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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. CHL—How Many Distinct Entities?
  5. CHL in Nonimmunosuppressed Hosts
  6. CHL in Immunosuppressed Hosts
  7. Refractory CHL
  8. Conclusions
  9. References

Epidemiologic and molecular findings suggest that classical Hodgkin's lymphoma (CHL) is not a single disease but consists of more than one entity and may occur in different clinical settings. This review analyzes similarities and disparities among CHL entities arising in different host's conditions with respect to pathobiology parameters, therapeutic options, and outcome. For the purpose of this analysis, CHL entities have been subdivided according to the immune status of the host. In nonimmunosuppressed hosts, according to the age, CHL include pediatric, adult, and elderly forms, whereas, in immunosuppressed hosts, according to the type of immunosuppression, CHL include human immunodeficiency virus (HIV)-associated, iatrogenic, and post-transplant types. CHL entities in different settings are similar in morphology of neoplastic cells, expression of activation markers, and aberrations/activation of NFKB, JAK/STAT, and P13K/AKT pathways, but differ in the association with Epstein-Barr virus (EBV) infection, persistent B-cell phenotype, and cellular background composition. Large B-cell lymphomas resembling CHL may also be observed in the same clinical settings. These lesions, however, do not fulfill the diagnostic criteria of CHL and clinically display a very aggressive behavior. In this article, current treatment options for the CHL entities, especially for elderly CHL and HIV-associated CHL, are specifically reviewed. ABVD remains the gold standard both in nonimmunosuppressed or immunosuppressed hosts even if there are several data suggesting a possible improvement in outcome using the aggressive BEACOPP regimen in advanced stages. Refractory CHL, a clinical condition that may occur throughout the entire spectrum of CHL, is discussed separately. Am. J. Hematol., 2011. © 2010 Wiley-Liss, Inc.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. CHL—How Many Distinct Entities?
  5. CHL in Nonimmunosuppressed Hosts
  6. CHL in Immunosuppressed Hosts
  7. Refractory CHL
  8. Conclusions
  9. References

The present classification of Hodgkin's lymphoma (HL) is primarily based on the histopathologic and immunophenotypic characteristics of two distinct types of the disease, namely nodular lymphocyte predominance HL and classical HL (CHL). Furthermore, new epidemiologic and molecular findings suggest that CHL is not a single disease but consists of more than one entity. It may occur in different settings with distinct pathological and clinical characteristics [1]. According to the acknowledged international literature [1], CHL arises either in the general population [2] or in the immunosuppressed host, specifically in human immunodeficiency virus (HIV)-infected individuals [3], and in post-transplant patients, most often in renal post-transplant patients [4].

Intriguingly, cases with features intermediate between CHL and other lymphomas (the so called gray zone lymphomas) may also be observed. In this context, a provisional unclassifiable B-cell lymphoma category with intermediate features between diffuse large B-cell lymphoma and CHL (usually involving the mediastinum in young men) has been introduced in the World Health Organization (WHO) classification [1, 5]. Moreover, Hodgkin-like lesions have been recognized among iatrogenic immunodeficiency-associated lymphoproliferative disorders [4, 6].

This review may render easier the comprehension of clinical, molecular, and biological similarities and disparities among CHL entities arising in different host's conditions. The review provides a synopsis of the main characteristics of these disease entities, highlighting their special impact on diagnosis, treatment, and outcome. Current treatment options for elderly CHL and HIV-associated CHL are specifically reviewed. Large B-cell lymphomas with Hodgkin's features, the Hodgkin-like lesions, and the so-called refractory CHL are reported separately.

CHL—How Many Distinct Entities?

  1. Top of page
  2. Abstract
  3. Introduction
  4. CHL—How Many Distinct Entities?
  5. CHL in Nonimmunosuppressed Hosts
  6. CHL in Immunosuppressed Hosts
  7. Refractory CHL
  8. Conclusions
  9. References

Table I shows the spectrum of CHL entities according to the age groups and the kind of immunosuppression. Tables II and III highlight clinical, phenotypic, and genetic similarities and disparities between CHL arising in nonimmunosuppressed individuals and CHL arising in immunosuppressed hosts with respect to therapeutic options and outcome.

Table I. Classical Hodgkin's Lymphoma (CHL) in Different Host's Conditions
  • a,b,c Lymphomas with Hodgkin-like features that contain Reed–Sternberg-like cells but do not fulfill the criteria of CHL include

  • a

    “B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and CHL”;

  • b

    Large B-cell lymphoma “senile type”; and

  • c

    Hodgkin-like lesions.

