
• in HIV there is a strong association with sexual transmission

Question 7

What is the etiology of MCD ?

Answer 7

• arises due to excessive cytokines, notably IL-6
• in HHV8 positive MCD the plasmablastic cells are infected with HHV8
  * these produce the IL6
  * note: HHV8 microRNA and proteins provide proliferative and anti-apoptotic signals
  (LANA1, LANA2, IL10, vFLIP, and miR-K1)
  * HHV8 also produces pro inflammatory and angiogenic factors and also constitutively activates
  The nuclear factor of activated T cells

Question 8

What is the localization of MCD ?

Answer 8

• usually there is extensive, generalized lymphadenopathy and splenomegaly

Question 9

What are the clinical features of MCD?

Answer 9

• patients are usually very sick, constitutional symptoms and splenomegaly
• Kaposi sarcoma is commonly also present
• often with have a skin rash
• Lab Findings
  * anemia, thrombocytopenia
  * hypoalbuminemia, hypergammaglobulinemia
  * elevated CRP