Table of contents :

Epidemiology Aetiology Pathogenesis Symptoms & signs Laboratory examinations Differential diagnosis Therapy  Prognosis Web resources

Epidemiology : 1% of all malignant tumors of adults; 25% of all lymphomas; incidence : 3 new cases every 100,000/yr. It affects twice as many males as females and has onset at age 20-30 or > 55. Whereas the incidence of NHL has been rising since World War II, the incidence of HL has been flat. 2 age-incidence peaks have long been recognized in North America and Western Europe: young adult and older adult. In developing countries and in parts of Asia, the young adult peak is much less prominent or even absent. Several epidemiologic studies suggested an association with small family size and other factors that might result in delayed exposure to common viral infections.
Aetiology : HL can be divided into 4 entities on the basis of EBV status and age at presentation, with 3 groups of EBV-associated cases and a single group of EBV^-. The aetiology of the latter cases is obscure although involvement of an infectious agent(s) is suspected^ref.

• 35% of tumor clones have HHV-4 / EBV genome in their chromosomes (40–60% in most industrialized countries, depending on their histology) genome and antigens in the Reed-Sternberg and Hodgkin's cells^ref : a causal association between infectious mononucleosis–related EBV infection and the EBV⁺ subgroup of HD is likely in young adults. Only serologically confirmed infectious mononucleosis was associated with a persistently increased risk of HL. 55% of tumors obtained from patients with infectious mononucleosis had evidence of EBV. There was no evidence of an increased risk of EBV-negative HD after infectious mononucleosis. In contrast, the risk of EBV⁺ HD was significantly increased (RR = 4.0). The estimated median incubation time from mononucleosis to EBV⁺ HD was 4.1 years (IC₉₅ = 1.8-8.3)^ref. Patients with EBV-associated HL also show increased levels of EBV-infected B-lymphocytes in blood compared with normal individuals and non-EBV-associated HL cases^ref. With effective combined treatment modalities in pediatric HL, latent EBV infection has no influence on FFS but is associated with an inferior overall survival in crucial subgroups^ref. Delayed exposure to EBV is a risk factor for the development of EBV-associated HL in young adults^ref. EBV may play a role in the pathogenesis of HD by the activation of anti-apoptotic factors in a premalignant germinal center B-lymphocyte. Regardless of their role in etiology or pathogenesis, EBV-latent antigens may represent a target for possible immune therapy. Areas within the HLA class I and class III regions are associated with susceptibility to HD, the association with class I being specific for EBV⁺ disease. This finding strongly suggests that antigenic presentation of EBV-derived peptides is involved in the pathogenesis of EBV⁺ HD^ref. Serologic studies have suggested modestly higher titers to EBV antigens in patients with HD than in controls, but the differences in titers have been modest. EBV is a ubiquitous virus and the vast majority of HD patients (and adults) are EBV seropositive. EBV nucleic acids and proteins have been identified in the tumor cells in a subset of patients. Approximately 30% of HL in the USA and North America harbor these nucleic acids and proteins, while much higher percentages of tumor cells show evidence of virus in some developing countries (approaching 100% in parts of Latin America, Africa and Asia)^ref. Formal guidelines for interpretation and comparisons of methods for detecting virus in fixed tissues have recently been published^{ref1, ref2}.


With some well-documented exceptions EBV is present in each of the tumor cells in a particular patient at all sites of disease, at presentation and at relapse. Aspects of the relationship between cases associated with the syndrome of infectious mononucleosis and tumors harboring virus have been problematic. On the one hand, those regions of the world in which HL is most consistently associated with EBV are those regions in which the syndrome of infectious mononucleosis is least common. On the other hand, regions in which infectious mononucleosis is most common have been those regions where the presence of EBV in tumor is least common. The questions that emerge are:
• is EBV only associated with HL that harbors the genome, or is the virus also associated with lymphoma in which the genome cannot be detected?
• is infectious mononucleosis associated with all HL or only with those cases in which viral gene expression can be demonstrated in tumor cells?
An association with HL that does not harbor the genome is not implausible. EBV infection of a lymphocyte might initiate tumorigenesis, perhaps leading to genetic instability or other change that ultimately renders the viral genome superfluous to the maintenance of the malignant state. Evidence has very recently been presented that EBV upregulates expression of activation-induced deaminase, the enzyme responsible for somatic hypermutation in germinal center B cells^ref. EBV need not leave any viral genetic sequences behind as a footprint. In contrast with tumor viruses whose DNA integrates into host cell DNA, loss of EBV episomes from malignancies in tissue culture is well documented in EBV tumor cell lines^ref. Some of these questions were answered in part by a population-based analysis of acute infectious mononucleosis and malignancy in Denmark and Sweden^ref. The relative risk of EBV⁺ HL was increased fourfold in patients with serologically confirmed infectious mononucleosis. There was no increase in the relative risk of EBV^- HL. The median estimated time interval from the diagnosis of mononucleosis to EBV⁺ HL was approximately 4 years. Thus infectious mononucleosis is clearly linked to EBV⁺ HL and there is no evidence to suggest that it is linked to EBV^- HL. Nonetheless, it should be noted that most patients with HL have no history of documented infectious mononucleosis. Indeed, almost nothing is known of the determinants of symptomatic primary EBV infection except for evidence that infection in young adults is more likely to be symptomatic than in children. These answers are, however, still incomplete. Why EBV-associated HL accounts for highest percentage of HL in those regions where infectious mononucleosis is least common is unresolved. Similarly, there are paradoxes in terms of the association with patient age. At the extremes, children under 10 years of age and adults over the age of 70, virtually all cases are EBV-associated. However, infectious mononucleosis is most commonly associated with primary infection in the teenage or early adult years. The EBV LMP1 has been recognized as a likely contributor to tumorigenesis. Expression of the protein is transforming in immortalized murine cell lines and leads to lymphoma when expressed in B cells in a transgenic model^ref. The protein is a member of the TNFR superfamily and most closely resembles CD40. However, in contrast to CD40, LMP1 signaling is constitutively active and requires no ligand. Among the multitude of activities of LMP1, it activates NF-kB by promoting the turnover of IkBa. LMP2A also seems likely to play an important role. As noted above the tumor cells of HL do not express immunoglobulin genes. B cells that lack functional Ig would be expected to die by apoptotic mechanisms as has clearly been shown in transgenic mouse models. However, LMP2A has been shown to provide a tonic signal that mimics that associated with immunoglobulin expression so as to prevent apoptosis of such cells—at least in a murine model^ref. The role of this viral protein in preventing apoptosis in tumor cells suggests the possibility that related pathways may be targeted by small molecules for therapeutic purposes^ref. Posttransplant lymphoma and nasopharyngeal carcinoma are both EBV-associated malignancies in which monitoring of viral genome copy number in peripheral blood mononuclear cells or plasma has proven to be useful diagnostically and prognostically. In particular, plasma levels of viral DNA have been shown to be very important prognostically in nasopharyngeal carcinoma^{ref1, ref2}. Failure to clear viral DNA with therapy is indicative of early progression or relapse. Studies to determine whether EBV DNA in PBMC or plasma is similarly useful in HL are underway in the oncology cooperative groups. Viral antigens expressed in HL are commonly recognized by CD8 T cells^{ref1, ref2}. The antigens are generally not mutated in HL^ref. Most EBV-associated HL express class I MHC antigens and studies of cell lines suggest that the antigen-processing machinery is intact. Studies using adoptive cellular immunotherapy approaches have been initiated with limited success to date^ref. However, improved targeting of the T cell lines to antigens such as LMP2A actually expressed in HL holds promise as may therapeutic vaccine strategies. Is classical HL one entity or several entities? Many investigators have argued in favor of 2 or 3 "disease" models.
• EBV^- HD (40-60%) : besides the "hit and run" mechanism of EBV the etiologic role of other viruses is assumed. Hitherto unknown virus may be responsible for the peak incidence in young adults, which is a feature of HD in developed countries^ref.
• HCV (RR = 12^ref)
• HGV (RR = 1^ref-1.5^ref-10^ref)
• HIV-infected patients have higher incidence of HL^ref. In contrast to NHLs that are "AIDS-defining" malignancies, the increased incidence of HL is more subtle. The increased risk of BL and brain lymphoma in AIDS patients is hundreds- or thousands-fold, whereas the increased incidence of HL in AIDS is approximately 3- to 10-fold. A recent population-based study of HIV-HL in the San Francisco Bay area showed that 90% of HLs in HIV patients were EBV⁺, that nodular sclerosis histology was only half as common among HIV-infected patients as in the general population, and that lymphocyte-depleted disease was much more common^ref. HIV patients were also more likely to have advanced-stage disease. Whether the contribution of HIV to Hodgkin’s lymphomagenesis is simply related to generic immunodeficiency or reflects some more specific contribution of particular HIV proteins or HIV-induced immune dysregulation is not clear. However, it is worth bearing in mind that the CD4 T cell count in HIV HL is typically much higher than that in some other EBV-associated malignancies in HIV patients, such as brain lymphoma. Interesting evidence regarding measles has also been presented^ref.
• measles virus (MV) especially in young adults^ref : there was an increased risk of HL among children exposed around birth to higher levels of measles (odds ratio for trend = 2.3)^ref. biopsies from 54.3% of patients showed a positive immunostain with at least 2 of the anti-measles antibodies used. LMP-1 immunostaining for EBV was positive in 31.1% of the patients examined. RT-PCR and ISH for measles RNA were positive in 7 and 10 of 28 patients, respectively^ref. Regression of HD after measles has been reported^{ref1, ref2, ref3}. Changes in chromosome structures observed in patient with concomitant HD and measles^ref. Report and observations on the presence of Warthin-Finkeldey cells in patients with HD^ref. Observation of cells resembling Sternberg-Reed cells in conditions other than HD^ref. Fatal subacute measles encephalitis complicating HD in an adult has been reported and considered an opportunistic infection^ref. IHC, RT-PCR and in situ hybridization studies have shown evidence of measles virus in HL tissues in slightly more than half of patients. These include patients with and without EBV in their tumors. Any contribution to pathogenesis remains highly speculative at this point.
• mumps virus antigens were demonstrated in biopsied tissues from HL patients by IFA. Impression smears from 10 lymph node and 2 spleen specimens revealed viral antigens in the nucleus, cytoplasm or both. Measles virus antigens were detected in 6 out of 7 HD tissue (lymph nodes) both in the nucleus and cytoplasm. All tissues tested for the presence of Newcastle disease virus (NDV) antigens were negative. Control tissues were obtained from patients with non-HLs, breast cancers, adenocarcinomas and a number of other disease processes. In control tissues mumps antigens were detected in 7 out of 31 specimens and measles antigens in 9 out of 18 tissues^ref.
• despite extensive investigation, no evidence has emerged to support a role for :
• novel herpesvirus : extremely unlikely^ref
• HHV-3 / VZV^{ref1, ref2}, higher antibody titres to herpesviruses were taken to be the result of the disturbed cellular immunity^ref
• HHV-5 / CMV (33% vs. 9% of EBV^+ref) genome and antigen is localized within H/RS cells^ref
• HHV-6
• HHV-7
• HHV-8
• mumps virus antigens were demonstrated in biopsied tissues from HL patients by IFA. Impression smears from 10 lymph node and 2 spleen specimens revealed viral antigens in the nucleus, cytoplasm or both. Measles virus antigens were detected in 6 out of 7 HD tissue (lymph nodes) both in the nucleus and cytoplasm. All tissues tested for the presence of Newcastle disease virus (NDV) antigens were negative. Control tissues were obtained from patients with NHL, breast cancers, adenocarcinomas and a number of other disease processes. In control tissues mumps antigens were detected in 7 out of 31 specimens and measles antigens in 9 out of 18 tissues^ref.
• rubella virus^ref
• JC virus
• adenovirus
• HTLV-1 or HTLV-2
• Bordetella pertussis^{ref1, ref2}
The ORs for lymphoma were decreased for exposure to sheep and goats (OR = 0.7), for rabbits and hare (OR = 0.7) and tetanus vaccination (OR = 0.5). Increased risk of lymphoma was associated with exposure to cattle (OR = 1.3) and immunization for tuberculosis (OR = 1.5)^ref
• intrinsic : consideration of familial HL illustrates how little we know of the fundamental pathologic processes. Although relatively rare, familial HL is well documented. Within a family’s pedigree EBV⁺ and EBV^- HL are recognized, as well as nodular sclerosis and mixed cellularity histologies. There must be several paths to HL. The relative contributions and temporal relationships of infection, immunodeficiency and other factors have yet to be answered. EBV may rescue 'crippled' (BcR^-) germinal center B cells from apoptosis^{ref1, ref2}. Identical twins of young adult HL case subjects are much more likely to develop the disease compared with fraternal twins of case subjects, suggesting a genetic determinant. IL-6 levels are increased in patients with HL and are correlated with a poor prognosis. Unaffected identical twins of case subjects (surrogate case subjects) had a 87.8% higher IL-6 level compared with matched control subjects (mean difference, +483.7 pg/mL). Analysis of the IL-6 174G>C promoter polymorphism genotypes showed that risk decreased with an increasing number of C alleles. The CC (low secreting) genotype was associated with a decreased risk of young adult HL relative to the GG (high secreting) genotype. Risk was decreased for both nodular sclerosis and other subtypes. Persons with genetically determined lower IL-6 levels may be less susceptible to young adult HL^ref

• Jackson-Parker classification, 1944
• paragranuloma
• granuloma
• sarcoma
• Lukes-Butler-Hicks classification, 1966
• nodular lymphocytic and/or histiocytic
• diffuse lymphocytic and/or histiocytic
• nodular sclerosis
• mixed cellularity
• Rye anatomopathological classification, 1965 (Symposium sponsored by the American Cancer Society & National Cancer Institute "Obstacles to the control of Hodgkin's disease". Held at the Westchester Country Club at Rye, NY, Sept. 13-15 (1965). Cancer Research 26 (6) (1966))
• type 1 : lymphocyte predominance type
• type 2 : nodular sclerosis type
• type 3 : mixed cellularity type
• type 4 : lymphocyte depletion type
• Revised European-American Classification of Lymphoid Neoplasms (REAL) anatomopathological classification by the International Lymphoma Study Group (I.L.S.G.), 1994 :
• nodular lymphocyte predominance
• classical HL :
• lymphocyte-rich HL
• nodular sclerosis
• mixed cellularity
• lymphocyte depletion
• WHO in the recently published WHO classification of hematological malignancies, the sub-classification of HD is broadly similar to the previous Rye classification^ref. Lymphocyte-predominant HL is clearly a distinct entity from other forms of the disease as shown by immunophenotype analysis. A very high proportion of patients present with Stage IA disease and a minimalist approach to treatment may be appropriate^ref. Lymphocyte-depleted HL is now rarely diagnosed in some centers; patients who were once labelled with this entity are now mainly classified as Grade II nodular sclerosis disease or as anaplastic large cell lymphomas. With the possible exception of localized lymphocyte-predominant disease, the remaining types of HL are treated in a similar way depending upon stage^ref.
• classical Hodgkin's lymphoma (cHL) : small population (<1%) of putative malignant cells
• mononucleated Hodgkin's cells (CD99^lo)
• plurinucleated Dorothy Reed-Sternberg (RS) giant cells (Sternberg C. Ueber eine eigenartige unter dem Bilde der Pseudoleukemia verlaufende Tuberculose des lymphatischen Apparates. Zeitschr.Hlk. 19:21-90 (1898); Reed DM. On the pathological changes in Hodgkin's disease, with special reference to its relation to tuberculosis. J.Hopkins Hosp.Rev. 10:133-196 (1902)) : giant histiocytic cells, typically with polylobated nucleus (rarely binucleate with the 2 halves of the cell appearing as mirror-images of each other => owl-eye cells); the nuclei are enclosed in abundant amphophilic cytoplasm and contain prominent nucleoli surrounded by clear perinucleolar halo. Recent advances in cell isolation techniques and molecular biology has identified Ig gene rearrangements within the majority of individual HRS cells, suggesting their B cell origin^ref. These are surrounded by a large population of apparently non-malignant lymphocytes and histiocytes, whose proliferation is likely to be mediated by the wide range of cytokines and chemokines released by the HRS cells^{ref1, ref2}. HRS cells have many characteristics in common with APCs such as activated B cells and dendritic cells (DCs)^ref. Indeed, the HRS cell lines (L428, HDLM-2, and/or KM-H2) express cell surface molecules required for costimulation/proliferation of T cells (MHC class II, CD40, CD80, and CD86)^{ref1, ref2, ref3}, cell adhesion molecules involved in DC-T cell interactions (LFA-1, CD11c, and ICAM-1–3)^{ref1, ref2}, and the DC-associated molecules (CD83 and fascin)^{ref1, ref2}. They also produce inflammatory cytokines (e.g. TNF-a and TNF-b)^ref, non-inflammatory cytokines (e.g. GM-CSF, IL-5 and IL-13)^{ref1, ref2}, and chemokines (e.g. TARC)^ref, which are associated with APCs. L428 cells have been used successfully to produce monoclonal antibodies (mAb) against DC differentiation antigens such as CMRF-44^ref and CMRF-56^ref and to clone the DC-associated molecules such as DEC-205^ref and the adenosylhomocysteine hydrolase-like molecule DCAL/AHCYL-1^ref. Cell surface molecules on HRS cell might also be candidate targets for antibody-based HL immunotherapy : indeed, CD20, CD25, and CD30 reagents (markers for B cells and activated lymphocytes) have been investigated in this regard^{ref1, ref2, ref3}, but molecules more restricted to HRS cells might be preferred as targets for more specific therapeutics. HRS cells cotranscribe an mRNA containing DEC-205 and DCL-1 prior to generating the intergenically spliced mRNA to produce a DEC-205/DCL-1 fusion protein. Cotranscription and intergenic splicing is a rare event in mammalian cells, and there are only a small number of reports describing the presence of fusion mRNA. These include MDS/ EVI1^ref, galactose-1-phosphate uridylyltransferase, and IL-11R genes^ref, Prnd/Prnp^ref and P2Y1/SSF1^ref. None of these reports, however, examined whether the fusion mRNA is translated endogenously into cognate fusion protein. The genes encoding DEC-205 (LY75)^ref and DCL-1 (KIAA0022)^ref are juxtaposed within chromosome band 2q24 and are separated by only 5.4 kb. These are independent genes, because DEC-205 and DCL-1 mRNA are each expressed independently in hematopoietic cell lines. The 5'-RACE experiment mapped the DCL-1 transcription initiation site at 44 bp upstream of DCL-1 translation start codon. Both 5'-proximal promoters of DEC-205 and DCL-1 have independent promoter activity. The DEC-205 promoter may drive the cotranscription of the DEC-205 and DCL-1 genes to produce the 9.5-kb DEC-205/DCL-1 fusion mRNA. This would result from leaky termination of DEC-205 transcription, a mechanism suggested to explain the cotranscription of galactose-1-phosphate uridylyltransferase and IL-11R genes^ref. However, this seems unlikely, because the expression of DEC-205 mRNA did not correlate to that of DEC-205/DCL-1 fusion mRNA. Interestingly, all HRS cell lines tested expressed the 9.5-kb DEC-205/DCL-1 fusion mRNA, but not 4.2-kb DCL-1 mRNA, whereas other myeloid and B cell lines expressed 7.5-kb DEC-205 and/or 4.2-kb DCL-1 mRNA, suggesting that expression of DEC-205/DCL-1 fusion mRNA is highly regulated. It is intriguing to speculate that HRS cell lines express certain transcription factors that may control cotranscription of DEC-205 and DCL-1 genes. At mRNA levels, 2 DEC-205/DCL-1 fusion mRNA variants (V34-2 and V33-2) were identified different by the presence of the DEC-205 exon 34. The deletion of exon 34 appears to be the only alternative splicing that occurs naturally in DEC-205 gene transcription. The fusion junctions in the V34-2 and V33-2 DEC-205/DCL-1 fusion mRNA are in-frame, suggesting both transcripts are translated. What would be the functional difference between DEC-205 and DEC-205/DCL-1 fusion protein? Because the fusion protein contains DCL-1 CP, not DEC-205 CP, it is conceivable that DEC-205 ligand (currently unknown) to DEC-205/DCL-1 fusion protein would induce distinct signals from that binding to DEC-205^ref. RS cells could be natural hybridomas between a neoplastic precursor and reactive T or B lymphocytes at the immunological synapse. In the murine system natural hybridoma formation was observed first in 1968-9. In the #620 to 818 system a mouse leukemia virus (MLV) produced diploid lymphoma cell fused with an immune plasma cell. The tetraploid fusion product cells grew in suspension cultures and as ascites tumors in mice and continued the production of MLV particles and MLV-neutralizing antibodies. Analogy between the #620 to 818 system and the origin of RS cells is proposed. Indirect evidence suggests retroviral infection of the mononuclear HD cell which presumably is an interdigitating reticulum (IR) cell. Reactive B and T cells interact in an abnormal manner and fuse with the retrovirally infected IR cell. The fusion product cells display hyperdiploidy and a disarray of markers as IR markers are lost due to dedifferentiation (and regained upon differentiation induction) and B and/or T cell markers are gained. Conventional theories for the origin of RS cells fail to explain the great heterogeneity of their markers. Derivation of RS cells from IR cells and B and/or T lymphocytes as natural hybridomas offers plausible explanation for all the features of RS cells^ref. The formation of natural hybridomas during the course of malignant lymphoproliferative diseases was observed many times thereafter, e.g. in African Burkitt's lymphoma (BL). RS cells may be formed when retroviral antigens expressed by the mononuclear Hodgkin's cell attract reactive B and T cells, and instead of an immune attack by reactive cells, fusion with reactive cells takes place. The resulting RS cells may further fuse with other reactive cells (e.g., with 2 B cells, one expressing k, the other l light chains) or with each other, forming quadromas. RS cells appear multinucleated and hyperploid; they express the products of activated genes of the interdigitating dendritic or reticulum cell (the retrovirally infected mononuclear Hodgkin's cell) and those of reactive B and/or T cells. Thus, RS cells present themselves with a great variety of marker expression. Molecular mediators and immunoglobulins released from RS cells are responsible for the activities of proliferating polyclonal reactive cells and/or for the depletion of these cells in HD lesions. Multinucleated giant RS cells in anaplastic lymphomas and the syncytial subtype of RS cells of nodular sclerosing HD should be studied first for retro- or herpes viral antigen expressions and for fusion with reactive cells or with other RS cells^ref.