Nonimmunosuppressed hosts
 Pediatric CHL
 Adult CHLa
 Elderly CHLb
Immunosuppressed hosts
 HIV-associated CHL
 CHL-type post-transplant lymphoproliferative disorderc
 Iatrogenic (immunosuppressive drugs) CHLc
Table II. Morphological and Molecular Features of Classical Hodgkin's Lymphoma (CHL) in Different Host's Conditions
CHL entitiesNonimmunosuppressed hostsImmunosuppressed hosts
Pediatric CHLAdult CHLElderly CHLHIV-associated CHLCHL-type PTLDIatrogenic (immunosuppressive drugs) CHL
  • a

    The ranges presented exclude series from South America, Africa, and some parts of Asia where much higher associations are consistently reported in adults and where, in children, the association may approach 100%.

  • b

    A high frequency of EBV association has been shown in CHL (80–100%) tissues from HIV-infected people [7]. An etiologic role of EBV in the pathogenesis of HIV-CHL is further supported by data showing that the EBV-transforming proteins, namely LMP1, is expressed in virtually all HIV-CHL cases [7–11].

  • c

    An increased number of small lymphocytes positive for TIA1 and/or granzyme B, accounting for >30% of background cells is observed.

  • d

    The HIV/AIDS-CHL microenvironment is characterized by inversion of the CD4+/CD8+ T-cell ratio, most likely as a consequence of CD4+ T-cell depletion induced by HIV in patients with severe immunosuppression [7].

  • DLBCL, diffuse large B-cell lymphoma; MC, mixed cellularity, NS, nodular sclerosis; (+), positive; (−), negative; ?, unknown.

Lymphomas with Hodgkin-like features  DLBCL/CHL [1, 5] “Senile type”   
HistologyAll CHL subtypesAll CHL subtypesDLBCL/CHL NSAll CHL subtypesDLBCL vs. CHLAggressive subtypesMC CHLMC CHL
PhenotypeCD30+, CD15+, CD20−/+CD30+, CD15+, CD20−/+CD30−/+, CD15−/+, CD20+, OCT2+, BOB1+, PAX5+CD30+, CD15+, CD20−/+CD20+, CD30+, CD15−CD30+, CD15+, CD20−/+, IRF4+, CD138+CD30+, CD15+, CD20−/+CD30+, CD15+, CD20−/+
EBV infection+ (30–40%)a+ (30%)a− or ++ (45–50%)+ (100%)+ (80–100%)b+ (100%)+ (100%)
EBV latency22222 or 3222
Activated pathwayEBV (LMP1), NFkB JAK/STAT, P13K/AKTEBV (LMP1), NFkB JAK/STAT, P13K/AKTEBV (LMP1), NFkB JAK/STAT, P13K/AKTEBV (LMP1), NFkB JAK/STAT, P13K/AKTEBV (LMP1)EBV (LMP1), NFkB JAK/STAT, P13K/AKTEBV (LMP1), NFkB JAK/STAT, P13K/AKTEBV (LMP1), NFkB JAK/STAT, P13K/AKT
Microenvironmental CD4 T-cellsAbundantAbundantVariablecAbundant?DepleteddDepletedDepleted
Table III. Comparison of the Clinical and Pathological Features of Classical Hodgkin's Lymphoma (CHL) in Different Host's Conditions
CHL entitiesNonimmunosuppressed hostsImmunosuppressed hosts
Pediatric CHLAdult CHLElderly CHLHIV-associated CHLCHL type PTLDIatrogenic (immunosuppressive drugs)
  1. DLBCL, diffuse large B-cell lymphoma.

Lymphomas with Hodgkin-like features  DLBCL/CHL [1, 5] “Senile type”   
M:F ratio2–3:11.3:12.5:11.2:11.4:16.6:19:18:2
Age, years≤1415–6032>6050–90358–1525–50
Stage I–II, %65–7060–7050–6040–4540–45305050
Stage III–IV, %30–3530–4040–5055–6055–60705050
Involvement
 LNFrequentFrequentFrequentFrequentRareFrequentFrequentFrequent
 MediastinalFrequentFrequentAlwaysRareRareRareRareRare
 AbdomenRareRareRareFrequentFrequentFrequentAlmost frequentAlmost frequent
 SpleenRareRareRareRareRareAlmost frequentRareRare
 BMRareRareRareFrequentRareFrequentRareRare
Elevated LDHRareRareFrequentRareFrequentFrequentRareRare
B-symptoms, %2540405050602525
Bulky diseaseFrequentFrequentAlwaysRareRareRareRareRare
Relapse after 2 years, %20–3020–4030–4020–3060–70406040
Outcome at 5 years, %949065–756525–305025–3040–50

CHL in Nonimmunosuppressed Hosts

  1. Top of page
  2. Abstract
  3. Introduction
  4. CHL—How Many Distinct Entities?
  5. CHL in Nonimmunosuppressed Hosts
  6. CHL in Immunosuppressed Hosts
  7. Refractory CHL
  8. Conclusions
  9. References

CHL, a monoclonal lymphoid neoplasm derived from B-cells, is composed of mononuclear Hodgkin's cells and multinucleated Reed–Sternberg (HRS) cells residing in an abundant cellular microenvironment. HRS cells consistently express CD30, CD40, and the plasma cell-specific transcription factor, interferon regulatory factor 4 (IRF4), [12–14] and express CD15 in the majority of cases. CD20 is positive in a minority of neoplastic cells in 30–40% of cases. Microenvironmental cell types include non-neoplastic B and T small lymphocytes, plasma cells, eosinophils, mast cells, histiocytes/macrophages, fibroblast-like cells, and interdigitating reticulum cells.

