Classical Hodgkin lymphoma

2016-04-01   Annunziata Gloghini , Antonino Carbone 

1.Department of Pathology Centro di Riferimento Oncologico Aviano (CRO), Istituto Nazionale Tumori, IRCCS, Aviano, Italy; acarbone@cro.it (AC); Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy; annunziata.gloghini@istitutotumori.mi.it (AG)
2.Department of Pathology Centro di Riferimento Oncologico Aviano (CRO), Istituto Nazionale Tumori, IRCCS, Aviano, Italy; acarbone@cro.it (AC); Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy; annunziata.gloghini@istitutotumori.mi.it (AG)

Abstract

Hodgkin lymphoma (HL) was one of the earliest cancers to be cured with multiagent chemotherapy even before its biology was understood.

Clinics and Pathology

Disease

Hodgkin lymphoma(HL) has been classified into classical HL (cHL), which accounts for 95% of all HL cases, and the less common nodular lymphocyte predominant HL (NLPHL), which is considered to be a separate entity (Stein et al., 2008; Poppema et al., 2008).
Classical HL is a distinct neoplastic entity with typical clinical, epidemiological, pathological, genetic, and virological features. It accounts for approximately 10% of all malignant lymphomas.

Phenotype stem cell origin

CELL ORIGIN
Hodgkin and Reed-Sternberg (HRS) cells, the tumour cells of cHL, derive from preapoptotic crippled germinal center (GC) B cells. In fact, molecular features of HRS cells in cHL demonstrate that they are derived from GC B cells that have acquired disadvantageous immunoglobulin variable chain gene mutations and normally would have undergone apoptosis (Kuppers et al., 2012).
As shown in gene expression profiling (GEP) studies, HRS cells have lost the expression of most B-cell genes and acquired expression of genes that are typical for other types of immune cells (Greaves and Gribben 2012; Steidl et al. 2012; Tiacci et al., 2012).
PHENOTYPE
Phenotypically, HRS cells of cHL are consistently positive for CD30, CD15, CD40, and IRF4/MUM1 (Stein et al., 2008).
Expression of molecular markers in cHL include (Younes et al., 2014)
- B-cell markers (CD20 and CD79) usually negative
- GC B-cell markers (BCL6 and AID) usually negative
- Plasma cell markers (MUM1/IRF4) usually positive
- Molecules involved in Ag presentation (MHC class II, CD40, CD80, CD86) positive
A surfaceoma study by TMA analysis indicated that gamma-glutamyltranspeptidase 1 is a potential additional marker for differential diagnosis of cHL versus non Hodgkin lymphoma (Hofmann et al., 2015).
Cellular components of the cHL microenvironment express molecules involved in cancer cell growth and survival (such as CD30L or CD40L), and in immune escape (programmed death 1 (PD-1). For example, CD30L+ eosinophils and mast cells, and proliferation-inducing ligand (APRIL)+ neutrophils, are consistently admixed to HRS cells, whereas CD40L-expressing CD4+ T lymphocytes rosette HRS cells. A fraction of infiltrating CD4+ T cells are regulatory T (Treg) cells. Treg cells and PD-1+ T cells also interact with HRS cells (Aldinucci et al., 2010; Liu et al., 2014; Carbone et al., 2015).

Epidemiology

Classical HL is the most common cancer in patients under 20 years (adolescents and younger adults). The first peak of incidence can be observed in patients under 35 years of age, whereas a second incidence peak can be observed in the elderly (Hjalgrim et al, 2008; Stein et al., 2008).
Atlas Image
Figure 1. A multinucleated giant cell, the so called Reed-Sternberg cell.
Atlas Image
Figure 2. Mononucleated giant cells, the so called Hodgkin cells.

Cytology

Binucleated and multinucleated HRS cells are giant cells wirh bi- or multinucleation and huge nucleoli. These cells and their mononuclear variant, the so-called Hodgkin cells, are pathognomonic for cHL identification.

Pathology

HRS cells reside in an inflammatory cell microenvironment.
Based on the characteristics of the HRS cells (lacunar cells, multinucleated giant cells, pseudosarcomatous cells) and of the reactive infiltrate, four histologic subtypes have been distinguished: lymphocyte-rich cHL (LRCHL) , nodular sclerosis (NS) cHL , mixed cellularity (MC) cHL , and lymphocyte depletion (LD) cHL . Most cHL can be classified as NS or MC subtypes. The remaining LRCHL and LD subtypes are uncommon. LRCHL cases display histological and clinical features intermediate between those of cHL and NLPHL (Poppema et al., 2008; Stein et al., 2008; Swerdlow et al., 2016).
In cHL, microenvironmental cell types include T- and B-reactive lymphocytes, eosinophils, granulocytes, histiocytes/macrophages, plasma cells, mast cells. In addition, a great number of fibroblast-like cells and fibrosis are frequently found (Aldinucci et al., 2010).
Atlas Image
Figure 3. The schema shows a Reed-Sternberg within its cell microenvironment.