The origin of the HRS cells of cHL has been enigmatic for a long time, as they express markers of different hematopoietic lineages. Only recently the analyses of Ig and T-cell receptor loci of single HRS cells revealed that the cells represent monoclonal populations of tumor cells, and in the vast majority of cases derive from B cells and only in a few cases from T cells^{ref1, ref2, ref3, ref4, ref5}. The rearranged Ig genes are usually mutated, and in about a quarter of cases originally potentially functional Ig rearrangements have acquired obviously crippling mutations destroying the coding capacity^{ref1, ref2, ref3}. Furthermore, the pattern of SHM (the ratio of R versus S mutations in FRs) indicated that the cells were only partially selected for the expression of a functional antigen receptor during the GC reaction^{ref1, ref2}. As GC B cells with unfavorable or crippling mutations are usually quickly eliminated by apoptosis, and as only a fraction of unfavorable mutations that cause apoptosis of GC B cells are easily identifiable as crippling mutations, HRS cells as a rule may represent preapoptotic GC B cells rescued by a transforming event^{ref1, ref2}. Viable H/RS cells can be isolated from HD affected tissues by high gradient magnetic cell sorting (MACS) according to expression of CD30^ref. EBV-harboring HRS-like cells are observed regularly in infectious mononucleosis^{ref1, ref2} and occasionally also in the setting of B-CLL^{ref1, ref2}. In 2 cases of B-CLL with EBV⁺ HRS-like cells, these cells represented clonal populations of cells unrelated to the B-CLL^ref, and it may be the particular microenvironment of the lymphomas allowing expansion of EBV-harboring B cells, which are normally tightly controlled by cytotoxic T cells^{ref1, ref2}. The case presented here may indicate that in rare instances, also in lrcHL, EBV-infected B cells can become a significant population, and that these cells may even acquire an HRS-cell morphology. Increased frequencies of EBV-infected B cells unrelated to the HRS cell clone^ref are indeed often observed in cHL^{ref1, ref2}. Reed-Sternberg cells with B-cell phenotypes have rearranged V_H genes; therefore, these cells arise from B cells. The pattern of VH gene mutations suggests that Reed-Sternberg cells can correspond to either immunologically naive or memory B cells. In half patients the population of Reed-Sternberg cells was polyclonal; in the other half, monoclonal or mixed cell populations were found. Correlation with the clinical stage suggests that polyclonal HL can present as a widespread lymphoma^ref.
Aetiology : EBV⁺ (40%); impaired immune status may contribute to the development of EBV⁺ cHL in older patients and strategies aimed at boosting the immune response should be investigated in the treatment of these patients.
Pathogenesis :
• FAS mutations are rare^ref and overexpression of c-FLIP is involved in the resistance to FAS-mediated apoptosis^{ref1, ref2}
• gene silencing associated with gene promoter hypermethylation as a common cause for this aberrant phenotype in cHL-derived cell lines and also in HRS cells microdissected from primary tumors, identifying CD19, CD20, CD79a, SYK, PU.1, BOB.1, BCMA, and LCK as targets for epigenetic modification : loss of Oct2 and BOB.1/OBF.1 expression is earlier than loss of PU.1, playing a dominant role in the hierarchy of B-cell transcription factors^ref.
• CCL28, which attracts eosinophils via CCR3 and plasma cells via CCR10 and CCR3, by HRS cells defines a major subtype of cHL with frequent infiltration of eosinophils and/or plasma cells^ref.
• HRS cells also produce and secrete high amounts of CCL17 and CCL22, that attract cells expressing the CCR4 receptor, such as T_h2 lymphocyte^ref.
• HL-infiltrating lymphocytes are anergic to stimulation with some mitogens and primary as well as recall antigens but also demonstrate that these cells suppress PBMC responses^ref. They identify the presence of IL-10–secreting cells and CD4⁺25⁺ regulatory T cells. The immunosuppressive effect of the HL-infiltrating cells could be neutralized with anti–IL-10, by preventing cell-to-cell contact, and by anti–CTLA-4. The lymphocytes in HL do not produce cytokines, such as IL-2, IL-4, and IFN-g, with primary (keyhole limpet hemocyanin [KLH]) and recall (purified protein derivative [PPD]) antigens and the mitogen concanavalin A (ConA). However, in previous studies the lymphocytes were found to produce these cytokines when stimulated with phytohemagglutinin (PHA) or with phorbolester (PMA)–ionomycin. Specifically, when the CD26^– CD4 cells immediately surrounding the Reed-Sternberg cells were purified and stimulated with PMA ionomycin, they produced IL-4 and IFN-g. The potential to produce IL-4 was the reason why these cells were previously considered T_h2-like^ref. The absence of IL-2 production upon stimulation is also associated with anergy. The exact nomenclature of these cells is thus a matter of semantics. In addition to the IL-10–producing cells (T_r1), there are also TGF-b–producing cells present in the infiltrate, and these have been termed T_h3. There are variations in the populations involved in different cases. It can be concluded that, as an overall population, the infiltrating lymphocytes do not have T_h1 type functions and are probably attracted into the tissues by chemokines CCL17 and CCç22 as CCR4-expressing T_h2 cells. Although these cells do not spontaneously produce IL-2 or IL-4, they produce IL-10, despite not being fully activated, and therefore function as T_r1 cells. The major remaining question is what causes the predominance of T cells with suppressor activity in HL. It appears that HRS cells, although they have the genotype of B cells, execute a functional program that is similar to antigen-presenting cells but results in tolerance. Mechanisms include the production of immunosuppressive cytokines like IL-10, especially in EBV⁺ cases, and TGF-b, especially in nodular sclerosis cases, as well as the expression of FASL that induces cell death in FAS-expressing activated T cells, while the Reed-Sternberg cells themselves are protected by overexpression of cFLIP or infrequently by FAS mutation^ref. The relevance of these findings is that they may allow a better design of new treatment modalities. There are indications that the infiltrating cells in fact support the growth and survival of the RS cells, and therefore blocking chemokines to prevent the influx of T cells may be effective. On the other hand, blocking of the immunosuppressive signals, such as IL-10 and TGF-b cytokines, or the removal of the suppressor regulatory T cells may enhance the effect of adoptive transfer of cytotoxic T cells^ref. A marker of regulatory T-cells, LAG-3 is strongly expressed on infiltrating lymphocytes present in proximity to HRS cells. Circulating regulatory T-cells (CD4⁺25^hi45RO^hi, CD4⁺CTLA4^hi and CD4⁺LAG-3^hi) were elevated in HL patients with active disease when compared to remission. Longitudinal profiling of EBV-specific CD8⁺ T-cell responses in 94 HL patients revealed a selective loss of interferon-gamma expression by CD8⁺ T-cells specific for latent membrane proteins (LMP) 1 and 2, irrespective of EBV tissue status. Intra-tumoral LAG-3 expression was associated with EBV tissue positivity, whereas FOXP3 was linked with neither LAG-3 or EBV tissue status. The level of LAG-3 and FOXP3 expression on the tumor- infiltrating lymphocytes was co-incident with impairment of LMP1/2-specific T-cell function. In vitro pre- exposure of peripheral blood mononuclear cells to HRS cell-line supernatant significantly increased the expansion of regulatory T-cells and suppressed LMP- specific T-cell responses. Deletion of CD4⁺ LAG-3⁺ T- cells enhanced LMP-specific immunity. These findings indicate a pivotal role for regulatory T-cells and LAG-3 in the suppression of EBV-specific cell-mediated immunity in HL^ref.
• HRS-specific genes include GATA-3, ABF-1, EAR3, and NRF3^ref
• as BCR represents the major survival signaling pathway in normal B-cells, the global down-regulation of its components in HRS cells seems to be contradictory, unless the acquisition of other survival programs (such as constitutive NF–kB activation)^ref, would obviate the necessity of the normal B-cell gene program and thus initiate a selection process against maintaining such a program. In this scenario, it is tempting to speculate that the silencing of the expression of the BCR-related genes is a benefit for HRS cells. Given the described roles of several BCR signaling components in regulation not only of B-cell proliferation but also of B-cell apoptosis, silencing the expression of these genes might actually be a selective advantage for HRS. Different reports have also shown that the levels of expression of BCR-signaling genes could be opposite of the levels of NF-kB activation, as is the case of PMLBCL^ref, a tumor closely related to cHL^ref. The lost B-lineage identity in HRS cells (as seen by immunophenotype and gene expression profiles^{ref1, ref2, ref3}) may explain their survival without BCR expression and reflect a fundamental defect in maintaining the B-cell differentiation state in HRS cells, which is likely caused by a novel, yet unknown, pathogenic mechanism. The B cell–specific transcription factor program was disrupted by overexpression of the HLH proteins ABF-1 and ID2. Both factors antagonized the function of the B cell–determining transcription factor E2A. As a result, expression of genes specific to B cells was lost and expression of genes not normally associated with the B lineage was upregulated. These data demonstrate the plasticity of mature human lymphoid cells and offer an explanation for the unique cHL phenotype^ref.
Laboratory examinations :
• immunophenotype : CD15⁺19^-20^-22^-30 / Ki-1 Ag⁺40^-45^-99^lo138^{+ref1, ref2, ref3}sIg^-. On the other hand, inappropriate lineage marker expression of dendritic cells, monocytes, or macrophages can be found in HRS cells^ref. Reactive CD4⁺40L⁺57^-- lymphocytes surrounding HRS cells
• cytomorphology : largePU.1^-refBCL6^{-ref1, ref2}Oct2^-BOB1/OBF.1^{- ref1, ref2}. Pax-5^+ref
• histology :
• nodular sclerosis (NS) HL (65-75%)
• grade 1 : hypocellulated
• grade 2 : cellulated
Epidemiology : bimodal peaks, developed countries with middle-high social status
Symptoms & signs : 40-60% diagnosed in stage I-II; mediastinum (> 60%), bone marow (5-10%)
Laboratory examinations :
• cytomorphology : RS cells are in the form of lacunar cells (large, irregular, single contracted nucleus with small nucleoli surrounded by an ample, pale-staining cytoplasm retracted during formalin fixation (possibly spanned by a few shreds of cytoplasm) enclosed in a sharply defined cell membrane)
• immunophenotype : CD15⁺20^-30⁺45^-BcR L k or l chain^+(sometimes)

..., and birifrangent (under polarized light microscope) bands of collagen divide the lymphoid tissue into nodules; there are varying numbers of lymphocytes and inflammatory cells such as histiocytes, eosinophils (causing prurigo), small lymphocytes and plasma cells. This type is most common in young women diagnosed at stage I  or II (60%) and often has a low grade of malignancy, usually affecting lower cervical, supraclavicular and mediastinic lymph nodes
• syncytial variant : sheets of very atypical Reed-Sternberg cells proliferate in the midst of the nodule. In some studies it has a slightly worse prognosis than cases of nodular sclerosis lacking this feature.
• Bennett II
• diffuse patterns
• lymphocyte depletion classical HL (LD-CHL) / Hodgkin's sarcoma (1-5%) : low number of lymphocytes and an abundance of Reed-Sternberg cells with fibrosis; it is the most aggressive of the 3 diffuse types of HL (prognosis is 10-39 months survival after chemotherapy).
• diffuse fibrosis : hypocellulated, rare RS cells, abundant connective tissue and fibrinoid material
• reticular form : minimal reactive component, lack of connective tissue, pleomorphic RS cells (eosinophilic and bizarre nucleoli)
Epidemiology : more common in people aged 50-60
Symptoms & signs : diagnosed at stage III/IV; retroperitoneal, bone marrow (50-75%)
• mixed cellularity (MC) HL (25-30%) : intermediate between the lymphocyte predominance and lymphocyte depletion types; RS cells are plentiful (mirror cells) and there are more inflammatory cells, such as eosinophils, histiocytes, neutrophils, small lymphocytes and plasma cells, than in the lymphocyte predominance type.

Epidemiology : advanced age, poor countries, low social status
Symptoms & signs : < 25% diagnosed in stage I-II; usually diagnosed at stage III or IV (50%) => worse prognosis; mediastinum (15-20%), bone marrow (20-25%). Primary HL of the nasopharynx^ref
• lymphocyte-rich classical HL (LR-CHL) (provisional entity), first described by Lennert and Mohri in 1974

Laboratory examinations :
• immunophenotype : NAT-105 / PD1^+ref. The neoplastic cell immunophenotype and microenvironment in lymphocyte-rich classical Hodgkin's lymphoma closely mimic that which are observed in the outer zone of the germinal center, where B-cell blasts with germinal-center markers co-express CD30 and the B-cell transcription program, surrounded by follicular T-cell rosettes. Lymphocyte-rich classical Hodgkin's lymphoma seems to be characterized by a stronger expression of the B-cell transcription program by the neoplastic cells and by a follicular T-cell background, occupying an intermediate position between classical Hodgkin's lymphoma and nodular lymphocyte-predominance HL^ref
• nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL) / paragranuloma (5-6%) : the neoplastic cells are atypical lymphocytic and histiocytic cells (L&H). The expression of several B-cell markers suggested a B-cell origin, and single-cell studies indeed revealed that the L&H cells carried rearranged Ig genes^{ref1, ref2, ref3, ref4}. Although the Ig rearrangements in both cHL and lpHL are mutated, the mutation patterns are different. In contrast to cHL, in most lpHL cases analyzed intraclonal diversity was observed and the rearranged Ig genes carried no crippling mutations and were selected for expression of a functional antigen receptor^{ref1, ref2, ref3}. These findings indicate that the L&H cells of lpHL are derived from mutating GC B cells.