In the microenvironment of CHL, the CD4+ T-lymphocytes represent the majority of the reactive cell population. Several receptors that activate the classical NFkB pathway are expressed by HRS cells, and ligands for these receptors are frequently expressed on activated CD4+ T-cells and other bystander cells surrounding RS cells [12, 13]. In Epstein-Barr virus (EBV)-positive CHL cases, the EBV-encoded latent membrane protein 1 (LMP1) also contributes to NFkB activation because it mimics an activated CD40 receptor [7, 8, 15]. An abnormal network of cytokines and chemokines and/or their receptors in HRS cells is involved in the attraction of many of the microenvironmental cells into the lymphoma background. HRS cells produce remarkable amounts of cytokines and chemokines “directly” involved in microenvironment formation such as interleukin (IL)-5 [16], Rantes/CCL5 [17, 18], thymus- and activation-regulated chemokine (TARC)/CCL17 [19, 20], macrophage-derived chemoattractant (MDC)/CCL22 [19], CCL28 [21], and CCL20 [22].

Based on the characteristics of the reactive infiltrate, four histologic subtypes have been distinguished: lymphocyte-rich CHL (LRCHL), nodular sclerosis (NS) CHL, mixed cellularity (MC) CHL, and lymphocyte-depleted (LD) CHL [2]; LRCHL cases account for only a small fraction (3–5%) of all HL [23] and are characterized histologically by a small number of HRS cells expressing a CHL immunophenotype. Generally, in the different histological subtypes, the immunophenotypic and genetic features of mononuclear Hodgkin's cells and HRS cells are identical, whereas their association with EBV shows differences. Interestingly, EBV infection might also affect the microenvironment composition [16, 22, 24–26].

Pediatric CHL

Childhood CHL is defined as affecting those patients ≤14 years of age. It represents around 10% of all diagnosed CHL and typically shows a significant prevalence of male gender and MC (30–35%) in comparison with CHL in adolescent/young adults or adults [27, 28]. Approximately 40–50% of HL cases are associated with EBV in developed countries [29–32] (Table II).

Clinically, up to 35% of patients had advanced stages of disease at diagnosis and 25% B-symptoms [33]. Similarly to the clinical practice in adult CHL, there are several risk group stratification systems for pediatric CHL. The international prognostic score (IPS) widely used in adult patients has not been yet validated in pediatric setting, and different groups have established different risk categories (low, intermediate, or high risk) according to the extension of disease at presentation [34–36]. Current treatment strategies for pediatric HL involve combination chemotherapy followed by low-dose involved field radiotherapy (IFRT) to the lymph nodes initially involved. In general, most recent trials have intensified therapy in those patients with high-risk disease to improve disease control, and have limited therapy in those patients with low-risk disease to avoid secondary effects.

The standard treatment of Stage IA/IIA nonbulky pediatric CHL is two to four cycles of chemotherapy followed by 15–25 Gy IFRT. The possibility to reduce the amount of radiotherapy (RT) is demonstrated in patients who achieved a complete remission (CR) after a short course of chemotherapy, whereas patients in partial remission should continue to receive 25–30 Gy IFRT [36]. In fact, the results of large trials suggest that low-risk pediatric patients could be cured without the use of high-dose, extended-field radiation therapy (EFRT), known to have long-term side effects. However, all patients continue to receive radiation therapy and, even at doses of 15 Gy, are not completely spared the long-term toxicities associated with its use.

Currently, several trials are testing the possibility to avoid radiation therapy at all in low-risk patients. Preliminary data from several trials seem to support the hypothesis that radiation therapy may not be needed in Stage I patients, although the results are variable for Stage II patients [35, 37–40].

All pediatric protocols differ from most adult protocols by modifying chemotherapy exposure according to sex to minimize the gonadotoxic effects of alkylating agents on men. Several regimens have successfully eliminated the use of alkylating agents altogether for favorable risk disease. Within the German–Austrian group, different regimens have been used for women (OPPA) or men (OEPA) with a low toxicity profile and an EFS and an overall survival (OS) at 5 years of 94% and 99.6, respectively [41]. Moreover, the French group evaluated the results of chemotherapy regimens eliminating both alkylating agents and anthracycline. The results of this study demonstrated that chemotherapy can be limited in good responders without a decrement in cure rate [42].

