Hodgkin Lymphoma (HL) includes classical Hodgkin lymphoma (CHL) which accounts for 95% of all cases (Stein et al. 2008). Lymphocyte depletion classical Hodgkin lymphoma (LDCHL) is the less common subtype of cHL (Benharroch et al., 2008). LDCHL is a subtype of cHL rich in Hodgkin and Reed-Sternberg (HRS) cells. These cells reside within a background depleted in non-neoplastic lymphocytes. In the past few decades, a fraction of these cases have been reclassified into different non-Hodgkin lymphoma entities (Benharroch et al., 2008).

LDCHL involves a clonal expansion of germinal center B-cell derived lymphocytes which mimic those observed in the other subtypes of cHL.

LDCHL accounts for only a small fraction, less than 1%, of all HL cases in Western countries. There is a male predominance. The median age ranges from 30 to 40 years. LDCHL is often seen in people infected with HIV and more often in developing countries (IARC, 2012).
People with HIV/AIDS are at increased risk of HL in the highly active antiretroviral therapy era. In HIV-infected people cHL is presently the most common non-AIDS defining cancer (Carbone et al., 2014).

Patients affected by LDCHL present with an advanced stage (III-IV stage) and with B symptoms more often than those affected by the other subtypes. LDCHL usually involves retroperitoneal lymph-nodes and extranodal sites including abdominal organs and bone-marrow (Younes et al., 2014).

A consistent feature is the predominance of HRS cells in relation to the cell density of the background. The HRS cells are pleomorphic with a sarcomatous appearance. A proportion of HRS cells may resemble anaplastic forms of tumour cells observed in some large cell non-Hodgkin lymphoma. The background is characterized by diffuse fibrosis and depletion in reactive lymphocytes.
Phenotype
The HRS cells show the same immunophenotype as in the other subtypes of CHL (Carbone and Gloghini, 2016); the immunophenotype is the following:
CD30+
CD15 usually+
MUM1/IRF4+
PAX5 usually+
CD20-/+

Virology
Tumour tissue is characterized by an unusual large proportion of HRS cells infected by EBV. EBV is found in nearly all cases of LDCHL occurring in patients infected by HIV. EBV infected tumour cells contain LMP1 which can activate critical signaling pathways including NF-kB.
It seems appropriate to mention here that the virologic characteristics of HL vary according to the immunocompetence status of the host and cHL subtype (IARC, 2012; Swerdlow et al., 2008) as follows:
cHL of the general population
- NS cHL, usually EBV negative
- MC cHL, usually EBV positive
- LRCHL, variably EBV positive
- LD cHL, variably EBV positive
Immunodeficiency-associated cHL
- HIV-associated cHL, EBV positive
- Post-transplant cHL, EBV positive
- Iatrogenic (methotrexate), variaby EBV positive
Etiology
LMP1 expression is observed in virtually all HIV associated LDCHL cases: it suggests that EBV play an etiological role in the pathogenesis of these tumours.
Cell microenvironment
HRS cells are usually seen in a microenvironment where several histiocytoid cells are admixed with few small lymphocytes. These lymphocytes predominantly express the CD3+, CD4+, CD8-/+, CD20- phenotype.
It has been recognized that EBV has the capability to modulate the tumour microenvironment (Dolcetti, 2015; Dolcetti et al., 2016).

The combination of cART with better supportive therapy has made standard ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), used for LDCHL occurring in the general population, feasible in patients with HIV-associated Hodgkin lymphoma (Carbone et al., 2014).

Most patients affected by LDCHL have a worse prognosis than do patients affected by other cHL subtypes (Younes et al., 2012).
Poor prognosis have been observed in patients affected by HIV-associated LDCHL. The outcome of HIV-associated cHL has dramatically improved since the introduction of cART with intensive chemotherapy regimens (Carbone et al., 2014).

Due to the small number of LDCHL cases analysed for genetics/cytogenetics characteristics and to the reclassification of cases into different lymphoma categories, the previously described genetics and cytogenetics findings are not unquestionably acknowledged.