Epidemiology : most patients are males under age 35 diagnosed at stage I or II (80%) and living in developed countries with middle-high social status
Aetiology : EBV^-
Pathogenesis : unexpected expression of IgD in 27% of cases. IgD is usually coexpressed with IgM in naive B cells but can also be seen as IgD-only in centroblasts (CD38⁺) or memory B cells (CD27⁺). Clinically, the IgD⁺ cases present at a younger median age (21 vs. 44 years) and have a striking male predominance (male-to-female ratio, 23:1 vs. 1.5:1). Cervical lymph nodes were more frequently involved (56% vs. 18.2%). L&H cells were localized in a predominantly extrafollicular distribution in the majority of IgD⁺ cases (69%). The IgD⁺ cases did not coexpress IgM or CD27 (a marker associated with memory B cells), and nearly all (93%) were weakly positive for CD38, supporting a GC derivation. The expression of Bcl-6, BOB.1, Oct2, and SWAP-70 was similar in the 2 groups. However, PU.1 expression was seen in 60% of the IgD⁺ cases in contrast to 86% of the IgD^- cases. The absence of PU.1 staining correlated with more L&H cells in an extrafollicular distribution, weakening the use of this marker in the differential diagnosis with T-cell rich/histiocyte rich B-cell lymphomas. To study IgD expression in "de-novo" T-cell rich/histiocyte rich B-cell lymphomas, we analyzed 20 cases and all but 1 were negative. In conclusion, cases of IgD⁺ NLPHL do not differ from IgD^- cases regarding cellular derivation and most other immunophenotypic characteristics. However, IgD⁺ NLPHL exhibits distinctive clinical features, and more often involves the interfollicular region in a background relatively rich in T cells. IgD⁺ may represent an additional useful marker in the diagnosis of NLPHL^ref
Symptoms & signs : mediastinum (5%), bone marrow (< 5%)
Laboratory examinations :
• histology : diffuse to slightly nodular infiltrate with abundant mature lymphocytes and varying numbers of benign histiocytes, eosinophils, neutrophils and small T cells resembling GC T cells (CD57⁺BCL6⁺)^ref; there are few neoplastic cells and the degree of malignancy is low
• immunophenotype : CD15^-19⁺20⁺22⁺30^-40⁺45⁺w75⁺79a⁺138^- EMA⁺ BcR L k or l chain^+(sometimes)NAT-105 / PD1^+ref. Reactive CD4⁺40L^-57⁺ lymphocytes that form rosettes around L&H cells
• cytomorphology : popcorn cells (multilobed nucleus that resembles an exploded popcorn kernel), BCL6^{+ref1, ref2}PU.1^-refOct2⁺BOB1/OBF.1^{+ref1, ref2}
Prognosis : 3-5% develop diffuse large B-cell lymphoma (DLBCL)

• unclassifiable HL

• painless, progressive enlargement of superficial lymph nodes
• lymph nodes and spleen (90%)
• laterocervical and supraclavear lymph nodes (70%)
• chest / mediastinum (45%) (including bulky mediastinal adenopathy if > 2/3 of maximal transverse chest diameter)
• paraaortic lymph nodes (35%)
• spleen (13%)
• axillary (20%)
• inguinal (10%)
• extranodal (10%)
• liver (10%)
• lung (6%)
• skeletal (5%; 15% overall)
• other (10%)
• primary gastrointestinal Hodgkin's disease (extremely uncommon)
Kaplan-Rosenberg contiguity theory : lymphogenous and hematogenous spreading
=>
• perineal and/or lower limb edema due to paraortic lymphadenomegaly obstructig inferior vena cava
• obstructive jaundice
• acute renal failure due to ureteral obstruction by retroperitoneal lymphadenomegaly
• spinal cord compression by infiltration of epidural spaces
• dermal and subcutaneous nodules
• systemic symptoms (40%) :
• anorexia
• fatigue
• weight loss (> 10% in the 6 months before diagnosis)
• Pel-Ebstein fever
• pruritus. Rarely itching attacks and immediately subsequent transient generalized hyperhydrosis^ref.
• night sweats
• anemia
• alcohol induces pain (15-30%) that begins within minutes and subsides within 30 minutes to a few hours^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8, ref9, ref10, ref11, ref12, ref13, ref14, ref15}, but this finding has been reported also in other neoplastic diseases^{ref1, ref2, ref3}. The pain induced by alcohol has been described as either sharp and stabbing or dull and aching. A patient frequently links the discomfort with alcohol ingestion and may voluntarily discontinue its use. There is no association with histological subtypes. Alcohol pain was associated with other factors generally considered to indicate an unfavorable prognosis--systemic symptoms, Stage II disease with multiple site involvement, Stage III or IV disease. Enlargment and a rise in temperature of lymph nodes were both present at or appeared at the site of pain in the majority (86%) of patients with this symptom^ref. Actually the incidence seems reduced to 1.5-5% due to early diagnosis^ref. Retrosternal pain has been noted with mediastinal lymph node involvement whereas with diseases axillay or cervical nodes, pain may be felt in the shoulder, neck or arm. The abdomen and groin are also sites of alcohol related pain, and back pain with or without radiation to leg has been described. When disease is present in several sites pain may not be felt in all of them.  An important observation is that tumor can invariably be identified at or near the site of the alcohol-related pain, if not at the time of initial presentation, then when relapse occurs. Several features seems to characterize  patients with HL who have alcohol-related pain. Nodular sclerosis HL is the predominant histologic type, and a higher than expected incidence of mediastinal involvement has been reported. More women than men tend to have this symptoms despite a 2:1 male predominance for the disease.

• Ann Arbor clinical staging (cS), Michigan, USA, 1970^ref :
• I : only 1 lymph node region (I) or 1 extranodal zone/organ (I_E) : every organ other than lymph nodes, spleen, thymus, Waldeyer's ring, appendix, Peyer's plaques) is involved. 10-yr OS = 79-90%
• II : 2 or more lymph node regions are involved on the same side of the diaphragm or local invasion of one extranodal organ or region (II_E). 10-yr OS = 74-80%
• III : different lymph node regions are involved on both sides of the diaphragm or local invasion of one extranodal organ or region (III_E) or of the spleen (III_S), or both (III_ES). 10-yr OS = 55-60%
• III₁A : when among subdiaphragmatic lymph nodes only high abdominal ones are involved, expecially splenic hilar, celiac and portal hilar, in addition to spleen
• III₂A : when among subdiaphragmatic lymph nodes only paraortic, iliac and mesenteric ones are involved, with or without involvement of high abdominal ones
• IV : diffuse or generalized in one or more extranodal organs, with or without any lymph node involvement (metastasis in bone marrow, liver or lungs (no in CNS)). 10-yr OS = 35-40%
... and attributes :
• A : no general symptoms
• B : general symptoms (weight loss > 10% in the 6 months before diagnosis, night sweats, chill-less fever > 38°C (oral) not due to infections)
Sites are named by capital letters : N (lymph nodes), L (lung), O (bone), H (liver), M (bone marrow), D (skin), S (spleen), P (pleura), K (kidney)
Clinical course :
• localized disease : I-IIA
• advanced disease : IIB-IV
• Cotswolds criteria, UK, 1989^ref :
• stage I : only 1 lymph node (I) or extranodal site (tonsilla, tonsilla lingualis, spleen, thymus) (I_E) is involved
• stage II : pathology in 2 or more sites on the same side of the diaphragm. The number of involved sites must be registered, e.g. II3
• stage III : pathology in lymph node regions on both sides of the diaphragm
• stage III1 : with or without lymph nodes at the hilus of the spleen, of the liver or in the coeliaca group
• stage III2 : with para-aortic, iliac and mesenteric nodes
• stage IV : one or more extranodal zone is involved, except those labelled as E
• systemic symptomatology
• A : no general symptoms
• B : general symptoms (fever, night sweats, weight loss (pruritus is not considered)
• X : bulky disease (> 10 cm large or broadening up to > 1/3) : if mediastinal lymphadenitis => dyspnea
• E : only one extranodal region is involved, contiguous to a normal nodal region

• CBC : autoimmune haemolytic anaemia (AIHA), eosinophilia
• sideropenia (sideremia, transferrin, ferritin), hypercupremia
• b₂-microglobulin, LDH, fibrinogen, creatinine, uricemia, bilirubin, SGOT, SGPT, g-GT, alkaline phosphatase, total serum proteins, serum protein electrophoresis with dosage of IgG, IgA, and IgM
• increased ESR, a₂-globulins and CRP
• bone marrow trephine biopsy (BMTB)(positive in 15%) : it is not necessary in clinical stage I-IIA. However, bilateral BMTB is recommended in the presence of B symptoms also in patients with localized stage disease^ref.
• echography of abdomen and soft tissues (neck, armpits, groin)
• whole-body CT (eventually partially replaced by chest X-rays)

• lymph node biopsy (cervical > mediastinoscopy / mediastinotomy) : FNAB
• ⁶⁷Ga-citrate scintigraphy
• MRI
• bipedal or pedal lymphangiography has no place in the evaluation of HD and is no longer practiced
• ¹⁸FDG-PET has a number of potential advantages for the hematologist-oncologist in refining and improving the management of HL.
• staging : HL is generally treated according to stage and risk profile; therefore, pretherapeutic staging provides the basis for different treatment strategies such as RT, chemotherapy or a combination of both. Owing to the increasing use of chemotherapy at early stages and the result of the EORTC H6-F study, staging laparotomy has disappeared as a routine staging procedure. Staging of Hodgkin’s lymphoma was, until recently, mainly based on computed tomography (CT). Although structural imaging provides exquisite anatomic detail, it requires perturbation or enlargement of anatomical structure to suggest tumor. Minimally affected lymph nodes of normal size or parenchymal involvement with insufficient contrast to surrounding tissue may therefore be missed, whereas enlarged inflammatory nodes are erroneously seen as tumor deposits. With regard to bone marrow involvement, which is expected in 5–15% of patients with untreated Hodgkin’s lymphoma, iliac crest biopsy is performed routinely, but due to patchy involvement lesions may be frequently missed. Recently, metabolic imaging with PET has been increasingly used in the management of lymphoma patients. Since PET relies on the detection of metabolic alterations observed in cancer cells, this examination yields data that are independent of associated structural characteristics. Furthermore, the ability to perform whole body imaging within one examination without increasing the radiation burden makes PET an ideal technique to "screen" patients for cancer deposits. The most frequently used tracer is the glucose analogue FDG. The use of FDG for in vivo cancer imaging is based upon the higher rate of glucose metabolism of cancer cells compared with nonmalignant tissue. With the exception of small lymphocytic and MALT lymphomas, most lymphomas, including Hodgkin’s lymphoma, exhibit moderate to high FDG uptake^ref. Several studies have investigated the role of FDG-PET for the initial staging of lymphoma^ref. The majority of these studies compared the performances of PET with other imaging modalities. Studies were often retrospective and included a mix of NHL and Hodgkin’s lymphoma patients without separately analyzing for these histologic subgroups. Another drawback is the lack of a true gold standard against which new imaging modalities can be compared. Discordant findings between scanning techniques are uncommonly evaluated with biopsy confirmation, and the alternative approaches of follow-up of therapy, or provision of treatment based on the results of one of the tests, have associated limitations as both false positive and negative findings are observed. Compared with gallium scintigraphy, FDG-PET appears to have advantages that include inherent superior resolution, higher sensitivity (especially in the abdomen and bone), lower radiation burden (10 mSv/PET versus 44 mSv/gallium scintigraphy) and a shorter examination time (2 hours for PET versus 3 days for gallium scintigraphy)^{ref1, ref2} FDG-PET was also found to be more sensitive and specific than bone scintigraphy for the detection of cortical bone involvement^ref and complementary to bone marrow biopsy for detection of marrow involvement distant from the biopsy site^ref. Most reports have focused on comparisons of PET with CT^ref. In most cases, PET was found to be more sensitive for detecting of both nodal (e.g., small sized nodes) and extra-nodal (especially spleen and bone) involvement, but PET-negative, CT-positive lesions do occur in a small number of cases. High FDG uptake in brown fat tissue or muscle can hamper the interpretation of the head and neck and mediastinal regions. Moreover, physiological uptake in gut and the renal collecting system can obscure evaluation of lymphoma in adjacent nodal sites. Therefore, optimum use of FDG-PET is likely in combination with CT. Combined use of PET-CT can improve accuracy by increasing the certainty of diagnosis in those difficult regions^ref. Incorporating PET in the initial staging in lymphomas results in upstaging or downstaging in 10–20% of patients, but the impact on treatment management is less obvious. Naumann et al^ref analyzed the potential impact of PET staging on therapy decision in 88 patients with HL. Concordant findings between PET and CT were found in 70/88 patients (80%). In 11 patients (13%), PET detected additional sites, which would have resulted in treatment intensification in 9 of them, all with early stage disease. Focusing on the patients with stage IA-IIB disease only (n = 44), treatment would have been intensified in 20%. Compared to conventional diagnostics, PET downstaged 7 patients (8%) but this was only correct in 1 patient (inflammatory enlarged cervical node). False negative PET findings would have erroneously led to a minimization of therapy in 6 patients (7%). Therefore, FDG-PET should not be used instead of but in combination with conventional diagnostics.
• evaluation of residual masses after treatment : approximately two-thirds of patients with HL will have a residual mass seen with standard imaging tests at the end of treatment, but only 20% of these patients will eventually relapse. The principal imaging modality for post-treatment follow-up is CT, but these scans are not able to accurately differentiate between a benign fibrotic mass and residual tumor. Early identification or prediction of patients who have not been cured with their primary treatment is important, since better outcomes with further treatment might be expected when this therapy is given at an earlier stage and with a lower tumor burden. It is common practice to consider RT to a residual mass of uncertain significance. However, late morbidities that include cardiovascular toxicity and secondary malignancies are potential risks that challenge this "standard" use of RT. Several recent reports have shown the effectiveness of FDG-PET in the evaluation of residual disease at the end of treatment, including studies assessing patients with HL^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8, ref9}. A high negative predictive value (NPV) of FDG-PET (81%–100%) has been consistently reported by most studies, clearly showing the ability of PET to identify patients with an excellent prognosis. Relapses are infrequent and occur rarely within the first year after completing treatment, and therefore probably reflect low tumor burdens that are below the limit of PET detection. Since a substantial number of patients received additional RT after a negative PET scan, reported progression-free survivals (PFS) and NPVs may represent overestimations. The question of whether, after first-line chemotherapy, RT can be omitted in patients with a negative PET scan is therefore still unanswered. Prospective randomized trials are needed to compare the PFS, overall survival (OS) and long-term complications observed in patients with a negative PET after chemotherapy who receive no further therapy or standard RT as planned at the initiation of treatment. Value of fluorodeoxyglucose–positron emission tomography (FDG-PET) in the detection of residual disease after treatment in HD patients :

	number	negative predictive value (NPV)	positive predictive value (PPV)	mean follow-up (FU) (range)	PFS@ 1 year
					PET– (complete metabolic response)	PET+ (residual disease on PET)
Hueltenschmidtref	63	98%	86%	24 (3–41)	ns	ns
Spaepenref	60	91%	100%	32 (13–50)	95%	40%
Dittmanref	24	94%	88%	> 6	ns	ns
Naumannref	43	100%	25%	35 (15–58)	100%	75%
Weihrauchref	29	84%	60%	28 (16–68)	95%	40%
De Witref	37	96%	46%	26 (2–34)	100%	75%
Lavelyref	20	81%	ns	36 (9–75)	ns	ns
Guayref	48	92%	92%	ns	100%	45%
Jerusalemref	36	94%	100%	ns	ns	ns

In contrast to the NPV, the positive predictive value (PPV) of PET is more variable (25–100%). We have observed that, for several reasons, false positive rates decrease with increasing experience in evaluating residual masses. First, the timing of PET scanning is crucial. If done immediately after completing RT, inflammatory changes can result in false positive interpretations. Therefore, it is better to perform PET before RT or to wait at least 3 months after completing RT. Second, patients with HL are often young and develop thymic hyperplasia at the end of treatment. This produces a typical pattern on FDG-PET with a butterfly-shaped configuration with moderate and homogeneous FDG uptake, whereas residual lymphoma is associated with a more intense and focal pattern^ref. Thirdly, intense FDG uptake in muscle and brown fat tissue may be seen in lean and young patients and can hamper the detection of residual nodes after treatment (Dobert N, Menzel C, Hamscho N, et al. Atypical thoracic and supraclavicular FDG-uptake in patients with Hodgkin’s and non-Hodgkin’s lymphoma. Q J Nucl Med. 2004;48:33–38); combined PET-CT images are often necessary to resolve these appearances. Finally, inflammatory lesions are known to cause false positive PET findings and occur more frequently after chemotherapy. Correlation of PET findings with pretreatment scans (a new lesion in a previously noninvolved region is rarely lymphoma), clinical history or other imaging modalities can help to identify these lesions. When PET images are interpreted in correlation with clinical history and CT by radiologists/nuclear medicine physicians with specific expertise in PET, the PPV of PET in patients with Hodgkin’s lymphoma is probably equivalent to that observed in NHL (> 80%) and residual positivity is highly suggestive of residual lymphoma for which additional treatment should be considered. In equivocal cases close follow-up or additional diagnostic procedures may be warranted to reduce risks of giving additional treatments that are based on false-positive results.
Sarcoid-like reactions can occur after ABVD chemotherapy, and FDG-PET imaging may not be capable of distinguishing between HL and sarcoidosis, so biopsy is sometimes still needed^ref.
• early response monitoring for risk stratification ("interim PET")^ref : since treatments that are more aggressive, but also more toxic, are available, there is a growing interest in the use of risk-directed approaches to utilize prognostic factors that predict for relapse. The International Prognostic Index (IPI) for HL^ref summarizes different prognostic clinical factors at presentation and has become an established parameter for risk stratification. The clinical features incorporated in the IPI reflect the biologic heterogeneity of the disease. However, the duration of a complete remission (CR) and other long-term outcomes might be more affected by the sensitivity of the tumor to chemotherapy than by the prognostic factors seen at presentation. Reliable predictions of outcome early in the treatment phase could lead to more immediate changes of therapy that might improve outcomes, including survival. Morphological imaging modalities, as a criterion for early response monitoring, are inefficient at differentiating responders from non-responders, in part because several courses of chemotherapy are necessary before effectiveness can be reliably determined. Using CT findings as a criterion for early response may label an unacceptable number of patients as poor responders and expose them to more aggressive or experimental therapies, even if these patients could achieve durable complete responses with standard chemotherapy. Promising results with FDG-PET can be obtained when evaluating treatment response. Because glucose provides the primary source of carbons for the de novo synthesis of nucleic acids, lipids and amino acids, FDG uptake is closely related to the number and proliferation capacity of viable cells. Treatment-induced changes resulting in tumor cell death or growth arrest reduce FDG uptake, making this a sensitive and early marker of response^ref. Romer et al^ref described a rapid decrease of FDG-uptake in patients with NHL as early as 7 days after commencing treatment. However, FDG-uptake at 42 days correlated better with long-term outcomes; early FDG reduction probably reflects initial chemosensitivity of the tumor whereas results of later evaluations are more related to the detection of resistant clones. Since that initial description, several studies have correlated PET response during treatment with final outcome, either focusing on the value of PET during initial induction treatment^{ref1, ref2, ref3, ref4, ref5, ref6} or prior to high-dose therapy and stem cell transplantation (HDT/SCT)^{ref1, ref2, ref3, ref4, ref5}.
• early response assessment of first-line induction chemotherapy : persistent PET positivity observed after a few cycles of chemotherapy is associated with a high probability of relapse at the end of treatment (PPV 67%–100%). To date, experience has been almost exclusively gained in patients with aggressive NHL. In the largest prospective study, by Spaepen et al^ref, evaluating 70 patients with aggressive NHL, 33 patients showed persistent abnormal FDG uptake after 3–4 cycles of doxorubicin containing first-line therapy and none of these patients achieved a durable CR (median PFS, 45 days). Of the 37 patients with a negative mid-treatment PET, only 6 relapsed with a median PFS of 301 days (P < 0.00001). In a multivariate analysis, FDG-PET at mid-treatment was a stronger predictor for PFS (P < 0.0000001) and OS (P < 0.000009) than the IPI (P < 0.58 and P < 0.03, respectively). Preliminary data in HL by Mikhaeel et al^ref show similar results: all 6 patients with persistent disease on PET relapsed compared to only 2 out of 26 patients with a negative PET scan mid-treatment. Prospective trials are now required to establish the clinical role of PET in this setting by comparing overall survival after randomizing patients with positive mid-treatment FDG-PET findings to either continue standard induction therapy or to switch to a more aggressive approach