As far as intermediate-risk patients, three large trials have demonstrated that combined modality treatment is the gold standard in this subgroup of patients. In particular, all studies showed a lower EFS for those patients who received chemotherapy alone in comparison with patients who received adjuvant IFRT after induction chemotherapy [35, 40, 43]. Again, an early response adapted strategy, in terms of reduced cycles of chemotherapy and omission or not of IFRT, is currently under investigation [44].

Similarly to adult patients, the treatment of high-risk patients is still a challenge. All studies using very aggressive chemotherapy regimens, including the classical MOPP/ABV, BEACOPP, or ABVD followed by IFRT showed a 5-year EFS ranging from 59% to 95% and an 5-year OS over 90%. The omission of IFRT is significantly associated with a worse outcome [35, 37–39, 42, 43, 45, 46] (Table III).

Adult CHL

Morphological, molecular features, and clinical features of CHL arising in adult patients are summarized in Tables II and III. Before the introduction of combining chemotherapy regimens, the survival of patients with CHL was poor, with only 10% of patients surviving at 5 years. Since the early 70s, the introduction of combined modality treatment has allowed a significant improvement of survival, and, up to now, more than 80–85% of patients diagnosed with CHL are alive at 5 years [47–49] even if the risk of treatment-related morbidity and mortality is still significant [50, 51], and modern therapies should attempt to maximize the chance of cure, while minimizing late toxicity.

Several prognostic and risk evaluation tools have been developed to stratify patients with early stages in different risk categories with the aim to adapt the intensity and duration both of chemotherapy and RT.

Up to now, four large randomized studies have definitively demonstrated the superiority of the combination of chemotherapy and RT over RT alone both in favorable and unfavorable early stages. Moreover, after three to four cycles of chemotherapy, an IFRT at 20 Gy can replace the more-toxic EFRT. ABVD remains the standard treatment in these patients. Patients with unfavorable early-stage disease should receive chemotherapy with four to six courses of ABVD followed by IFRT (30 Gy, with additional 6 Gy to the bulk) [52–58]. In an attempt to reduce long-term toxicity of these patients, four studies have evaluated the role of chemotherapy alone [59–62]. At present, data on the effectiveness of chemotherapy alone compared with combined modality treatment are not conclusive and do not allow to recommend this method outside of clinical trials.

The first chemotherapeutic regimen widely used to treat advanced disease was MOPP, with half patients cured but with significant long-term toxicity [63, 64]. After the evaluation of efficacy data of ABVD, several randomized trials have demonstrated the superiority of the latter scheme compared with MOPP [65, 66]. Subsequently, several studies that have evaluated the effectiveness of combined strategies MOPP/ABVD or alternating hybrids showed that ABVD is superior to MOPP and comparable to the hybrid or alternating patterns but with less toxicity [67–72].

Two randomized trials have demonstrated that the systematic use of IFRT after six to eight cycles of chemotherapy does not improve results and is, therefore, to be avoided in patients in CR at the end of chemotherapy [73, 74]. More controversial is the need to irradiate or not bulky areas (>10 cm) at presentation, although the preliminary results of a recent German trial suggest the possibility of avoiding this type of radiation [75].

The ABVD six to eight cycles followed by IFRT only on bulky masses must, therefore, be considered, in our opinion, the gold standard for advanced Stages IIB–IV. However, with regard to the role of radiation in advanced disease as well as in early-stage disease, there is not a broad consensus, at least in North America. It remains to define the role of BEACOPP that has not yet demonstrated a clear superiority over ABVD, although some randomized studies seem to show an advantage for this scheme in comparison with classical ABVD or hybrid regimens, though with a significantly higher toxicity [76–80].

There are no randomized trials on the optimal number of courses of chemotherapy in advanced disease. An American trial [70] demonstrated that six to eight courses of ABVD were equivalent to 12 courses of the alternating MOPP and ABVD regimens and indicated six to eight courses of ABVD as the standard amount of administered cycles. However, other European groups using BEACOPP consider that eight courses still remain the standard. A randomized comparison between six and eight courses has not been conducted. We believe that six cycles should not be considered the standard of care for all patients with advanced stage disease.

Finally, there is no role for early intensification in patients with poor prognosis. In fact, a study from European Bone Marrow Transplantation group showed that, after four cycles of ABVD, there is no difference between continuing the same pattern or step with high-dose chemotherapy (HDC) and peripheral stem cell rescue [79, 81].

In this setting, cases with features intermediate between CHL and other lymphomas (the so called gray zone lymphomas) have been recognized. We focus on large B-cell lymphomas with Hodgkin features: “B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and CHL” [1].

This is a newly recognized category that includes B-lineage lymphomas that demonstrate overlapping clinical, morphologic, and immunophenotypic features between CHL and DLBCL (Tables II and III) [5, 82]. These lymphomas have a gene expression profile that is intermediate between DLBCL and HL but closely resembles primary mediastinal large B-cell lymphoma (PMLBCL) [5].