Other features

EBV infection
The immunophenotypic and genetic features of HRS cells are identical in the different histologic subtypes of cHL. Conversely, the association with EBV shows differences. EBV is found in HRS cells preferentially in cases of MC and LD cHL, and less frequently in NS and LRCHL. Notably, EBV is found in HRS cells in nearly all cases of cHL occurring in patients infected with HIV (Younes et al., 2014; Dolcetti et al., 2016).
The virologic characteristics of cHL vary according to the immunocompetence status of the host and cHL subtype (IARC, 2012) 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

Treatment

Cure rates approaching 80% have been achieved in patients undergoing chemo-radiotherapy, qualifying cHL as a chemosensitive disease (Santoro et al., 1987, Canellos et al., 2014) . However, 25% to 30% of these patients show either primary refractoriness to chemotherapy, early disease relapse or late disease relapse (Canellos et al., 2014; Carbone et al., 2015).

Prognosis

The implementation of novel agents for the treatment of multi-relapsed cHL patients has improved the outcome of these patients and will significantly impact the history of multi-relapsed cHL in the near future when the results of combination studies become available. For example, the synergistic effect of Dehydroxymethylepoxyquinomicin (DHMEQ) with three chemotherapeutic drugs widely used in cHL treatment, doxorubicin, gemcitabine and cisplatin, has recently been demonstrated (Locatelli et al., 2014).

Note

Recurrent genetic alterations have been identified in HRS cells of cHL. These lesions affecting members of the NF-kappaB or JAK/STAT signalling pathways include inactivating mutation in NFKBIA (10-20% of cases), NFKBIE (10%), TNFAIP3 (40%), SOCS1 (40%), genomic gains of RELA (30%) and JAK2 (30%) and rare BCL3 translocations. TNFAIP3 mutations are found in Epstein-Barr virus-negative cases of cHL. Mutations have been found in the tumour suppressor genes FAS (CD95) and TP53. Further genomic imbalances, identified by comparative genomic hybridization studies include gains of IKBKB, CD40 and MAP3K14 that are regulators of NF-kappaB signaling (Küppers and Re, 2007; Hartmann et al., 2008; Steidl et al., 2010; Küppers 2011; Küppers et al., 2012; Pasqualucci and Dalla Favera, 2014).Interestingly, HRS cells show aberrant somatic hypermutation of several proto-oncogenes (PIM1, RHOH (TTF), MYC, PAX5) in a considerable fraction of cases (Küppers et al., 2012; Pasqualucci and Dalla Favera, 2014).

Bibliography

Pubmed IDLast YearTitleAuthors
205270192010The classical Hodgkin's lymphoma microenvironment and its role in promoting tumour growth and immune escape.Aldinucci D et al
96783291998Cytogenetics of Hodgkin's disease.Atkin NB et al
244415262014Treatment of Hodgkin lymphoma: a 50-year perspective.Canellos GP et al
259536222015Primary refractory and early-relapsed Hodgkin's lymphoma: strategies for therapeutic targeting based on the tumour microenvironment.Carbone A et al
267730452016A lymphomagenic role for HIV beyond immune suppression?Dolcetti R et al
231975792012Lymphoid neoplasia. Laser-capturing the essence of Hodgkin lymphoma.Greaves P et al
186410272008Detection of genomic imbalances in microdissected Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma by array-based comparative genomic hybridization.Hartmann S et al
190171782008Infectious aetiology of Hodgkin and non-Hodgkin lymphomas: a review of the epidemiological evidence.Hjalgrim H et al
260764412015Surfaceome of classical Hodgkin and non-Hodgkin lymphoma.Hofmann A et al
97133401998Chromosomal abnormalities in Hodgkin's disease are not restricted to Hodgkin/Reed-Sternberg cells.Jansen MP et al
230237152012Hodgkin lymphoma.Küppers R et al
238673032014The microenvironment in classical Hodgkin lymphoma: an actively shaped and essential tumor component.Liu Y et al
245615192014BIM upregulation and ROS-dependent necroptosis mediate the antitumor effects of the HDACi Givinostat and Sorafenib in Hodgkin lymphoma cell line xenografts.Locatelli SL et al
24334091987Long-term results of combined chemotherapy-radiotherapy approach in Hodgkin's disease: superiority of ABVD plus radiotherapy versus MOPP plus radiotherapy.Santoro A et al
193806392009TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma.Schmitz R et al
214830012011Molecular pathogenesis of Hodgkin's lymphoma: increasing evidence of the importance of the microenvironment.Steidl C et al
229559182012Gene expression profiling of microdissected Hodgkin Reed-Sternberg cells correlates with treatment outcome in classical Hodgkin lymphoma.Steidl C et al
203390892010Genome-wide copy number analysis of Hodgkin Reed-Sternberg cells identifies recurrent imbalances with correlations to treatment outcome.Steidl C et al
269807272016The 2016 revision of the World Health Organization classification of lymphoid neoplasms.Swerdlow SH et al
229559142012Analyzing primary Hodgkin and Reed-Sternberg cells to capture the molecular and cellular pathogenesis of classical Hodgkin lymphoma.Tiacci E et al

Citation

Annunziata Gloghini ; Antonino Carbone

Classical Hodgkin lymphoma

Atlas Genet Cytogenet Oncol Haematol. 2016-04-01

Online version: http://atlasgeneticsoncology.org/haematological/1569/classical-hodgkin-lymphoma

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