	number	histology	treatment	timing PET cycles	positive predictive value (PPV) for relapse	mean follow-up (FU) (months)	PFS@ 1 year
							PET+ (residual disease on PET)	PET– (complete metabolic response)
Jerusalemref	28	NHL	first-line relapse	2–5	100%	28	20%	81%
Mikhaeelref	23	NHL	first-line	2–4	87%	30	12%	100%
Mikhaeelref	32	HD	first-line	2–4	100%	36	0%	92%
Kostakogluref	30	NHL/HD	first-line relapse	1	87%	19	13%	87%
Spaepenref	70	NHL	first-line	3-4	100%	36	10%	92%
Zijlstraref	26	NHL	first-line	2	75%	25	42%	80%

Early interim FDG-PET during BEACOPPesc therapy^ref
• prognostic value of FDG-PET before HDT/SCT : improvements in therapy may mean that patients with nonresponding or relapsing disease represent a cohort that has an even more unfavorable prognosis. Currently, many centers consider high-dose therapy with autologous stem cell transplantation as the treatment of choice for these poor prognosis lymphoma patients. The most important prognostic factors to predict favorable outcome after HDT/SCT are the duration of remission prior to progressive disease and the chemosensitivity of the tumor to salvage therapy administered prior to SCT. Since FDG-PET has become a potential tool to differentiate between responders and non-responders early during chemotherapy, several groups have investigated the value of [¹⁸F]FDG-PET to identify patients who would benefit from this aggressive treatment. Again, high PPVs with short PFS are recorded in patients with persistent disease on PET. Co-existing inflammatory disease is more frequently seen in this population and can cause false-positive PET results. Correlations of PET, clinical and morphological imaging data are therefore essential. Superior PPVs are obtained if PET is performed just prior to transplantation (> 87%) compared with those performed early during the administration of salvage therapy (Schot et al^ref, PPV = 65%). This is not surprising since resistant clones can only become apparent when the sensitive ones are killed. These findings are confirmed by quantitative analyses: only a major decrease in the amount of FDG uptake and not the reduction in metabolic volume is predictive for favorable outcome. Further studies are necessary to define the optimal timing of PET and response criteria before this technique can be used as a standard practice to determine patient eligibility for HDT/SCT. For post-treatment evaluation, especially if a residual mass is present, PET has become a standard procedure in routine clinical practice and has replaced gallium scintigraphy as an adjunct to CT. In cases where, after completing first-line treatment, abnormal FDG-uptake is seen in initially involved sites and there is a low suspicion of co-existing inflammation, strong consideration for providing alternative therapy should be given. In HL patients with stage III or IV disease, negative PET results do not exclude minimal residual disease and/or the risk of late relapse. These patients might benefit from repeated follow-up scans. Patients with early-stage Hodgkin’s lymphoma and a negative FDG-PET scan after therapy are considered as CR and follow-up scanning is indicated only if recurrent disease is suspected. The increasing use of integrated PET-CT systems requires systematic evaluation, including assessment of the radiation burden associated with repetitive combined imaging studies. For prognostic determination in the early phases of therapy, there are promising data for the predictive role of FDG-PET, but larger patient populations and longer follow-ups are necessary for confirmation. As current studies are extended, data regarding the timing of the interim scan, definition of PET response criteria, and utility in tailoring RT, stem cell transplantation and radio-immunotherapy will become available. These assessments of utility, potentially supported with the results of economic evaluations, will inform the process to determine new standards of practice.
 

	number	histology	indication  SCT	timing PET		positive predictive value (PPV) for relapse	negative predictive value (NPV)	PFS@ 2 year estimated from Kaplan Meier plots
								PET response	PET non-response
Bechererref	16	HD/NHL	not spec	prior to SCT	no or minimal residual disease	87%	87%	88%	18%
Cremeriusref	22	NHL	first-line	prior	> 25% decrease to SCT	86%	67%	72%	28%
Filmontref	20	HD/NHL	first	prior relapse	no residual disease to SCT	92%	87%	88%	8%
Schotref	46	HD/NHL	first	mid relapse	no residual disease induction	65%	67%	62%	38%
Spaepenref	60	HD/NHL	first	prior relapse	no residual disease to SCT	87%	90%	100%	24%

The 2-year progression-free survival was 93% vs. 10% for patients with negative and positive PET after 2 cycles of salvage chemotherapy (PET2)^ref.
• staging laparotomy with eventual liver biopsy
• splenectomy increases risk of secondary leukemia

• treatment of localized disease :
• external beam radiotherapy (EBRT) (highly radiosensitive : 40-45 Gy in 4 weeks) : extent of radiation fields : for those patients in whom radiotherapy alone is employed, the extent of the radiation field is critical in determining the relapse rate but probably not the overall survival. Specht and colleagues in the International Hodgkin's Disease Collaborative Group carried out a meta-analysis of 8 randomized trials involving 1,974 patients who received more or less extended radiation fields^ref. The use of more extensive radiation fields was associated with the reduction in the actuarial relapse rate at 10 years from 43% to 31% (P < 0.00001), but the overall survival at 10 years was 77% regardless of the extent of the radiation field. Selected series of patients with localized Hodgkin's disease treated with different radiation fields :

radiation field	center	patients	no. of patients	DFS	survival	years (time point for DFS and overall survival)
involved field irradiation	MD Anderson (7)	pathological stage (laparotomy-staged) (PS) I and II (A and B)	87	54%	-	10
		clinical stage (CS) I and II (A and B)	133	35%	-	10
	British National Lymphoma Investigation (BNLI) (3)	PS I and IIA	107	54%	81%	10
mantle field irradiation	BNLI (3)	PS I and IIA	212	57%	79%	10
	Melbourne (8)	CS I and II (A and B)	64	46%	89%	5
		PS I and II (A and B)	66	67%	90%	5
	EORTC (5)	CS I and II (A and B)	152	38%	60%	12
	Toronto (4)	CS I and IIA	121	62%	-	10
extended field irradiation mantle	Boston (9)	PS I and IIA	108	74%	89%	5
	Chicago (10)	PS I and IIA	92	77%	71%	10
	EORTC (5)	CS I and II (A and B)	108	63%	80%	7
subtotal lymphoid irradiation (STLI) / subtotal nodal irradiation (STNI)/total lymphoid irradiation (TLI) / total nodal irradiation (TNI)	Stanford (11)	PS I and II (A and B)	109	77%	84%	10
	Denmark (12)	PS I and II (A and B)	133	90%	90%	7

Side effects : radiation-induced breast and lung cancers
More extensive radiotherapy fields or the addition of chemotherapy to radiotherapy in the initial treatment of early-stage Hodgkin's disease had a large effect on disease control, but only a small effect on overall survival. Recurrences could be prevented by more extensive radiotherapy or by additional chemotherapy. However, if chemotherapy had not been given initially, recurrences were generally salvageable by re-treatment with chemotherapy. Hence, less intensive primary treatment--particularly a reduction in radiotherapy fields--appears to achieve similar survival rates as more intensive treatment, although more randomized evidence is needed to confirm this^ref. Patients who relapse are generally responsive to chemotherapy.
• combined modality therapy : many centers have explored the use of combination chemotherapy + extended field irradiation to treat localized disease and this undoubtedly reduces the relapse rate compared to the use of radiotherapy alone. In the EORTC H1 trial the administration of weekly vincristine for 2 years after the completion of regional radiotherapy for CS I and II (A and B) disease markedly improved relapse-free survival (61% vs 38% at 12 years; p < 0.001) and there was a trend to improved overall survival (70% vs 60%; p = 0.08)^ref. Most trials have not, however, demonstrated a survival advantage. The International Hodgkin's Disease Collaborative Group performed an analysis of 13 trials involving the randomization of combined modality treatment against radiotherapy alone. The addition of chemotherapy halved the 10-year risk of failure from 32.7% to 15.8% (p = 0.00001), but the improvement in survival was insignificant (79.4% to 76.5%)^{ref1, ref2}. A trial from a French co-operative group of combined modality therapy in CS I, IIA and IIIA disease suggested that in the context of combined modality treatment, more limited radiation fields were fully efficacious and that 3 cycles of MOPP were as effective as 6 cycles^ref. A number of other studies have addressed the use of fewer cycles of chemotherapy or the use of less intensive chemotherapy regimens with the aim of reducing the undoubted toxicity of combined modality therapy. At Stanford subtotal nodal irradiation (STNI) was compared with involved field (IF) radiation plus VBM (vinblastine, bleomycin, methotrexate) chemotherapy (non-sterilizing and low leukemogenicity) in laparotomy-staged patients with localized disease^ref. There was a highly significant improvement in disease-free survival (95% vs 70%) but again no survival difference. A further study using 6 weeks of VBM in a different schedule, however, revealed considerable pulmonary toxicity attributed to the bleomycin given before the mediastinal radiation^ref. In Manchester a month's course of VAPECB (vincristine, doxorubicin, prednisolone, etoposide, cyclophosphamide and bleomycin), another non-sterilizing regimen was added to radiation therapy and compared with radiation alone in a randomized phase II study^{refRadford JA, 66}. The progression-free survival at 4 years was 90% with the combined modality, compared to only 64% with radiation alone.
• chemotherapy alone : at the National Cancer Institute patients with PS IB, IIA, IIB and IIA1 disease were randomized to STNI or MOPP alone^ref. The projected 10-year disease-free survival of patients randomized to receive radiation was 60% compared to 86% in those who received MOPP (p = 0.009). There was also a borderline significant survival benefit for the MOPP recipients but this was mainly seen in patients with bulky mediastinal disease. In contrast to these excellent results with MOPP an Italian study in PS I and II disease found similar rates of freedom from progression but reduced survival in the MOPP recipients due to a frequent failure of salvage therapy after a relapse from MOPP therapy^ref.
• first-line chemotherapy :
• ABVD
• hybrid MOPP/ABVD
• Stanford V
• salvage therapy :
• IEV
• IGEV
HL is an uncommon form of cancer. In Canada, a country of approximately 32 million people, the most recent available annual statistics (from 2000^ref) show that 134,413 people were diagnosed with cancer and 62,672 deaths were attributed to this disease. The most common hematologic neoplasm was NHL, with an incidence of 5444 new cases and 2537 deaths. In contrast, a new diagnosis of Hodgkin’s lymphoma was made in 811 people and 128 deaths observed. These data exemplify the success of current therapies that have resulted in high expectations of cure for patients with HL, but also demonstrate the nature of future challenges; strategies are needed to identify and provide successful therapy to the 15%–20% of patients who are not cured, and for the more than 80% of patients who have had their cancer successfully eradicated, long-term threats to quality of life and survival need to be reduced. Given the uncommon nature of Hodgkin’s lymphoma, evaluation of interventions to improve long-term outcomes will require international collaborations and, by definition, long periods of follow-up. For patients with limited-stage Hodgkin’s lymphoma, the development of successful therapies that control the malignancy makes evaluation of the competing objectives to eradicate the cancer while reducing the risks of long-term treatment-related toxicities particularly important. This balance has evolved even over the past 15 years. In 1989, an international collaboration of single institutions and cooperative groups led to the Paris International Workshop and Symposium. At this workshop, the outcomes of 14,702 patients diagnosed with Hodgkin’s disease between the early 1960s and 1987 were pooled, allowing for an analysis of results that extended over approximately 20 years (Henry-Amar M, Aeppli DM, Anderson J, et al. Long term survival and study of causes of death. In: Somers R, Henry-Amar M, Meerwaldt JK, Carde P, eds. Treatment Strategy in Hodgkin’s Disease. London: John Libbey and Co; 1990: 381–418). This analysis included 9041 patients assessed as having "early-stage" Hodgkin’s disease; 1957 (22%) of these patients had died. An actuarial analysis of cumulative deaths by cause demonstrated that over the first decade of follow-up, most deaths were directly attributed to Hodgkin’s disease. However, by 13 years of follow-up, deaths attributed to other causes surpassed those due to progressive Hodgkin’s disease. Furthermore, the observed number of deaths attributed to other causes exceeded those expected in comparison with an age- and gender-matched control group. Specific "other" causes of death included an increased occurrence of cardiovascular events and second cancers. As new treatment strategies improve control of Hodgkin’s lymphoma and reduce the incidence of death from this cause, recent randomized controlled trials evaluating therapy in patients with limited-stage disease already demonstrate, with much shorter durations of follow-up, that causes other than progressive Hodgkin’s lymphoma or acute treatment-related toxicity will account for the majority of deaths. In a randomized trial comparing extended-field radiation therapy with combined-modality therapy, Sieber et al observed that with a median follow-up of 22 months, 17 deaths had been observed in 572 patients; 10 deaths (59%) were attributed to causes other than progressive Hodgkin’s lymphoma or acute treatment-related toxicity (Sieber M, Franklin J, Tesch H, et al. Two cycles ABVD plus extended field radiotherapy is superior to radiotherapy alone in early stage Hodgkin’s disease: results of the German Hodgkin’s Lymphoma Study Group (GHSG) Trial HD7 [abstract]. Blood. 2002;100:93a). In a randomized trial comparing a strategy that includes radiation therapy with chemotherapy alone, Meyer et al observed that with a median follow-up of 4.2 years, 15 deaths had been observed in 399 patients; 9 deaths (60%) were attributed to causes other than progressive Hodgkin’s lymphoma or acute treatment-related toxicity (Meyer RM, Gospodarowicz M, Connors J, et al. A randomized phase III comparison of single-modality ABVD with a strategy that includes radiation therapy in patients with early-stage Hodgkin’s disease: the HD-6 trial of the National Cancer Institute of Canada Clinical Trials Group (Eastern Cooperative Oncology Group Trial JHD06) [abstract]. Blood. 2003;102:26a). Thus, to further improve long-term survival, reduction in deaths from other causes will become the major focus of new interventions. 2 basic principles of clinical trial design require attention in order to reduce the risk of bias that might confound resulting conclusions (Sackett DL, Haynes RB, Guyatt GH, Tugwell P. Clinical Epidemiology: A Basic Science for Clinicians. Toronto: Little, Brown and Co; 1991). The first principle requires that when a study aim is to determine the clinical course of a disease or prognosis of specific patient groups, it is necessary to evaluate an inception cohort of patients with the specific disease who have been identified at a relatively uniform time point in the disease process. The second principle requires that when a study aim is to evaluate whether new interventions should replace an existing form of therapy, these interventions should be tested in randomized controlled trials. Particularly in evaluating new modalities of therapy, systematic reviews that include meta-analyses of randomized trials testing similar interventions can enhance an understanding of the consistency, precision and generalizability of trial results^ref. Randomized controlled trials and meta-analyses need to include evaluations of relevant outcome measures that would properly inform determinations of standard treatment policies. For most clinical problems, a hierarchy of relevant outcomes can be constructed (Meyer RM, Kouroukis CT. Understanding outcome measures. Evidence-based Oncol. 2001;2:172–176). This hierarchy includes specific domains such as survival, quality of life and health care economics. Often other outcomes that serve as proxy measures for these specific domains will be reported; these surrogate measures can include parameters of disease control or treatment-related toxicity that might predict for overall survival or quality of life. The use of surrogate outcomes to formulate standard treatment practices requires caution as the predictive properties of the surrogate marker for a specific domain may vary. The management of patients with limited-stage Hodgkin’s lymphoma exemplifies this dilemma. Historically, as new treatment strategies were developed to deal with an otherwise fatal malignancy, it is understandable that evaluations of disease control would be a central outcome measure. As it is now apparent that, in these patients, long-term survival and likely quality of life have complex determinants, the need to directly evaluate these specific outcomes is recognized, with a reduced reliance upon use of proxy measures, such as the more narrow evaluation of disease control. Further complicating evaluation of new therapies for patients with limited-stage Hodgkin’s lymphoma is the discrepancy of time lines for evaluating different outcomes. Assessments of disease control, such as progression-free survival, can be reported with reliability after relatively short follow-up periods of 3–5 years, whereas evaluations of long-term overall survival will require more than a decade of follow-up. This discrepancy results from the time required to observe the long-term toxicities of therapy. Recognition of this requirement is particularly important given the young age of most patients with limited-stage Hodgkin’s lymphoma; these patients are unlikely to have confounding comorbidities that would otherwise influence long-term survival, meaning that detrimental late effects of therapy will have a greater proportionate effect on survival. As a result of this time line discrepancy, completion of accrual to randomized trials evaluating new forms of therapy, and reporting of surrogate outcomes such as progression-free survival, will be possible well before the long-term outcomes of previously tested therapies are completely understood. The historical complexity of managing patients with limited-stage Hodgkin’s lymphoma is exemplified by the number of different interventions that have been tested in randomized controlled trials. These include assessments of invasive staging by laparotomy, different fields of radiation therapy, radiation therapy as a single modality versus combined-modality therapy, different chemotherapeutic regimens, and chemotherapy as a single modality. One landmark report was the H6 trial of the European Organisation for Research and Treatment of Cancer (EORTC), which demonstrated that no benefits were detected through use of surgical in comparison with clinical staging^ref. Another landmark report on 2 individual patient-data meta-analyses demonstrated that more extended fields of radiation therapy reduced the risk of disease recurrence at 10 years but did not alter overall survival, and that use of combined-modality therapy in comparison with radiation therapy alone also reduced the risk of recurrent disease but did not significantly alter 10-year overall survival^ref. These reports contributed to evolution of treatment from previous practices of evaluating disease stage and risk by laparotomy and complex prognostic factor schema with treatment including extended-field radiation, to more recent practices in which evaluation of stage emphasizes use of imaging modalities and treatment is with an abbreviated course of chemotherapy combined with involved-field radiation therapy. The choice of chemotherapy to be combined with radiation therapy has also been clarified. Randomized trials have confirmed that in comparison with MOPP, treatment with doxorubicin (Adriamycin^®), bleomycin, vinblastine and dacarbazine (ABVD) or MOPP-ABV(D) (with or without dacarbazine) provides superior disease control (Connors JM, Noordijk EM, Horning SJ. Hodgkin’s lymphoma: basing the treatment on the evidence. Hematology (Am Soc Hematol Educ Program). 2001;178–193). Randomized trials comparing ABVD with MOPP-ABV(D) have failed to detect differences in disease control or overall survival (Connors JM, Noordijk EM, Horning SJ. Hodgkin’s lymphoma: basing the treatment on the evidence. Hematology (Am Soc Hematol Educ Program). 2001;178–193); treatment with ABVD is associated with less treatment-related toxicity and is considered to carry a lower long-term risk of infertility and development of acute leukemia or myelodysplasia. These results have led to ABVD becoming a standard regimen in treating patients with limited-stage disease. Based on the above results, a recent generation of randomized trials conducted by multiple cooperative groups has been reported. These trials have tested combined-modality therapy, in which the extent of a therapeutic modality is reduced, or use of chemotherapy alone. In 3 studies of an abbreviated course of chemotherapy (ABVD (Sieber M, Franklin J, Tesch H, et al. Two cycles ABVD plus extended field radiotherapy is superior to radiotherapy alone in early stage Hodgkin’s disease: results of the German Hodgkin’s Lymphoma Study Group (GHSG) Trial HD7 [abstract]. Blood. 2002;100:93a), AV^ref, or MOPP-ABV (Hagenbeek A, Eghbali H, Fermé C, et al. Three cycles of MOPP/ABV hybrid and involved-field irradiation is more effective than subtotal nodal irradiation in favorable supradiaphragmatic clinical stages I–II Hodgkin’s disease: preliminary results of the EORTC-GELA H8-F randomized trial in 543 patients [abstract]. Blood. 2000;96:575a)) combined with radiation therapy (extended (Sieber M, Franklin J, Tesch H, et al. Two cycles ABVD plus extended field radiotherapy is superior to radiotherapy alone in early stage Hodgkin’s disease: results of the German Hodgkin’s Lymphoma Study Group (GHSG) Trial HD7 [abstract]. Blood. 2002;100:93a)^ref or involved-field (Hagenbeek A, Eghbali H, Fermé C, et al. 3 cycles of MOPP/ABV hybrid and involved-field irradiation is more effective than subtotal nodal irradiation in favorable supradiaphragmatic clinical stages I–II Hodgkin’s disease: preliminary results of the EORTC-GELA H8-F randomized trial in 543 patients [abstract]. Blood. 2000;96:575a)) compared with extended-field radiation therapy, disease control was superior in each trial in the groups receiving combined-modality therapy. In one trial, overall survival was also superior (Hagenbeek A, Eghbali H, Fermé C, et al. Three cycles of MOPP/ABV hybrid and involved-field irradiation is more effective than subtotal nodal irradiation in favorable supradiaphragmatic clinical stages I–II Hodgkin’s disease: preliminary results of the EORTC-GELA H8-F randomized trial in 543 patients [abstract]. Blood. 2000;96:575a). These results have led to a reasonable choice of standard therapy including 2–3 cycles of ABVD and involved-field radiation therapy. The National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) led a trial involving 399 patients with non-bulky stages I–IIA disease that compared 4–6 cycles of ABVD with standard therapy that included radiation therapy (extended-field radiation alone in favorable risk patients and combined-modality therapy in unfavorable risk patients).4 With a median follow-up of 4.2 years, 5-year freedom from disease progression was superior in patients allocated to radiation therapy (93% vs. 87%; P = 0.006), but no difference in overall survival was detected (94% with radiation therapy and 96% with ABVD; P = 0.4). The potential role of this trial in determining current standard practices will be discussed below. Selected recent randomized trials testing therapies in patients with limited-stage HL :