Tumor cells, including larger cell, resembling HRS cells, express B-cell antigens namely, CD20 and CD79a, OCT2, BOB1, and Pax5, are expressed in conjunction with variable amounts of CD30 and CD15. Thus, many of these cases resemble CHL but have a large number of tumor cells expressing CD45, CD20, and B-cell transcription factors, in addition to diminished background inflammatory cells and sclerosis. Alternatively, cases may resemble PMLBCL morphologically but contain HRS cells and display an aberrant phenotype [82].

Clinically, B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and HL typically occurs in the mediastinum of young men between ages 20 and 40. They generally have a more aggressive clinical behavior and poorer outcome than either PMLBCL or CHL. Treatment is controversial. Importantly, the recognition of these lymphomas primarily as highly aggressive B-cell lymphomas [5] will result in a more uniform and appropriate approach to treatment. Some authors have proposed treating these cases as aggressive large B-cell lymphomas [83–85].

Elderly CHL

Despite the major advances in the treatment of CHL obtained in the last three decades, the prognosis of elderly patients remains poor. Several analyses showed worse outcome of patients with advanced HL aged 60 or more compared with younger patients, when similar treatments were given [86–92]. These different results can be explained, in part, with a more aggressive biology of the disease [86] and, in part, with the fact that aging itself and associated factors such as increased comorbidity [93], reduced tolerability of conventional therapy [94, 95], leading to more severe toxicity and treatment-related deaths [96] and poorer outcome after relapse (Table III).

It is generally accepted that elderly patients differ in clinical presentation from younger patients. In particular, elderly patients tend to have more advanced stages of disease, B-symptoms, elevated erythrocyte sedimentation rate, higher ECOG performance status, and less large mediastinal mass and bulky disease [86, 90, 97–99]. There are also fewer patients with intermediate clinical stages and more at the low and high ends. However, a suboptimal staging in elderly patients is more frequent than in younger patients, especially for marked variations of radiological standards, delay in computed tomography (CT) scanning, and lack of bone marrow assessments [99, 100].

As far as the treatment of elderly patients with CHL, different approaches have been used. The most important data in early stages come from German and Italian studies. In particular, the recent analysis of elderly patients with early unfavorable stage enrolled in the randomized GHSG H8 trial, compared with younger patients, demonstrated lower 5-year freedom from treatment failure (FFTF) and OS in elderly patients (FFTF 64% vs. 87%; P < 0.001 and OS 70% vs. 94%; P < 0.001). Moreover, elderly patients had poorer outcome when treated with extended field radiation compared with IFRT, 5-year FFTF (58% vs. 70%; P = 0.034), and OS (59% vs. 81%; P = 0.008). In addition, increased toxicity was also observed when receiving EFRT [101]. Moreover, in a Italian cooperative group, the specifically designed VEPEMB regimen [102] used in 48 patients leads to a CR rate of 98% and a 5-year failure-free survival (FFS) and OS of 79% and 94%, respectively.

In advanced stages, the standard regimens used in young patients (i.e., ABVD or BEACOPP) are often too much toxic, especially in patients older than 70 years. The introduction of anthracycline in the chemotherapeutic regimens for CHL has significantly improved the outcome of these patients, but, in elderly patients, the use is often limited because of comorbidities. Two large studies have compared anthracycline-containing regimens with those without anthracycline and confirm the superiority of anthracycline-based chemotherapy also in elderly patients [91, 103]. Elderly patients enrolled in the randomized H9 trial, carried out by the German Hodgkin Study Group, were planned to receive eight cycles of COPP/ABV or eight cycles of BEACOPP baseline, but only 69% of patients in the COPP/ABV arm and 55% in the BEACOPP arm were able to complete the treatment without delays or dose reduction. The CR was superimposable in both arms (76%) as the relapse rate, but more toxic deaths were observed in the BEACOPP arm (17% vs. 4%). The 5-year FFTF was 46% for both arms and disease-specific FFTF at 5 years was better for BEACOPP than for COPP/ABVD, 74% vs. 55% (P = 0.13), but the 5-year OS was similar in the two groups probably because of higher toxicity in the BEACOPP arm [104]. Because the high toxicity rate in elderly of the standard regimens generally used in advanced CHL in younger patients, several results of specifically designed schedules of treatment have been published. Within an Italian network, the mild aggressive CVP/CEB [95] and the VEPEMB [102] have been tested. The first regimens allowed a 73% of CR rate even if the 5-year event-free survival and OS were 32% and 55%, respectively; the latter regimen achieved a CR rate of 58% and an FFS and OS at 5 years of 34% and 32%, respectively. The Vancouver group used the ODBEP, but the results did not differ from that obtained with the classical MOPP/ABV [91].

In the last few years, a new tool is available for the evaluation of elderly patients with cancer: the comprehensive geriatric assessment including functional status, medical comorbidities, nutritional status, social and psychological status, medication requirement is able to stratify patients into three groups: fit patients suitable of standard treatment, unfit patient suitable of “tailored regimens” and frail patients suitable only of palliative care [105].