author	control group therapy	experimental group therapy	number evaluated	disease control outcome	overall survival
Sieber M, Franklin J, Tesch H, et al. Two cycles ABVD plus extended field radiotherapy is superior to radiotherapy alone in early stage Hodgkin’s disease: results of the German Hodgkin’s Lymphoma Study Group (GHSG) Trial HD7 [abstract]. Blood. 2002;100:93a	extended-field radiation (EF RT)	combined modality therapy (CMT) : 2 ABVD + EF RT	571	2-yr freedom from treatment failure (FFTF) : 96% vs 84%; P < 0.05	2-yr: 98%  vs 98%;  P = ns
Pressref	EF RT	CMT: 3 doxorubicin (Adriamycin), vinblastine (AV) + EF RT	326	3-yr failure-free survival (FFS) : 94% vs 81%; P < 0.001	3-yr:  both > 95%;  P = ns
Hagenbeek A, Eghbali H, Fermé C, et al. Three cycles of MOPP/ABV hybrid and involved-field irradiation is more effective than subtotal nodal irradiation in favorable supradiaphragmatic clinical stages I–II Hodgkin’s disease: preliminary results of the EORTC-GELA H8-F randomized trial in 543 patients [abstract]. Blood. 2000;96:575a.	EF RT	CMT: 3 MOPP-ABV + involved-field radiation (IF RT)	543	4-yr FFS: 99% vs 77%; P < 0.001	4-yr: 99%  vs 95%;  P = 0.019
Meyer RM, Gospodarowicz M, Connors J, et al. A randomized phase III comparison of single-modality ABVD with a strategy that includes radiation therapy in patients with early-stage Hodgkin’s disease: the HD-6 trial of the National Cancer Institute of Canada Clinical Trials Group (Eastern Cooperative Oncology Group Trial JHD06) [abstract]. Blood. 2003;102:26a	EF RT  (favorable cohort)  or CMT  (unfavorable cohort):  2 ABVD + EF RT	ABVD: 4 cycles if CR  after 2 cycles 6 cycles if no CR  after 2 cycles	399	5-yr freedom from progression (FFP) : 87% vs 93%; P = 0.006	5-yr: 96%  vs 94%; P = 0.4

Through cooperative group mechanisms, the above trials have included larger sample sizes with homogeneous groups of patients with limited-stage HL. 2 randomized trials conducted at single institutions also provide supporting data to the findings described above, although conclusions from these trials are limited by inclusion of smaller numbers and more heterogeneous groups of patients. To evaluate the role of radiation field size, Bonadonna et al have reported the outcomes of 140 patients with stage I-II A/B disease including 20% who had bulky mediastinal disease^ref. Patients received 6 cycles of ABVD followed by involved-field or subtotal nodal radiation; no differences in 12-year PFS (94% vs 93%) or OS (94% vs 96%) were detected in the two respective groups. To test the role of chemotherapy alone, Straus et al have reported the results of a randomized trial comparing ABVD plus involved or more extended fields of radiation to ABVD alone in 152 patients with stage I-II A/B and IIIA disease (Straus DJ, Yahalom J, Zelenetz AD, et al. Results of a prospective randomized trial of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) alone vs. ABVD + radiation therapy for early stage non bulky Hodgkin’s disease [abstract]. Blood. 2001;98:769a). No differences in 5-year freedom from progression (86% vs 81%) or overall survival (97% vs 92%) were detected in the groups who were or were not randomized to receive radiation therapy. Assessments of the risks of second cancers and cardiovascular events in patients treated for HL have been facilitated by the availability of large inception cohorts evaluated by co-operative groups and single institutions. Particularly for assessment of second cancers, large geographically based registries allow comparison of the observed risk of developing a second neoplasm with the expected risk of developing cancer in a control population. Pooling of data by multiple groups further strengthens these evaluations. Dating back to the 1989 Paris Workshop, analyses have clearly identified that patients treated for Hodgkin’s disease were at increased risk of developing second cancers, including solid tumors, acute leukemia and NHL (Henry-Amar M, Aeppli DM, Anderson J, et al. Study of Second Cancer Risk. In Somers R, Henry-Amar M, Meerwaldt JK, Carde P, eds. Treatment Strategy in Hodgkin’s Disease. London: John Libbey and Co; 1990:355–379). For each of these malignancies, older age at the time of treatment predicted for an increased risk of developing the malignancy. The risk of developing a solid tumor was also associated with wide-field radiation therapy and combining any radiation therapy with MOPP-like chemotherapy. A review of these reports requires an appraisal of variables that differ between studies including patient and disease-related factors (e.g., age at diagnosis, stage or other risk features that might influence clinical course or treatment received, need for second or subsequent-line therapy), treatment factors (e.g., radiation therapy, chemotherapy, combined modality therapy, stem cell transplantation), and methodologic features of the study (e.g., details of constructing the inception cohort, duration of follow-up, loss to follow-up, calculation of relative risk and/or absolute excess risk). Studies that report both the relative risk of developing a second malignancy and the absolute excess risk observed are particularly informative. Relative risk refers to the ratio of observed cancers to that expected; high relative risks might be associated with the frequent development of a specific cancer in patients previously treated for Hodgkin’s lymphoma, or conversely the observation of malignancies that would be uncommonly expected in control populations. Absolute excess risk refers to the absolute number of excess cancers observed in comparison with those expected with conversion of this value to account for the number of patient-years of follow-up; this value more appropriately reflects the additional burden of the second malignancy. Selected recent trials evaluating second cancers in patients treated for HL :

author	years of accrual	no. of  treated  patients	range of follow-up	no. of pts. with second cancers			relative risk = ratio of observed vs. expected events			absolute excess risk refers to the number of observed events minus expected events per 10,000 patient–years of follow-up)
				all cancers	solid  tumors  (% of second cancers)	leukemia	all cancers	solid  tumors  (% of second cancers)	leukemia	all cancers	solid  tumors  (% of second cancers)	leukemia
Doresref	1935–1994	32,591	1 – > 30 yrs  (mean = 7.8 yrs; > 15 yrs = 19%)	2,153	1,726  (80)	249  (12)	2.3	2.0	9.9	47.2	33.1  (68)	8.8  (19)
Swerdlowref	1963–1993	5,519	1 – > 25 yrs  (mean 8.5 yrs)	322	227  (70)	45  (14)	2.9	ns	14.6	44.5	25.9  (58)	8.9  (20)
Ngref	1969–1997	1,319	< 1 – > 20 yrs  (median 12 yrs)	181	131  (72)	23  (13)	4.6	3.5	82.5	89.3	59.1  (66)	14.3  (16)
Van Leeuwenref (eligibility restricted to patients less than 40 years of age when treated for Hodgkin’s lymphoma)	1966–1986	1,253	1 – > 20 yrs  (median 14.1 yrs)	137	106  (77)	18  (13)	7.0	6.1	37.5	2.3	54.5  (75)	10.8  (15)
Metayerref (eligibility restricted to patients less than 21 years of age when treated for Hodgkin’s lymphoma)	1935–1994	5,925	1 – > 20 yrs  (mean = 10.5 yrs;  > 15 yrs = 27%)	195	157  (81)	28  (14)	7.7	7.0	20.9	ns	24.0 nd	ns nd
Bhatiaref (eligibility restricted to patients less than 16 years of age when treated for Hodgkin’s lymphoma)	1955–1986	1,380	0.1 – 37 yrs  (median 11.4 yrs)	79	47  (59)	26  (33)	18.8	11.8	78.8	ns	ns nd	ns nd

These studies demonstrate several consistent features:
• solid tumors comprise the most common type of second malignancy, accounting for 59–80% of cases and 58–75% of absolute excess risk.
• leukemia and NHL make up a relatively small number of second cancers observed, but are associated with very high relative risks because of the uncommon expectation of these malignancies in the control populations.
• studies evaluating age of treatment for HL demonstrate that younger age is associated with higher relative risks for developing a solid tumor^{ref1, ref2}; this in part reflects the relatively lower incidence of malignancies expected in matched control populations. Within adult populations, absolute excess risks appears to increase with increasing age—this finding may be particularly weighted by risks associated with developing lung cancer^{ref1, ref2, ref3}
• the cumulative risk of developing a solid tumor continuously increases, until at least 25 years of follow-up. In contrast, the risk of developing acute leukemia is predominantly confined to the first 10 years of follow-up^ref
• treatment received is associated with different risks of developing specific second cancers. The risk of developing a solid tumor is increased in patients receiving radiation therapy in comparison with those receiving chemotherapy alone^{ref1, ref2, ref3}. This risk may be further increased by use of larger radiation fields^ref and, at least for some solid tumors, by use of combined-modality therapy^{ref1, ref2, ref3, ref4, ref5}. Risk of a second malignancy progressively increases over time in patients who have received radiation therapy, whereas a plateau in cumulative incidence is suggested in patients who receive chemotherapy alone^ref. Data regarding the risk of long-term cardiovascular events in patients treated for HL are less comprehensive as geographic registries for cardiovascular disease are less sophisticated than those seen for cancer. In addition, different types of cardiovascular events exist (e.g., coronary and non-coronary artery disease, valvular and pericardial disease) and these can be defined by different outcome measures (e.g., symptomatic or asymptomatic detection, association with hospitalization and/or surgical intervention, death). Observations from these studies include the following:

Selected recent trials evaluating cardiovascular events in patients treated for Hodgkin’s lymphoma :

no. of pts. with cardiovascular events

relative risk = ratio of observed vs. expected events

absolute excess risk refers to the number of observed events minus expected events per 10,000 patient-years of follow-up

author

years of accrual

no. of  treated  patients

range of follow-up

cardiac

noncardiac

valvular

cardiac

noncardiac

valvular

cardiac

noncardiac

valvular

Hullref

1962–1998

415

2.1–36.3 yrs  (median 11.2 yrs)

42

30

25

1.63 (refers to number of surgical interventions performed in comparison with a matched control population)

ns

1.63 (refers to number of surgical interventions performed in comparison with a matched control population)

ns

ns

ns

Reindersref

1965–1980

258

0.7–26.2 yrs  (median 14.2 yrs)

31

ns

ns

5.3 (refers to fatal cardiac ischemic events)

ns

ns

281 (refers to fatal cardiac ischemic events)

ns

ns

Erikssonref

1972–1985

157

10–23 yrs  (median 16 yrs)

13 (refers to fatal cardiac ischemic events)

ns

ns

5.0 (refers to fatal cardiac ischemic events)

ns

ns

51 (refers to fatal cardiac ischemic events)

ns

ns

Leeref

1970–1986

210

0.35–26.5 yrs  (median 15.6 yrs)

28 (refers to myocardial infarction; 31 other patients had other cardiac events; 16 deaths (25% of all deaths) were attributed to a cardiovascular event)

16 (refers to stroke, transient ischemic attack or carotid artery narrowing)

ns

ns

ns

ns

ns

ns

ns

The actuarial risk of developing symptomatic coronary artery disease appears to be in the range of 6% at 10 years and 10–20% at 20 years^{ref1, ref2}. These rates represent relative risks for surgical intervention or hospitalization of 1.5–2.0. The actuarial risks of death from cardiac ischemia appear to be 2–6% at 10 years and 10–12% at 15 to 25 years. These rates represent relative risks of approximately 5 in comparison with control populations^{ref2, ref2}. The actuarial risk of non-cardiac (e.g., carotid or subclavian vessel) vascular events is approximately 3% at 10 years and 7% at 20 years^ref. The actuarial risk of valvular heart disease is 4% at 15 years and 6% at 20 years. These represent relative risks of 8 to 9 with respect to the need for valve replacement^ref. Increased risks of cardiac events are particularly observed in patients who have known cardiac risk factors such as hypertension and hyperlipidemia. Use of chemotherapy, in addition to radiation treatment, does not appear to confer a higher risk^{ref1, ref2}. In summary, patients treated for Hodgkin’s lymphoma are at increased risk for second cancers and cardiovascular complications; these events now comprise the major causes of death in patients with limited-stage Hodgkin’s lymphoma. These risks are principally due to the use of radiation therapy. While it is reasonable to propose that reductions in radiation field size and dose might reduce these risks, long-term follow-up of randomized trials testing these strategies, and associated meta-analyses, will be required to confirm these hypotheses. Based on current data, there are two reasonable options of therapy for patients with limited-stage Hodgkin’s lymphoma. The choice between these options requires that patients be informed of the trade-offs of potential superior disease control when radiation therapy is included versus the risks of late effects associated with this therapy. One standard option is treatment with combined-modality therapy that includes 2–3 cycles of ABVD and involved-field radiation therapy (Diehl V, Stein H, Hummel M, Zollinger R, Connors JM. Hodgkin’s lymphoma: biology and treatment strategies for primary, refractory, and relapsed disease. Hematology (Am Soc Hematol Educ Program). 2003;225–247). Details within this option may be clarified by the results of new trials, including the role of 2 versus 4 cycles of ABVD, based on data from the German Hodgkin’s Study Group (GHSG) HD-10 trial, and the role of different doses of involved-field radiation therapy, such as 20 versus 30 Gy (GHSG HD-10 trial) and 20 versus 36 Gy (EORTC H9 trial). Further minimization of chemotherapy, such as use of AV as reported by Press et al in a trial conducted by the Southwest Oncology Group^ref, is now being tested by the GHSG in their H-13 trial that compares ABVD with AV, ABV and AVD. However, all of these options will continue to include some long-term risk associated with use of radiation therapy, and while reporting of disease control may be possible within the next 3–5 years, evaluations of long-term toxicities are unlikely to become apparent for another decade. An alternative current option is to consider treatment with ABVD alone. Based on the data of the NCIC-CTG trial, long-term disease control can be expected in 87% of patients. While this degree of disease control is less than that observed in patients receiving combined modality therapy, the risks of inferior disease control may be counterbalanced by a reduced risk of long-term toxicities. Further analysis of this trial may permit identification of specific patient groups that are particularly likely to experience long-term disease control, and evaluations of quality of life may facilitate determination of patient preferences in considering risk-benefit trade-offs during the decision-making process. Future advances may result from developments in diagnostic testing. Application of new imaging modalities, such as PET scanning, may facilitate abilities to more confidently identify at earlier points in therapy those patients who have received sufficient treatment to provide long-term disease control, thus potentially permitting an ability to avoid exposure to additional therapies. Enhanced understandings of the basic pathogenic mechanisms of Hodgkin’s lymphoma, including molecular profiling, may also assist in identifying specific prognostic groups that might receive different therapies. However, advances in these, and other related fields, will require the completion of randomized controlled trials that have sufficient follow-up to properly assess overall survival.
• treatment of advanced HD :
• combination chemotherapy regimens : the introduction of MOPP by DeVita and colleagues in the 1960s^{ref1, ref2} represented a major advance in the treatment of advanced HD. The interest in the mustard compounds followed observations made during World War I, when exposure to mustard gas was found to induce marrow hypoplasia and involution of lymphoid tissue^ref.3 Research on the biologic effects of these agents was published during the 1920s and 1930s (The pathology of mustard poisoning. In: Winternitz MC. Collected studies on the pathology of war gas poisoning from the Department of Pathology and Bacteriology, medical science section, chemical warfare. New Haven, CT: Yale University Press, 1920:101-16)^ref. Initial clinical trial with a nitrogen mustard at Yale University^ref. Goodman and Gilman, who were in the section of Chemical Warfare during World War II, conducted experiments on the mustard compounds in the Department of Pharmacology at Yale University, which led to the initial clinical trial in 1942, antedating the famous Bari incident (Infield GB. Disaster at Bari. New York: Macmillan, 1971). Many modifications of this regimen were developed to reduce acute toxicity and this was probably achieved without any loss of anti-tumor activity^ref (e.g.
• ChlVPP
• GEM-P
The development of ABVD by Bonadonna and colleagues a decade later, represents the next most important step in Hodgkin's therapy and is usually regarded as the modern therapeutic `gold standard.' It probably has more anti-tumor activity than MOPP^{ref1, ref2} and is less sterilizing and less leukemogenic. Doxorubicin 25 mg/m² IV days 1, 15, bleomycin  10 units/m² IV days 1, 15, vinblastine 6 mg/m² IV days 1, 15, dacarbazine 350-375 mg/m² IV days 1, 15. Repeat cycle every 28 days. Grade 3-4 neutropenia (21%), grade 3 anemia (5%), grade 3-4 infection (2%), thrombocytopenia (5%), nausea/vomiting (33%), grade 3 alopecia (24%), pulmonary toxicity (6%), peripheral neuropathy (1%) => death due to pulmonary toxicity (3%), > 80% of patients received full-dose doxorubicin. Emetogenic potential days 1, 15 level 5^ref.
The ABVD regimen was combined early on with MOPP in an alternating schedule^ref, and since then many alternating or hybrid schedules have been designed. Overall, these alternating and hybrid regimens have proven to be superior to MOPP but not to ABVD^ref. Nonetheless, there has appeared to be a steady improvement in survival over the last 3 decades^{Vaughan Hudson B, 212}, due as much to improvements in supportive care and the ability to administrate full-dose therapy as to the development of new regimens. Selected randomized trials in advanced HD :

study group	patients	regimens	no. of patients	survival results
				FFS	OS	years (time point for FFS and OS)
Cancer and Acute Leukemia Group B (CALGB) (24)	stages IIIA2 IIIB and IV or RT relapses	MOPP	123	50%	66%	5
		MOPP alt ABVD	23	65% (significant difference)	75%	5
		ABVD	115	61% (significant difference)	73%	5
CALGB 8952 (26)	Stage III or IV or RT relapses	ABVD	428	65%	87%	3
		MOPP/ABV hybrid	428	67%	85%	3
Instituto Nazionale Tumori (INT) MILAN (27)	Stage IB, IIA (bulky)	MOPP alt ABVD	211	67%	74%	10
	III and IV	MOPP/ABV hybrid	204	69%	72%	10
Eastern Cooperative Oncology Group (ECOG), CALGB, Southwest Oncology Group (SWOG) (28)	Stage IIIA2 IIIB and IV or RT relapses	MOPP/ABVD sequential	344	54%	71%	8
		MOPP/ABV hybrid	347	64% (significant difference)	79% (significant difference)	8
National Cancer Institute of Canada (NCI-C) (29)	Stage IIIB or IV or RT relapses	MOPP alt ABVD	148	67%	83%	5
		MOPP/ABV hybrid	153	71%	81%	5

Patients who relapse ...
• immediately can undergone nonmyeloablative allogeneic HSCT
• within 1 year can be treated with the same chemotherapeuticals + autogeneic BMT or PBSCT or with other chemotherapeuticals;
• after 1 year can continue the same chemotherapy : 25% recover
• consolidation external beam radiotherapy (EBRT) : it is a common practice to give consolidation radiotherapy to sites of bulk disease in patients achieving a complete remission with chemotherapy, but the evidence is not compelling. In the Groupe d'Etude des Lymphomes de l'Adulte (GELA) H89 trial, patients in CR or good PR after 6 cycles of chemotherapy were randomized to receive two more cycles of the same chemotherapy or STNI^ref. There was no advantage to radiotherapy consolidation when a doxorubicin-containing regimen had been used. A meta-analysis by the International Database on Hodgkin's Disease Overview Study Group concluded that, providing an adequate number of chemotherapy cycles were administered, the addition of radiotherapy did not improve tumor control and was associated with a reduced survival probably due to long-term toxicity^ref.
• escalated therapies : recently 2 regimens have been reported to have an improved disease-free survival, namely
• Stanford V
• escalated BEACOPP is a very dose-intensive regimen requiring growth factor support
 The overall survival in these regimens is impressive but in a recent BNLI and CLG trial, although the failure-free survival at 3 years in the non-escalated alternating ChlVPP/PABLOE (ChlVPP + prednisolone, doxorubicin, bleomycin, vincristine and etoposide) arm was only 77%, the overall survival at 3 years was 91%^ref. A very large trial with long-term follow-up is likely to be required to demonstrate that any other regimen results in better overall survival than this. Preliminary results of recent regimens for advanced Hodgkin's disease :

regimen	no. of patients	FFS	OS	years (time point for FFS and OS)
Stanford V (32)	94, single center	89%	93%	6
Stanford V (33)	47, multicenter	85%	96%	6
BEACOPP (34) (escalated)	403, multicenter	88%	91%	3

A further extension of dose-intensification is the use of high-dose therapy in first remission as reported by Carella and colleagues^ref. This approach is clearly only appropriate in highly selected patients because most patients will already be cured when they achieve complete remission. Selection is also not straightforward, because most of the poor risk features predict for a reduced complete remission rate and their impact is reduced, albeit not eliminated, once remission is attained^{ref1, ref2}.
• anti-CD20 monoclonal antibody targeting normal B cells in HD lesions (which contribute to the survival of malignant Hodgkin and Reed-Sternberg cells) : 22% of treated patients achieve a complete remission lasting a median of 7.8 months, while 36% see their disease stabilize
• allogeneic HSCT is still controversial. Early results of allogeneic HSCT after conventional conditioning indicated TRM > 50% and survival < 20%. The introduction of reduced-intensity conditioning (RIC) prior to transplantation has reduced TRM. Unfortunately GVHD, relapse rates and survival have not substantially changed^ref. In patients with multiply relapsed HL allogeneic HSCT has been limited by prohibitive non-relapse-related mortality rates and by a lack of definitive evidence for a therapeutic GvT effect
• reduced-intensity conditioning allogeneic HSCT
• 49 patients with multiply relapsed Hodgkin's lymphoma, 44 (90%) of whom had progression of disease after previous autologous transplantation (median age 32 years [range 18-51], number of previous treatment courses was 5 [range 3-8], and time from diagnosis 4.8 years [range 0.6-4.8]). 31 patients had HLA matched donors who were related and 18 had donors who were unrelated. Median follow-up was 967 days (range 102-2232). The primary endpoints were engraftment, toxic effects, non-relapse-related mortality, incidence of graft-versus-host disease (GVHD), and the toxic effects of adjuvant DLI. All patients engrafted. 8 of 49 (16%) had grade II-IV acute GVHD and 7 (14%) had chronic GVHD before DLI 16 (33%) patients received DLI from 3 months after transplantation for residual disease or progression. 6 (38%) of the 16 developed grade II-IV acute GVHD and 5 developed chronic GVHD. 9 (56%) showed disease responses after infusion (8 complete, 1 partial). Non-relapse-related mortality was 16.3% at 730 days (7.2% for patients who had related donors vs 34.1% for those with unrelated donors, p=0.0206). Projected 4 year OS and PFS were 55.7% and 39.0%, respectively (62.0% and 41.5% for related donors). These data show the potential for durable responses in patients who have previously had substantial treatment for HL. The low non-relapse-related mortality suggests the procedure could be undertaken earlier in the course of the disease^{ref1, ref2}.
• 40 patients with relapsed or refractory HL were homogeneously treated with an RIC protocol (fludarabine 150 mg/m² intravenously plus melphalan 140 mg/m² intravenously) and cyclosporin A and methotrexate as GVHD prophylaxis. 21 patients (53%) had received >2 lines of chemotherapy, 23 patients (58%) had received radiotherapy, and 29 patients (73%) had experienced treatment failure with a previous autologous stem cell transplantation. Twenty patients (50%) were allografted in resistant relapse, and 38 patients received hematopoietic cells from an HLA-identical sibling. Five patients (12%) died from early transplant-related mortality (before day +100 after allo-RIC). 1-year transplant-related mortality was 25%. Acute GVHD developed in 18 patients (45%). Chronic GVHD developed in 17 (45%) of the 31 evaluable patients. The response rate 3 months after the allo-RIC was 67% (21 [52%] complete remissions and 6 [15%] partial remissions). 11 patients received DLIs for disease relapse. The response rate after DLI was 54% (3 CR and 3 PR). OS and PFS were 48% +/- 10% and 32% +/- 10% at 2 years, respectively. Refractoriness to chemotherapy was the only adverse prognostic factor for both OS (63% +/- 12% versus 35% +/- 13%; P = .05) and PFS (55% +/- 16% versus 10% +/- 9%; P = .006). For patients with failure of a prior autologous HSCT, results were especially good for those who experienced late relapses (>/=12 months: 2-year OS and PFS were 75% +/- 16% and 70% +/- 18%, respectively). These data suggest that allo-RIC is feasible in heavily pretreated HL patients and has an acceptable early transplant-related mortality. Results are better in patients allografted in sensitive disease. Both responses observed after the development of GVHD and DLI may suggest a graft-versus-HL effect. Allo-RIC has to be considered an effective therapeutic approach for patients who have had treatment failure with a previous autologous HSCT^ref
• anti-CD52 monoclonal antibody (McKinnon ?)
• bortezomib for relapsed classical HL^ref
• patients with active disease display functional impairment of Ag-specific CD8⁺ T cells due to expansion of regulatory T cells at sites of disease and in the peripheral blood. Adoptive cellular immunotherapy based on EBV-specific CD8⁺ T cells has been explored with limited success to date. It has been proposed that improved targeting of these CD8⁺ T cells toward viral Ags that are expressed in HL may enhance future therapeutic vaccine strategies. In this study, we have developed a novel replication-deficient adenoviral Ag presentation system that is designed to encode glycine alanine repeat-deleted EBNA1 covalently linked to multiple CD8⁺ T cell epitopes from latent membrane proteins 1 and 2. A single stimulation of CD8⁺ T cells from healthy virus carriers, and patients with HL with this adenoviral construct in combination with IL-2, was sufficient to reverse the functional T cell impairment and restored both IFN-gamma production and cytolytic function. More importantly, these activated CD8⁺ T cells responded to tumor cells expressing membrane proteins and recognized novel EBNA1 epitopes. Flow cytometric analysis revealed that a large proportion of T cells expanded from patients with HL were CD62L^high and CD27^high, and CCR7^low, consistent with early to mid effector T cells. These findings provide an important platform for translation of Ag-specific adoptive immunotherapy for the treatment of EBV-associated malignancies such as HL and nasopharyngeal carcinoma^ref
It will be increasingly difficult to demonstrate that new regimens improve overall survival, and multinational collaboration will be required. Most trials are likely to use event-free survival as their end-point, but reliance on this parameter alone must be seriously questioned. Follow-up of trials for extended periods will be required to allow full assessment of long-term side effects, and quality-of-life studies will be necessary. These kinds of studies are exceedingly complex because they need to take into account any salvage therapies as well as the primary therapy. Extended radiation fields such as STNI in localized Hodgkin's disease may result in increased morbidity and possibly more secondary malignancies than a mantle field but they will result in a lower proportion of patients being exposed to full-dose chemotherapy. The more intensive regimens for advanced disease will undoubtedly have greater immediate morbidity and cost and possibly more long-term sequelae, but they will result in fewer patients receiving very high dose therapy with hemopoietic stem cell rescue. Increasingly patients will be involved in the choice of their therapy, which will be a challenge to the design of clinical trials. Patient attitudes are culturally dependent and may not always correspond to those of their physicians, further complicating treatment choice and trial recruitment. The early side effects of importance to patients include nausea and vomiting, fatigue and hair loss. Sexual dysfunction and infertility are major problems to some patients, and the next section of this review addresses the issue of fertility. Social and psychological dysfunction following the diagnosis and management of a malignant disease can be profound and the psychological trauma of relapse should not be underestimated, particularly if the patient is not fully prepared for this eventuality. Other long-term sequelae of treatment include cardiac disease and the development of secondary malignancies. The latter topic is dealt with in the final section.
• strategies for fertility conservation : infertility, premature ovarian failure and hypo-estrogenism are acknowledged side effects of high-dose chemotherapy and abdominal irradiation in patients undergoing curative treatment for malignant diseases. While semen cryopreservation for young men is a routine safeguard for genetic parenting, females have fewer options for fertility conservation and prepubertal boys and girls have none. New strategies, which promise to help more patients, including minors, are now emerging :

procedure	male	female
ligand-receptor mediated	GnRHa	GnRHa, steroids
inhibition of apoptosis	-	Bax
surgical	-	lateral ovarian transposition
cryopreservation	sperm, spermatogonia	embryos, oocytes, primordial follicles