Large B-cell lymphomas with Hodgkin features have been recognized in elderly patients. In this context, we focus on the so-called “senile type”/“EBV-positive DLBCL of the elderly.” This is an EBV+ clonal B-cell lymphoid proliferation that occurs in patients >50 years and without any known immunodeficiency or prior lymphoma [106]. In Asian countries, EBV+ DLBCL of the elderly accounts for 8–10% of DLBCL [107, 108], whereas in Western countries they account for 0–5% [106] (Table II)

The so-called EBV+ DLBCL of the elderly have the morphology of common DLBCL, often with some Reed–Sternberg like cells; sometimes polymorphic. The neoplastic cells are usually positive for CD20+, except for plasmablastic cases. Expression of CD30, EBER, and LMP1 is detectable in >90% of cases. Clonality of the immunoglobulin genes and EBV can usually be detected by molecular techniques. The clinical course is aggressive, with a median survival of about 2 years [107–110] (Table III).

CHL in Immunosuppressed Hosts

  1. Top of page
  2. Abstract
  3. Introduction
  4. CHL—How Many Distinct Entities?
  5. CHL in Nonimmunosuppressed Hosts
  6. CHL in Immunosuppressed Hosts
  7. Refractory CHL
  8. Conclusions
  9. References

HIV-associated CHL

CHL represents the most common non-acquired immunodeficiency syndrome (AIDS) defining tumor diagnosed in patients with HIV infection, and the risk is significantly increased in all ages, with a risk relative to the general population ranging from 5- to 15-fold [111–114]. Moreover, a significant increase in the incidence of CHL in patients treated with highly active antiretroviral therapy (HAART) has been observed [115, 116].

HIV-HL exhibits pathological features that are different from those of HL in “general population” [9, 10]: HIV-HL is characterized by the predominance of unfavorable histological subtypes (MC and LD) [9, 10, 117]. Most HIV-related HL cases display the BCL6−/CD138+/IRF4+ phenotype, thus reflecting post-GC B-cells [7] (Table II).

One of the peculiar clinical features of HIV-CHL is the widespread extent of the disease at presentation and the frequency of systemic B-symptoms. At the time of diagnosis, 70–96% of the patients have B-symptoms, and 74–92% have advanced stages of disease with frequent involvement of extranodal sites, the most common being bone marrow (40–50%), liver (15–40%), and spleen (around 20%) (Table III) [117].

The widespread use of HAART has resulted in substantial improvement in the survival of patients with HIV infection and lymphomas because of the reduction of the incidence of opportunistic infections, the opportunity to allow more aggressive chemotherapy, and the less-aggressive presentation of lymphoma in patients in HAART compared with those lymphomas which arise in patients who never received HAART [118]. In fact, compared with patients who never received HAART, patients in HAART before the onset of CHL generally are older, have less B-symptoms, and a higher leukocyte and neutrophil counts and hemoglobin level [119].

Optimal therapy for HIV-CHL has not been defined yet. Because most patients have advanced stages of disease, they have been treated with combination chemotherapy regimens, but the CR rate remains lower than that of CHL in the general population, with the OS being approximately 1.5 years [117]. Because of the low incidence of the disease, no randomized controlled trials have been conducted in this setting. However, several Phase II studies have evaluated the feasibility and activity of different regimens. Before the introduction of HAART, patients were not able to tolerate standard treatment, and the use of low-intensity regimen (i.e., EVB or EBVP) leads to disappointing results in terms of CR rate (53–74%) and survival (around 30% at 3 years) [120, 121]. Similarly, the use of standard ABVD showed a 43% of CR rate and a median survival of 18 months [122]. The widespread use of HAART allows the use of more aggressive chemotherapeutic regimens generally used in CHL in HIV negative patients. Stanford V regimen, consisting of short-term chemotherapy (12 weeks) with adjuvant RT, was used in 59 consecutive patients within the framework of the European Intergroup Study HL-HIV. This regimen was well tolerated, and 69% of the patients completed treatment with no dose reduction or delayed chemotherapy administration. The most important dose-limiting side effects were bone marrow toxicity and neurotoxicity. Eighty-one percent of the patients achieved a CR, and, after a median follow-up of 17 months, 33 of 59 (56%) patients are alive and disease-free. The estimated 5-year OS was 59%, and the IPS [123] was the only prognostic factor significantly associated with survival. In particular, the percentage of survival at 3 years was 76% and 33% (P = 0.0004), respectively, for patients with IPS < 2 and >2 [124].