The focus is now on immature germ cells—spermatogonial stem cells, primordial follicles and germinal vesicle oocytes—which can be harvested with less delay, without hormonal priming and at any day of the menstrual cycle. Theoretical and applied methods of safeguarding future fertility in patients undergoing high-dose cytotoxic treatment.
• the cytotoxic basis of infertility : there is ample evidence that ionizing radiation and certain chemotherapeutic drugs, such as alkylating agents and platinum compounds, harm the fertility potential of both males and females^ref. While effects on the reproductive system are manifold, the gonads are particularly vulnerable. Destruction of germ cells manifests in males as infertility, usually with undiminished virilization^ref. Sterility in females is accompanied by lower serum estrogen levels and the onset of climacteric symptoms because the endocrine and germ cells are united in the developmental units, the follicles. Cyclophosphamide is one of the most common chemotherapeutic and immunosuppressive agents for neoplastic and autoimmune diseases, and is an example of an agent causing premature reproductive failure. It destroys primordial follicles in the ovary, and this effect can be sufficiently extensive to trigger premature, irreversible ovarian failure^{ref1, ref2, ref3, ref4}. Whether there is any genetic risk for future children is still debatable. As yet, follow-up studies of the children of cancer survivors have not revealed an excess risk of congenital abnormalities. On the other hand, it would be surprising if the risk to the germ cells was negligible, and animal studies have indicated that reproductive wastage and genetic damage can be transmitted to offspring, even via the male partner^{ref1, ref2, ref3, ref4, ref5}. Powerful new reproductive technologies, such as intracytoplasmic sperm injection (ICSI), raise potential concerns. They provide a chance of genetic parenthood for male cancer patients who received greater cytotoxic damage and were rendered almost completely azoospermic compared with patients in older studies who spontaneously recovered fertility.
• in vivo protection of fertility : there is both clinical and experimental evidence that suppressing gonadotropic stimulation to produce a hypogonadal state can mitigate the sterilizing effects of chemotherapy and radiotherapy. Greater resistance of the ovary to cytotoxic injury before puberty seems to provide prima facie evidence for the hormonal hypothesis, although the advantage of youth is now thought to be mainly due to a larger follicle store rather than a subdued response. Reduced follicle stimulating hormone (FSH) and/or luteinizing hormone (LH) stimulation inhibits entry of spermatogonial stem cells into the expanding and differentiating population, which, it has been supposed, reduces the number of vulnerable cells in mitosis. There is no exact parallel in the ovary, however, because 1) hypogonadotropism does not inhibit follicle recruitment from the primordial pool^ref, and 2) primordial follicles are more sensitive to ionizing radiation (and perhaps alkylating agents) than subsequent stages^ref.13 The theory therefore appears to be more robust for males than females. Nevertheless, there is limited clinical and experimental evidence that follicle inhibition, produced either by steroidal contraception^ref or gonadotropin-releasing hormone (GnRH) agonists to downregulate the pituitary gonadotrophs, is chemo- and/or radio-protective of the gonad^ref. On the other hand, conflicting results have been obtained in animals,16 and there is, as yet, no consensus about the clinical utility of this approach^{ref1, ref2, ref3, ref4, ref5}. An alternative hypothesis has been offered for the mechanism of protecting spermatogenesis by GnRH agonists. Usually, a residue of spermatogonia survives even after high doses of cytotoxins, but they remain dormant and fail to produce progeny for sperm maturation. It has been suggested that the microenvironment may be inappropriate and that high levels of testosterone found in the seminiferous tubules are inhibitory^ref. We must bear in mind, however, that if this strategy does assist the recovery of spermatogenesis there is a potential risk of generating more sperm with damaged DNA and mutations. A similar concern arises from attempts to prevent germ cell apoptosis. In the mouse ovary, the bax gene is crucial for executing the cell death program in follicular oocytes. When bax-/- mice were created by targeted mutagenesis, follicular reserves were found to be larger in old mice than in controls and, moreover, the animals were more resistant to doxorubicin^{ref1, ref2}. In theory, Bax protein inhibitors could prevent early ovarian failure in young patients undergoing sterilizing chemotherapy, but the quality of their oocytes may be compromised. Radiotherapy to the subdiaphragmatic areas in Hodgkin's disease is usually in the form of an inverted Y field irradiation that includes the ovaries. In an attempt to protect the ovaries from radiation, the ovary can be transposed to an extra-pelvic site to avoid the radiation field (lateral ovarian transposition). Traditionally, this is done by laparotomy, either as a part of surgical staging when radiotherapy is anticipated or as a separate procedure^{ref1, ref2, ref3, ref4, ref5}. Lateral ovarian transposition by laparotomy is associated with preservation of ovarian function in 83% of patients after pelvic radiation^ref and is more effective than transposing the ovaries behind the uterus and protecting them with a lead block^ref. In addition, the lead block also may shield affected nodes. Another method is exteriorization of the ovaries under the skin through an opening in the flank. This approach is not widely used and has been associated with ovarian cyst formation^ref. A more complicated technique is heterotopic ovarian transplantation^ref. In this procedure, vascular anastomosis was performed and the ovary was implanted on the inner face of the arm. Ovarian transposition by laparotomy is associated with a larger abdominal incision, a long hospital stay and an increased risk of adhesion formation and intestinal obstruction. In 1998, we described laparoscopic ovarian transposition in a 34-year-old woman with rectal carcinoma^ref. It is a simple procedure without dissection of the cecum. In this case, we transected the ovarian ligament and transposed the ovaries without cutting the fallopian tubes. The ovaries were positioned laterally and anteriorly to the level of the anterior-superior iliac spines, and we also cryopreserved a portion of the left ovary. Despite a large dose of pelvic irradiation in combination with intrathecal brachytherapy, the patient's menstrual cycles were never interrupted and she continued to menstruate regularly every 28 days. She conceived spontaneously 2 years after surgery and, at the time of writing, is in her third trimester of pregnancy. A similar technique in a 17-year-old female with non-Hodgkin's lymphoma was reported, and 3 months after irradiation she was having regular menses with normal day 3 serum FSH^ref. There is, of course, a small risk that the transposed ovary may harbor metastases^ref, but this is a very unusual site of spread in HD.
• low temperature banking of gametes and germ cells :
• current practices :
• sperm cryopreservation is standard for young men prior to sterilizing chemotherapy and irradiation. Given that it is routine, inexpensive and technically undemanding, it is tempting to regard it as an infallible procedure whereas in practice it has shortcomings. For a start, it cannot be used for pre-adolescents. Fertile men sometimes have difficulty producing a specimen under the stress of recent cancer diagnosis and may produce inferior specimens because of pyrexia or other disease-associated effects Moreover, the supply of frozen straws is limited and artificial insemination has a relatively low success rate per cycle even under optimal conditions using donor sperm^ref. Donor sperm for conception is generally regarded as a last resort, which is why development of methods for retrieving mature or immature spermatozoa from the male genital tract has been widely welcomed. A testicular biopsy often produces enough sperm for intracytoplasmic sperm injection (ICSI) of their partner's oocytes collected after controlled ovarian stimulation^ref.
• the female equivalent of sperm banking is oocyte cryopreservation, but this is not (yet) a routine procedure. Worldwide, > 40 babies have been conceived after freeze-thawing oocytes, although, to our knowledge, none of them were born to former cancer patients. Following a few case reports in the 1980s, there were warnings of metaphase spindle defects and hardening of the zona pellucida after cooling human oocytes or exposing them to cryoprotective agents^ref. Recently, there has been a flurry of isolated reports of success with oocyte cryopreservation, attributed to ICSI and different cryoprotective agents to overcome hardening and other problems. We shall probably see further improvements in success rates using either or both equilibrium cooling and ultra-rapid freezing (vitrification) for oocytes, but these will not guarantee fertility conservation until in vitro fertilization (IVF) technology makes more efficient use of precious oocytes. Nor, indeed, does embryo cryopreservation provide a full safeguard, even though it is much more established and routine in clinically assisted reproduction^ref.
• frozen embryo banking was introduced for storing surplus embryos after in vitro fertilization to avoid the need to collect more fresh oocytes by repeating a full treatment cycle^ref. A typical cycle requires 4 or more weeks to down-regulate the pituitary gonadotrophs with GnRH agonists followed by controlled stimulation with FSH until the most advanced follicle has a diameter of 18+mm and the oocytes (10) can be aspirated for IVF^{ref1, ref2}. There have been a few case reports of pregnancy after embryo banking for cancer patients^{refAtkinson HG, 199}, but several limitations are acknowledged. First, creation of embryos requires a male partner or donor sperm and, second, oocyte collection from prepubertal girls is inappropriate. Third, there are concerns that embryos could become orphaned and, fourth, there may not be enough time to carry out the procedure before chemotherapy begins. And, lastly, the average chances of a live birth pregnancy from a single IVF treatment cycle are not high, judging from UK national statistics for healthy women with fresh embryos (11.0%) (Human Fertilisation and Embryology Authority, Annual Report. London:HMSO, 1998). For these reasons, attention is turning to the opportunities of banking immature germ cells from either ovaries or testes.
• new opportunities : frozen banking of spermatogonia and immature ovarian follicles are still at an experimental stage; clinical trials have hardly begun although the potential of these methods for helping patients is clear. While appearing to be new concepts, it was over forty years ago in London that Ruth Deansley, Alan Parkes and Audrey Smith demonstrated that spermatogenesis and follicular maturation resume in rat tissues after freeze-thawing and grafting fragments to an abdominal or subcutaneous site^{Deanesley R, 201-206, Parkes AS, 520-528}. With automated freezers and applying modern understanding of cryoinjury, better results can be now be obtained, with the possibility of retrieving sperm or oocytes for assisted fertilization (ICSI) or even restoring natural fertility. A testicular biopsy can be prepared for banking either as intact seminiferous tubules or after isolation of spermatogonial stem cells. The second strategy requires enzymatic disaggregation of seminiferous tubules to produce a semi-purified suspension of germ cells, including the stem cells. When isologous germ cells were reintroduced by microinjection into the seminiferous tubules or via the rete testis of sterilized laboratory rodents, sperm production resumed a few weeks later^ref, and efforts are underway to apply these methods to larger species, including humans^ref. What is more, the stem cells restore sperm production after freeze-thawing and transfer^ref. Cryopreservation of germ cells is slightly more advanced in females than in males, though it should still be regarded as experimental until the results of prospective trials are announced. Being densely fibrous, the human ovary does not appear ideal for cryopreservation, but this pessimism now seems misplaced, and there is a case report of a woman who ovulated after her cryopreserved ovarian autograft was hormonally stimulated^ref. This result follows a substantial number of studies in laboratory and farm animals showing that grafts can function for extended periods and produce normal offspring. Autografting frozen-thawed tissue to the orthotopic site restored ovulatory cycles and potential fertility for at least 22 months in sheep^ref, and oocytes have been retrieved for fertilization from heterotopic grafts^ref. Cryopreserved grafts were capable of providing long-term fertility, at least in mice, and the offspring were normal^ref. Such encouraging results have led to the establishment of ovarian tissue banking in many centers around the world, but we shall have to wait a few more years before the value of this procedure can be gauged objectively^{Gosden RG, 107-114}. Tissue storage does have some limitations. The store of primordial follicles declines with age and the chances of long-term graft function is likely to decline pari passu. It is not possible to define an upper age limit, short of the menopause, though it is likely that banking will turn out to be most successful with children's ovaries. At any age, there will be some patients who are unsuitable for autografting because their cancer has disseminated to the ovaries, and there is a theoretical risk that their original disease will relapse from a transplant^ref. Growing oocytes in immunodeficient mice, provided the disease does not kill the host^{ref1, ref2}, might avert the danger. Methods for growing immature follicles in vitro for harvesting oocytes for IVF are still in their infancy^ref. The attraction of this approach is that it will be possible to exclude malignant cells during embryo transfer to the uterus and perhaps utilize scarce oocytes more economically. On the other hand, the patient would not be able to enjoy any of the physiological benefits that a hormonal graft might provide, and she would have to continue receiving hormone replacement therapy. Lastly, there is a small cohort of immature oocytes represented by antral follicles at every stage of the cycle, even at prepubertal ages, which can be retrieved without prior hormonal stimulation. If cryotechnology of germinal vesicle oocytes became sufficiently reliable, in vitro oocyte maturation would provide one more option for fertility. High pregnancy rates can be obtained in women with polycystic ovaries who undergo in vitro maturation and fertilization of oocytes followed by embryo transfer^{ref1, ref2}. It is partly because the number of options emerging for the conservation of fertility (Figure 1) gives us confidence that cancer patients in future need not surrender all hope of genetic parenthood.
Practical and theoretical options for conserving fertility by cryopreservation :

• secondary neoplasms after Hodgkin's disease : the incidence of secondary neoplasms among survivors of Hodgkin's disease has exceeded the expected incidence of primary tumors in the general population. Death from secondary neoplasms has contributed more than other causes except Hodgkin's disease to the excess mortality rates observed in large populations of treated patients. Experience reported from single institutions and larger population data compiled from multiple centers and cancer registries have confirmed an excess incidence of leukemia, non-Hodgkin's lymphoma, lung cancer, breast cancer, gastric cancer, melanoma, thyroid cancer, and sarcomas of bone and soft tissue in survivors of Hodgkin's disease^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8, ref9, ref10, ref11, ref12, ref13, ref14, ref15, ref16, ref17, ref18, ref19, ref20, ref21, ref22, ref23, ref24}. Tucker et al summarized the experience with secondary cancers in the Hodgkin's disease population at Stanford in 1988^ref. This study was based upon 83 cases among 1,507 patients treated between 1968 and 1985, representing 9,239 person-years of observation and a mean follow-up of 6.2 years. These data have been updated to include 197 secondary cancers observed in a population of 2162 patients^{ref1, ref2}. The follow-up interval at the time of analysis averaged 9.3 years, representing 20,100 person-years of observation. Treatments varied: 1,141 patients initially received radiation therapy alone, 312 of whom required subsequent chemotherapy for recurrent disease; 848 patients received both chemotherapy and irradiation as initial therapy; 71 received radioactive colloidal 198Au to increase the radiation dose to the liver in advanced stage III or IV disease, with half of these patients also receiving chemotherapy; 102 patients received chemotherapy alone as initial treatment, 27 of whom required subsequent irradiation. The follow-up interval averaged 10.9 years for those exposed only to irradiation, 8.8 years for those who received chemotherapy for recurrence, 8.2 years after initial combined modality, and 5.5 years after chemotherapy alone, due to more recent accrual and higher early mortality related to advanced presentations of Hodgkin's disease. The mean age at treatment for all patients was 29 years and was similar for all treatment groups. Since the earlier study by Tucker et al, the risk for all cancers relative to general population risk for an initial primary malignancy has risen from 5.2 to 6.4^ref. The relative risk for leukemia remained quite high at 37.7. With more prolonged follow-up the relative risk for non-Hodgkin's lymphoma has increased from 18 to 35.3. The relative risk for secondary solid tumors increased from 3.2 to 4.3. Specific solid tumor risks are summarized in Table 8. Solid tumors in which the relative risks have increased included lung cancer (from 7.7 to 10.3), melanoma (from 8.9 to 11.6), and soft tissue sarcoma (from 15 to 24.3). The relative risk decreased, somewhat, for gastric cancer (from 10 to 4.9) and osteogenic sarcoma (from 31 to 12.3), but remained significantly elevated. Several tumors that had not been observed in excess in the earlier analysis developed significant risk elevation with more prolonged follow-up. These include the breast (from 1.8 to 4.1), thyroid (10.6), pancreas (3.9), and salivary glands (37.9). The relative risk for all urogenital cancers combined became significantly elevated at 2.2. However, no specific urogenital site was associated with a significantly increased risk.

Risks for secondary cancers after HD :

tumor site	observed / expected	relative risk	IC95	absolute risk is the excess number of observed cancers (or deaths) per 10,000 patients per year according to the formula: Absolute risk = [(observed - expected) / person-years] x 10,000
all cancers-incidence (risks for all cancers and for leukemia or myelogenous leukemia exclude 3 cases of myelodysplastic syndrome because this disease is excluded from the general population rates published by S.E.E.R., which was used for these relative risk calculations)	197/30.8	6.4	5.5 - 7.3	84.4
leukemia	38/1.0	37.7	25.7 - 49.7	18.4
AML	35/0.24	144.1	96.4 - 191.9	17.3
NHL	33/0.9	35.3	23.2 - 47.3	16.0
all solid tumors	126/90.4	4.3	3.5 - 5.0	48.8
all cancers-mortality	104/16.6	6.3	5.1 - 7.5	43.5

Risks for secondary solid tumors after HD treatment according to primary site :

tumor site	observed/expected	relative risk	IC95	absolute risk is the excess number of observed cancers per 10,000 patients per year according to the formula: absolute risk = [(observed - expected) / person-years] x 10,000. Absolute risks are not specified when 95% confidence intervals for relative risk include 1.0.
lung/pleura	36 / 3.5	10.3	7.0 - 13.7	16.2
breast	25 / 6.1	4.1	2.4 - 5.7	21.5
melanoma	9 / 0.8	11.6	5.7 - 21.3	4.1
soft tissue (sarcoma)	8 / 0.3	24.3	11.3 - 48.3	3.8
bone (osteosarcoma)	2 / 0.2	12.3	2.1 - 41.6	0.9
stomach	8 / 1.6	4.9	2.3 - 9.4	3.2
salivary gland	5 / 0.1	37.9	13.8 - 84.2	2.4
thyroid	5 / 0.5	10.6	3.9 - 23.6	2.3
urogenital sites	15 / 6.8	2.2	1.3 - 2.9	4.1
pancreas	3 / 0.8	3.9	1.0 - 10.5	-
colon or rectum	6 / 4.7	1.3	0.5 - 2.7	-
unknown primary	3 / 0.9	3.4	0.8 - 9.2	-
oral cavity	1 / 1.5	0.7	0.0 - 3.3	-

The relative risk of developing a secondary cancer at any site was somewhat higher among patients treated with initial combined modality therapy (7.9) than among patients treated with either initial chemotherapy alone or initial radiation alone with or without subsequent treatments for relapse (5.5). As noted in the earlier analysis, the relative risk was highest after treatment with irradiation and colloidal ¹⁹⁸Au hepatic infusion (9.9), with or without chemotherapy^ref.
Secondary cancer risk according to initial treatment for Hodgkin's disease :

cancer type	therapy	observed cases	relative risk	IC95
all cancers	radiation alone	81	5.4	4.2 - 6.6
	radiation + salvage chemotherapy	24	6.1	3.7 - 8.5
	radiation ± salvage chemotherapy	105	5.5	4.5 - 6.6
	radiation + adjuvant chemotherapy	67	7.9	6.0 - 9.8
	radiation + 198Au ± chemotherapy (37 of 71 patients treated with radiation and 198Au received chemotherapy; 10 of 15 cancers arose in patients with both chemotherapy and radiation exposure)	15	9.9	5.7 - 13.2
	chemotherapy alone	11	5.5	2.8 - 9.8
leukemia	radiation alone	3	6.3	1.6 - 17
	radiation + salvage chemotherapy	5	39.1	14.3 - 87
	radiation + adjuvant chemotherapy	23	76.6	45.3 - 108
	radiation + 198Au ± chemotherapy (37 of 71 patients treated with radiation and 198Au received chemotherapy; 10 of 15 cancers arose in patients with both chemotherapy and radiation exposure)	3	62.8	15.7 - 171
	chemotherapy alone	4	72.1	22.7 - 174
non-Hodgkin's lymphoma	radiation alone	14	31.5	17.8 - 45
	radiation + salvage chemotherapy	7	56.8	24.8 - 112
	radiation + adjuvant chemotherapy	11	43.8	23.7 - 73
	chemotherapy alone	1	21.1	0.0 - 104
solid tumors	radiation alone	64	4.4	3.3 - 5.5
	radiation + salvage chemotherapy	12	3.2	1.7 - 5.4
	radiation + adjuvant chemotherapy	33	4.1	2.7 - 5.5
	radiation + 198Au ± chemotherapy (37 of 71 patients treated with radiation and 198Au received chemotherapy; 10 of 15 cancers arose in patients with both chemotherapy and radiation exposure)	12	8.4	4.5 - 14
	chemotherapy alone	5	1.7	1.0 - 6.4