Within the German group, the very intensive BEACOPP regimen has been tested in 12 untreated patients with a 100% of CR rate but a high incidence of opportunistic infections [125]. Recently, the results of a large prospective Phase II study with ABVD plus HAART have been published. The scheduled six to eight ABVD cycles were completed in 82% of cases. Six patients died during induction, 54 (87%) achieved a CR, and 2 were resistant, and the estimated 5-year OS was 76%. Interestingly, the immunological response to HAART had a positive impact on OS (P = 0.002) and event-free survival (P = 0.001) [126]. Finally, within the GICAT, we have recently concluded the accrual of 71 patients in a prospective Phase II study aiming to evaluate the feasibility and activity of a novel regimen including epirubicin, bleomycin, vinorelbine, cyclophosphamide, and prednisone (VEBEP regimen). Seventy percent of patients had advanced stages of disease, and 45% had an IPS > 2. The CR rate was 67%, and 2-year OS, disease-free survival, time to treatment failure, and event-free survival were 69, 86, 59, and 52%, respectively [127].

Because a large proportion of HIV-CHL progresses and relapses, the use of HDC and autologous stem cell transplantation (ASCT) has been tested in this setting. Several data from different groups have demonstrated the feasibility of this approach, which can be considered the gold standard in the salvage setting [128–130].

CHL-type post-transplant lymphoproliferative disorder

Post-transplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of monoclonal or polyclonal lymphoproliferative lesions that occur in immunosuppressed recipients after solid-organ or bone marrow transplantation [131, 132].

CHL occurs in the post-transplant setting, most often in renal transplant patients, is almost always EBV-positive and should fulfill the diagnostic criteria for CHL (see above) [4, 133–135].

Because RS-like cells may be seen in other PTLDs, the diagnosis of HL must be based on both classical morphologic and immunophenotypic features, preferably including both CD15 and CD30 expression [135] (Table II). In Hodgkin-like lesions, the EBV+ RS-like cells are CD45+, CD15−, and CD20+. Small and intermediate-sized EBV+ lymphoid cells are also present [4]. The distinction of Hodgkin-like PTLD from true Hodgkin-type PTLD may be difficult, although the Hodgkin-like PTLD are better characterized as either a polymorphic or monomorphic PTLD.

Clinically, the majority of patients are men and all ages are affected. All patients received post-transplant immunosuppression, which variably included cyclosporine, tacrolimus (FK506), and/or mycophenolate mofetil, even if some cases in patients receiving methotrexate, additional prednisone, and/or antiviral agents such as acyclovir and gancyclovir have been reported [136–141].

Generally, the time from transplant to the onset of the disease ranges from few months (4–6 months) to several years, with a median time of 113 months, significantly longer than that of classical B-cell PTLDs. Half cases presented as extranodal masses, especially in the liver or in the lung even if other extranodal sites (especially tonsil) can be involved.

The best therapeutic approach is not well defined yet. The majority of patients are initially managed by reduction and/or withdrawal of immunosuppression, but it is very difficult to achieve a good balance between the need to reduce the immunosuppression and the need to continue to avoid transplant rejection. The clinical course is generally very aggressive, and the outcome remains poor (Table III). The use of chemotherapy is limited by the clinical condition of patients, and the response rate is generally lower than that observed in all other forms of c-HL. Recently, rituximab has also gained favor in the treatment of PTLD because of its targeting of CD20-positive B cells, with fairly promising results [142], but, although some patients with HL-like PTLD have responded to therapy, a significant improvement in the outcome has not been observed.

Iatrogenic CHL

The iatrogenic lymphoproliferative disorders are lymphoid proliferations or lymphomas that arise in patients treated with immunosuppressive drugs [6, 143]. They comprise a spectrum ranging from polymorphic proliferations to cases that fulfill the criteria for large B-cell or T/NK-cell lymphomas or CHL. Methotrexate was the first reported immunosuppressive agent associated with lymphoproliferative disorders [144]. In this setting, EBV is detected more frequently in CHL (80%) than in DLBCL (about 25%) (Table III). Among iatrogenic lymphoproliferative disorders, other than PTLD, there is an increase in frequency of CHL and lymphoid proliferations with Hodgkin-like features. Thus, lesions containing RS-like cells but do not fulfill the criteria of CHL, the so-called Hodgkin-like lesions, have been included in this setting [6].

Because CHL has only recently been recognized as an iatrogenic complication, few cases have been reported in the medical literature [6]. The effective therapeutic approach is not well defined yet.

Refractory CHL

  1. Top of page
  2. Abstract
  3. Introduction
  4. CHL—How Many Distinct Entities?
  5. CHL in Nonimmunosuppressed Hosts
  6. CHL in Immunosuppressed Hosts
  7. Refractory CHL
  8. Conclusions
  9. References

There are a fraction of patients (20–25% with advanced stage disease) not responding to first-line chemotherapy, or progressed during treatment or relapsed within 3 months after the first-line therapy who are defined as refractory [145, 146]. Many of these patients have a poor OS and may die as result of their disease. The choice of the best salvage approach should rely on the evaluation of prognostic factors and clinical characteristics of patients.

To date, there is no consensus on biological markers that add value to usual parameters (which comprise the IPS) used at diagnosis to predict outcome [147–152]. The prognostic significance of CD20 expression in CHL is controversial and a matter of ongoing debate [147–151]. Indeed, some studies found no significant association between CD20 expression in HRS cells and the outcome of CHL [148, 150], whereas others reported a worse clinical outcome in CD20-positive patients [149, 151]. A recent retrospective study of 59 patients presenting either a refractory and early relapse CHL or a responding disease provided evidence that new immunohistochemical markers might predict the response to treatment of CHL based both on features of tumoral cells and on microenvironment [152]. This study revealed that in refractory CHL, HRS cells present at diagnosis an overexpression of BCL2 marker and a frequent absence of CD20 expression and that there is an excess of cytotoxic TiA1+ and ckit-positive mast cells in the microenvironment. These markers could help to predict at diagnosis the treatment response of patients with CHL [152]. However, it is likely insufficient to determine whether the immunohistochemical markers are independent of known clinical factors.

Two randomized trials and a series of prospective or retrospective studies have evaluated the results obtained in patients with refractory disease, who have attained at least a partial response after salvage therapy. All studies showed that, after a debulking chemotherapy, an intensification with HDC significantly improves the outcome of patients, with more than 60% of patients with chemosensitive disease alive and disease free at 5 years and a transplant-related mortality less than 5% [153, 154]. However, patients with primary refractory disease still showed a worse prognosis, with only 30% of patients surviving at 5 years.

Some studies have highlighted several prognostic factors for patients with chemosensitive disease that affect the rescue after HDC and results that could guide a more rational therapeutic strategy. Among the prognostic factors, sensitivity to salvage therapy remains the strongest in terms of survival [155].

In patients with early relapse or resistant to up-front therapy, the role of conventional dose chemotherapy as salvage therapy is twofold: to achieve a maximum tumor reduction before HDC, and to efficiently mobilize progenitor cells into peripheral blood (PBPC) for subsequent autologous rescue. Conventional dose chemotherapy can also be used in patients who are not candidates for HDC because of age and/or poor performance status. Several regimens of different intensity and toxicity have been developed; the more widely used include DHAP, ICE, and IGEV [156–158]. However, up to now, no randomized studies are available comparing the relative efficacy of these different regimens.

Taking into consideration all published studies, HDC followed by autologous stem-cell transplantation can be considered in adult and pediatric patients as the gold standard for refractory CHL. Recently, data suggest the feasibility and activity of this procedure also in HIV patients where it can be considered the standard approach for refractory or relapsed patients [130, 159].

Allogeneic HDC was first explored in selected individuals with advanced CHL and proved that some patients, who had failed many lines of therapy, did survive long term [160, 161]. All studies reported an OS at 5 years of 44%, a progression-free survival of 20%, a relapse rate of 57%, and a treatment-related mortality of 52% [160–163]. Recently, the development of reduced intensity conditioning regimens (RIC) provided a new opportunity to use allo HDC. Overall, the results showed a significantly lower toxicity in comparison with myeloablative transplant, with a 10% improvement in progression-free survival and OS [164–167]. At the present time, RIC is indicated in those patients in good clinical conditions who relapsed after autologous transplant.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. CHL—How Many Distinct Entities?
  5. CHL in Nonimmunosuppressed Hosts
  6. CHL in Immunosuppressed Hosts
  7. Refractory CHL
  8. Conclusions
  9. References

CHL in nonimmunosuppressed individuals and CHL in immunosuppressed hosts are similar in morphology of neoplastic cells, expression of activation markers such as CD30 and CD15, and aberrations/activation of NFKB pathway, but differ in the strict association with EBV infection, persistent B-cell phenotype, and slightly CD4-depleted cellular background composition in CHL in immunosuppressed hosts (Table II).

ABVD remains the gold standard both in nonimmunosuppressed or immunosuppressed hosts even if there are several data suggesting a possible improvement in outcome using the aggressive BEACOPP regimen in advanced stages. In the next few years, the ongoing studies will help us to optimize the integration of chemotherapy and RT to ameliorate the cure rate, minimizing the long-term toxicity. In particular, the early biological response, assessed with positron emission tomography (PET) scan, allowed us to reduce the amount of treatment in responder patients and to early intensify the treatment in non- or slow-responding patients. Finally, the widespread use of CGA will improve the approach and outcome of elderly patients with CHL, whereas the best integration of chemotherapy and antiretroviral therapy will increase the number of HIV patients who can be cured from CHL.

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  1. Top of page
  2. Abstract
  3. Introduction
  4. CHL—How Many Distinct Entities?
  5. CHL in Nonimmunosuppressed Hosts
  6. CHL in Immunosuppressed Hosts
  7. Refractory CHL
  8. Conclusions
  9. References
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