• secondary leukemia : in the more recent data from Stanford, 35 of the 38 cases of leukemia were of the acute myelogenous or myelomonocytic type (AML). Since earlier analyses of leukemia risk^ref, the relative risk for AML has become significantly increased after radiation alone with two reported cases (17.5; 95% C.I.: 2.9-58). Chemotherapy exposure conferred higher leukemia risks. The relative risk was 126 (95% C.I.: 39.9-305) for patients who received chemotherapy for recurrent Hodgkin's disease after initial radiation, 290 (95% C.I.: 169-412) for those managed with combined modality therapy, 281 (95% C.I.: 70-766) after radiation and colloidal ¹⁹⁸Au, and 360 (95% C.I.: 113-868) after chemotherapy alone. Twenty-nine cases of AML arose among 922 patients who received MOPP. 4 cases developed among 286 patients who received procarbazine, melphalan, and vimblastine (PAVe) with irradiation. Myelodysplastic syndrome developed in 2 patients after initial combined modality therapy and in one patient treated with irradiation alone. Many studies have implicated chemotherapy regimens containing alkylating agents or epipodophyllotoxins as the primary factor determining the risk of secondary leukemia after Hodgkin's disease therapy^{ref1, ref2, Boivin JF, 571 -585, ref4, ref5, ref6, ref7, ref8, ref9}. Among the patients treated at Stanford with irradiation alone, 82.3% received total lymphoid irradiation or subtotal lymphoid irradiation, in which the external iliac, inguinal and femoral lymph node groups were omitted from treatment. Despite exposure of a substantial proportion of the marrow cavities in the axial skeleton to relatively high radiation doses, radiation has been a comparatively weak leukemogen. In a study from the BNLI Swerdlow et al reported a relative risk for acute leukemia of 2.5 (95% C.I.: 0.1-14.1) after treatment with radiation alone, 27.9 (95% C.I.: 12.7-52.9) after chemotherapy alone and 21.5 (95% C.I.: 7.9-46.8) after combined chemotherapy and irradiation^ref. In an analysis from the International Database on Hodgkin's Disease Henry-Amar reported no significant increase in the risk of acute leukemia after localized, regional or extended field irradiation of HL (RR 1.0, 1.2 and 1.3, respectively)^ref. The relative risk of leukemia was increased with chemotherapy alone (3.5 for MOPP-like regimens and 4.3 for other regimens) and was higher with combined radiation and MOPP-like chemotherapy regimens (5.3). Among 1,939 patients treated for Hodgkin's disease in the Netherlands, Van Leeuwen et al found no significant increase in the relative risk of leukemia after treatment with radiation alone (3.1; 95% C.I.: 0.1-17.3)^ref. The risk was 93.4 with initial chemotherapy only (95% C.I.: 25.4-239), 50.6 with initial irradiation and chemotherapy (95% C.I.: 18.6-110) and 51.7 for initial irradiation and chemotherapy at relapse (95% C.I.: 19.0-113). In a subsequent case-control analysis from this population, Van Leeuwen et al found no evidence that radiation use in combined modality treatment regimens increased the risk of acute leukemia above that associated with chemotherapy alone^ref. The extent of the irradiation fields added to chemotherapy made little difference. The relative risk was 1.1 (95% C.I.: 0.15-7.8) with treatment of involved fields only, 0.67 (95% C.I.: 0.08-6.0) with sub-total lymphoid irradiation, and 2.5 (95% C.I.: 0.32-18.8) after total nodal irradiation^ref. Similar conclusions regarding the lack of apparent interaction between irradiation and subsequent leukemia risk were reached by Kaldor et al in an earlier analysis derived from analysis of 163 cases of leukemia among 29,552 patients with Hodgkin's disease^ref. A contrary finding was reported by Andrieu et al, who found a low 2.2% actuarial risk of leukemia with MOPP chemotherapy alone, or combined with mantle, supra-diaphragmatic irradiation and a 9.0% risk for those who received inverted-Y, sub-diaphragmatic irradiation, sub-total lymphoid, or total lymphoid irradiation^ref. Splenectomy was associated with a higher risk of leukemia in some analyses^{ref1, ref2, ref3, ref4, ref5} but not in others^ref. This potential risk factor could not be assessed in the Stanford data because staging laparotomy was routinely employed during the period in which chemotherapy regimens based upon alkylating agents were commonly used. As has been reported in most studies, the peak incidence of secondary leukemia occurs in the first decade after therapy with risk declining after 10 years^{ref1, ref2, ref3, ref4, ref5}. In the Stanford series, all cases of leukemia developed from 1 to 12.5 years after therapy.
• NHL : in contrast to acute leukemia, the risk of developing a non-Hodgkin's lymphoma persists or increases during the second decade after treatment for HL and appears to be relatively independent of the type of initial therapy or total treatment exposure^{ref1, ref2, ref3, ref4, ref5, ref6, ref7}. Among patients treated at Stanford, the relative risk of a secondary NHL was 31.5 after treatment with irradiation alone, 56.8 after radiation and chemotherapy at relapse, and 43.8 after initial chemotherapy and irradiation, but was not significantly elevated in the small cohort managed with chemotherapy alone (21.1). In the BNLI data, the risk for NHL after HL was the same for cohorts of relatively comparable size whether treated with chemotherapy alone, radiation and chemotherapy, or radiation alone^{ref1, ref2}. The risk for secondary NHL is thought to relate to compromised immune function associated with HL and its therapy, because NHLs are also seen with increased frequency in other illnesses associated with significant immune compromise^ref
• secondary solid tumors : the increased risk of developing a secondary solid tumor has generally been attributed to the direct effects of irradiation. Some of the tumors have arisen within or at the margin of irradiated tissue. The latency period between treatment and the development of a solid tumor has tended to be prolonged, which is consistent with theories of radiation carcinogenesis^ref. Several studies have identified extended field irradiation and young age at treatment as major factors contributing to solid tumor risk after treatment^{ref1, ref2, ref3}. In the population of patients treated at Stanford, the relative risk of solid tumors tended to be highest for patients treated with radiation therapy and colloidal ¹⁹⁸Au hepatic infusions with or without chemotherapy^{ref1, ref2}. The relative risk of a secondary solid tumor was 8.4 in this group (95% C.I.: 4.5-14). 6 of the 12 solid tumors that have developed in this small population were lung cancers. The high risk for lung cancer observed in this group has been attributed to uptake of the colloidal ¹⁹⁸Au by the reticuloendothelial cells in the lung^ref. The relative risk for a secondary solid tumor was nearly comparable for treatment with irradiation alone (4.4; 95% C.I.: 3.3-5.5), initial irradiation with chemotherapy at relapse (3.2; 95% C.I.: 1.7-5.4) or initial chemotherapy and irradiation (4.1; 95% C.I.: 2.7-5.5). The risk of a secondary solid tumor was not significantly elevated in the small cohort of patients treated with chemotherapy alone (1.7; 95% C.I.: 1.0-6.4). Swerdlow et al have reported similar relative risks for lung cancers and other solid tumors among cohorts of patients treated with chemotherapy alone, extensive radiotherapy, or combined modality therapy in the BNLI experience^ref. In a case-control study derived from population-based cancer registries and cancer centers, Kaldor et al found that patients treated with chemotherapy alone for HL had twice the risk of secondary lung cancer of those treated with radiotherapy alone^ref. Boivin et al studied secondary neoplasms identified among HL patients from 14 cancer centers in the United States and Canada^ref. They found that chemotherapy exposure was associated with a significantly increased risk of respiratory or intra-thoracic tumors in the first 5 years after therapy (2.2; 95% C.I.: 1.1-4.3). Radiation exposure was associated with an increased relative risk of lung cancer only in the cohort at risk more than 10 years beyond therapy (2.7; 95% C.I.: 1.1-6.8). In an analysis of HL patients in the Surveillance, Epidemiology, and End Results (SEER) Program Travis et al identified an increased relative risk for lung cancer of 2.68 for patients treated initially with chemotherapy alone, 3.09 after treatment with radiation alone, and 3.03 after initial irradiation and chemotherapy^ref. However, the comparability of risk remains in question in this study because information on subsequent therapies was not available to clearly evaluate risk in those patients who never received irradiation.
• lung cancers or pleural malignancies have been the most common secondary solid tumor observed among patients treated for HL at Stanford.25 The relative risk was 10.3 (95% C.I.: 7.0-13.7). Cigarette smoking was implicated as a probable cofactor in secondary lung cancers in the earlier analysis of the Stanford experience and in cases studied by List et al.^{ref1, ref2} In a case-control study from the Netherlands, Van Leeuwen et al reported a relative risk of lung cancer of 4.1 (95% C.I.: 0.48-36) after irradiation when compared to patients treated with chemotherapy alone.34 Lung cancer risk increased with radiation dose to the lung and with exposure to cigarette smoke. Among the smoking variables evaluated, the number of pack-years smoked after diagnosis of HL was most closely correlated to increased lung cancer risk. Among patients who received a radiation dose to the lung of 5 Gy or more, those with less than 1 pack-year of smoking had a relative risk for lung cancer of 2.5 (95% C.I.: 0.21-29.4). Those reporting greater than one pack-year of smoking after diagnosis had a relative risk for lung cancer of 9.1 (95% C.I.: 0.78-106). Chemotherapy exposure was not clearly associated with increased lung cancer risk in this study.
• secondary breast cancer has emerged as a significant concern for women after treatment of HL and appears most closely associated with exposure of breast tissue to irradiation at young age^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8, ref9, ref10, ref11, ref12, ref13, ref14, ref15, ref16, ref17, ref18, ref19}. In the Stanford experience, women who were treated for HL before 20 years of age had a relative risk of developing breast cancer that exceeded 19 and risk declined with increasing age^ref. No excess risk was identified among women treated after 30 years of age. The risk of developing breast cancer within 15 years of treatment was significantly increased for those treated with MOPP chemotherapy with radiation (relative risk 6.3; 95% C.I.: 3.1-11.6). Early risk was not significantly increased among those treated with radiation alone (relative risk 0.8; 95% C.I.: 0.1-2.5). However, risks appeared comparable beyond 15 years for those treated with irradiation alone or with chemotherapy and irradiation. In a recent update, 50 cases of breast cancer were identified among 1,064 women who had been treated for HL at Stanford^ref. The relative risk for secondary breast cancer was 4.7 (95% C.I.: 3.4-6.0). The relative risk became significantly increased between 5 and 9 years after therapy (2.9; 95% C.I.: 1.1-5.9) and rose dramatically between 15 and 19 years after treatment (11.1; 95% C.I.: 6.4-15.8). Within 15 years of treatment the relative risk was not increased for women after irradiation alone (1.8; 95% C.I.: 0.6-3.9), but was significantly increased for women who received irradiation with MOPP or PAVe (3.7; 95% C.I.: 1.8-6.8). This trend to increased risk with chemotherapy exposure persisted for women who were more than 15 years beyond therapy with a relative risk of 12.1 (95% C.I.: 6.6-17.3) after irradiation and MOPP or PAVe chemotherapy, compared to 8.8 (95% C.I.: 5.1-10.9) after irradiation alone. The importance of young age at exposure in determining risk of secondary breast cancer in women was also observed in studies by Mauch et al from Harvard, who found an excess relative risk of breast cancer confined to women treated before 25 years of age, and by Bhatia et al in analysis of secondary cancers among children treated for HL in the Late Effects Study Group cohort^{ref1, ref2}. The prolonged latency of breast cancer risk was also reported by Van Leeuwen et al, who observed significantly increased risk confined to women who were followed more than 15 years after irradiation^ref. Although many of the breast cancers observed after treatment in the Stanford study developed at prolonged latent intervals, 80% of the women affected were under 50 years of age at the diagnosis of a secondary breast cancer^ref. The use of mammography has been controversial for screening individuals in the general population before 50 years of age. However, 12 of the secondary cancers observed in women at Stanford were identified solely by mammography performed before 50 years of age. Dershaw et al have also reported a favorable rate of identification of breast cancer using mammography in young women who had been treated for HL^ref.
• the risk for malignant melanoma was elevated in the recent and previous Stanford experience as well as in reports of several other large populations of patients treated for HL^{ref1, ref2, ref3, ref4, ref5}. Tucker et al analyzed eight melanomas arising in six patients who had been treated for HL^ref. All appeared to be invasive tumors, and most arose within 5 years of treatment. Melanomas appeared to develop equally in irradiated or in unirradiated sites. They showed little histologic evidence of a host immune response, similar to the melanomas observed in renal transplant recipients^ref. Although these findings suggested that compromised host immunity may contribute to the increased risk of melanoma, 5 of the patients displayed manifestations of dysplastic nevus syndrome, which predisposes to malignant melanoma.
• late thyroid cancers have been infrequently observed and seem to feature a prolonged latent interval after HL therapy^ref. Radiation exposure at young age has been clearly implicated in the risk of this neoplasm^ref. A relative risk of 16 was observed in the predominantly young adult population treated for HL at Stanford. In a recent update of secondary cancers in 697 patients treated before 21 years of age at Stanford, Wolden et al reported a relative risk of thyroid cancer of 9.7 (95% C.I.: 2.4-26.4) based upon three cases that arose between 8.2 and 10.7 years after therapy^ref. A somewhat higher relative risk of 68 was observed among children treated for HL in the Late Effects Study Group cohort^ref
The further increase in the relative risks of second cancers in the more recent Stanford data derives from additional person-years of observation at prolonged intervals from HL treatment. Treatments have evolved substantially over the past 40 years. In the early 1960s most patients received aggressive primary radiation treatments alone, which were typically administered at a rate of 2.2 to 2.75 Gy per fraction to 1 of 2 opposed fields each day to a total dose of 44 Gy or more. Daily radiation doses for HL have decreased to 1.5 to 1.8 Gy with normal tissue doses equalized and minimized by treating both opposed fields each day. Most patients now receive limited field irradiation to lower total radiation doses—particularly in younger patients who have had the highest risks for radiation-induced tumors. Chemotherapy has also evolved from alkylating agent-intensive regimens to combinations that appear to be less damaging to bone marrow and fertility. It is hoped that such regimens may cause fewer adverse effects in other normal tissues^{ref1, ref2, ref3,ref4, ref5, ref6}. However, the risk of developing a secondary neoplasm after treatment of HL has changed modestly. Among 1,458 patients treated for HL at Stanford between 1960 and 1980, the actuarial freedom from developing a secondary cancer within 15 years of treatment was 85.9% ± 1.1% compared with 87.1% ± 1.7% for 1,216 patients treated since 1980. The relative stability of the secondary neoplasm risk after therapy for HL has led some to search for germ-line abnormalities that may pre-dispose to malignancy. Ben-Yehuda et al reported increased microsatellite instability and a relatively high (38%) rate of p53 gene mutations in a small cohort of individuals with therapy-related secondary leukemia^ref. This finding suggested a possible "mutator" phenotype that would predispose to an increased risk of malignancies. Felix et al observed the contrary in a cohort of children with therapy-related secondary leukemia^ref. One of 19 children showed evidence of a germ-line p53 mutation that might influence the risk for neoplasia. Otherwise, p53 mutations appeared to be infrequent. Among 11 patients who developed secondary lung cancer, De Benedetti et al identified 4 missense and 2 silent p53 point mutations in 5 patients^ref. The authors reported that the pattern of mutational change observed seemed more typical of responses to oxidative injury or radiation than to smoking. The increased frequency of secondary neoplasms has suggested the possibility of a more radiation-sensitive phenotype to some investigators. Nichols et al searched for evidence of heterozygous germ-line mutations in the ataxia-telangiectasia gene but found no cases in 52 patients who had developed one or more neoplasms after treatment of HL^ref. Thus far, no intrinsic genetic factor has been identified to explain the increased risk of secondary neoplasms after HL. The prevalence of secondary tumors underscores the importance of continued careful follow-up for all individuals after treatment of HL. Follow-up care should include aggressive programs to minimize smoking and careful screening programs, such as breast self-examination and mammography in women irradiated at young age, thyroid examination, skin examinations and periodic chest imaging to identify secondary tumors when they have the greatest potential for cure.

• in cHL : increased number of CD68⁺ macrophages  was correlated with a shortened progression-free survival (P=0.03) and with an increased likelihood of relapse after autologous HSCT (P=0.008), resulting in shortened disease-specific survival (P=0.003). In multivariate analysis, this adverse prognostic factor outperformed the International Prognostic Score for disease-specific survival (P=0.003 vs. P=0.03). The absence of an elevated number of CD68⁺ cells in patients with limited-stage disease defined a subgroup of patients with a long-term disease-specific survival of 100% with the use of current treatment strategies^ref.
• EORTC risk groups :
• early favorable stage : Ann-Arbor I-II without risk factors
• early unfavorable (intermediate) stage : Ann Arbor I-II with at least 1 risk factor (bulky mediastinal adenopathy, age > 50 years, high ESR, > 4 sites)
• advanced stage : Ann Arbor III-IV
• for localized disease (patients with stages I and II supradiaphragmatic HL) : Mendenhall score, 1994^ref the only factors independently predicting a high rate of relapse were :
• tumor dimension (> 6 cm)
• number of sites (> 4 sites)
At 10 years, in patients with and without the two poor prognostic factors treated with radiotherapy alone, the freedom from relapse rates were 53% and 84% (p < .0001) and the absolute survival rates were 72% and 85% (p = .004), respectively. Combined modality therapy significantly improved freedom from relapse, but not absolute survival, in patients with one or both poor prognostic factors.
• for advanced disease : Hasenclever-Diehl score, 1998^ref : 7 factors had similar independent prognostic effects:
• a serum albumin level < 4 g/dl
• hemoglobin level < 10.5 g/dl
• male sex
• age > 45 years
• stage IV disease (according to the Ann Arbor classification)
• leukocytosis (WBC > 15,000/mm³)
• lymphocytopenia (a lymphocyte count < 600/mm³, a count < 8 percent of the WBC or both)
The score predicted the rate of freedom from progression (FFP) of disease as follows :
• good prognosis :
• 0, or no factors (7% of the patients), 84 %
• 1 (22% of the patients), 77%
• 2 (29% of the patients), 67%
• bad prognosis :
• 3 (23% of the patients), 60%
• 4 (12% of the patients), 51%
• >= 5 (7% of the patients), 42%.

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