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Advances in Anatomic Pathology:
doi: 10.1097/PAP.0000000000000002
Review Articles

Hodgkin Lymphoma: Pathology, Pathogenesis, and a Plethora of Potential Prognostic Predictors

King, Rebecca L. MD*,†; Howard, Matthew T. MD; Bagg, Adam MD

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Author Information

*Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia

Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

Division of Hematopathology, Mayo Clinic, Rochester, MN

All figures can be viewed online in color at

The authors have no funding or conflicts of interest to disclose.

Reprints: Adam Bagg, MD, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 7.103 Founders Pavilion, 3400 Spruce Street, Philadelphia, PA 19104-4283 (e-mail:

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Hodgkin lymphoma (HL) encompasses 2 unique clinicopathologic entities, classical Hodgkin lymphoma (CHL) (∼95% of cases) and nodular lymphocyte predominant HL (∼5% of cases). Both subtypes demonstrate a paucity of surreptitious (in CHL) neoplastic B cells within a background of reactive inflammatory cells underscoring both the relatedness of these 2 entities to each other, as well as their distinction from other types of lymphoid neoplasia. Clinically, they are primarily nodal diseases that disseminate in a predictable manner to contiguous nodal regions. The biology of HL as a whole, as well as the genetic and pathologic features that distinguish CHL from nodular lymphocyte predominant HL and other lymphomas has been the subject of a wealth of investigation in recent decades. The aim of this review is to detail the pathologic features of HL and to highlight the recent insights into its molecular basis and the myriad prognostic markers being described.

Hodgkin lymphoma (HL) is a unique entity not only among lymphomas but also among all human malignancies because of the paucity of neoplastic cells found within the tumor. Dating back to the early 1800s, this feature also led to much confusion among pathologists as to whether it represented a reactive process or a neoplastic one.1,2 Although the description of the classic Reed-Sternberg (RS) cell and its inflammatory milieu is over 100 years old, it has only been within the past 2 decades, with the discovery of clonal immunoglobulin gene rearrangements in microdissected Hodgkin cells, that our understanding of HL as a neoplasm of B-cell origin has taken shape.3,4 Stemming from the seminal discovery of its origin as a B-cell lymphoma, a wealth of scientific literature focusing on both the biology and histopathologic features of HL has been produced over the past 20 years. Despite this, many questions about the pathogenesis of HL still remain, and attempts to understand how the pathologic features of this neoplasm translate into its clinical behavior are the subject of ongoing studies. This review will discuss the clinicopathologic features of HL with emphasis on recently described prognostic features, and highlight novel insights into the genetic basis of this unique lymphoma.

Overall, HL accounts for 12% to 30% of all malignant lymphomas.5,6 However, under the umbrella of HL exists 2 clinicopathologic subgroups, classical Hodgkin lymphoma (CHL) and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL).6 The vast majority of HL cases (∼95%) are CHL and the remaining 5% NLPHL. Although these 2 subgroups share enough features to be grouped together as HL, they differ in many clinicopathologic and biological features, and therefore will be frequently discussed separately throughout this review.

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Classical Hodgkin Lymphoma

Another somewhat unusual feature of HL is its bimodal age distribution. The United States sees approximately 9000 new cases of HL each year, with a peak incidence among young adults aged 15 to 35 years and a second peak after the age of 55.5,7 This peak in young adulthood is accounted for primarily by CHL, and more specifically, by the nodular sclerosis (NS) subtype which is the most common of the four histopathologic subtypes of CHL.7–9 Overall, the male to female ratio is 1.5:1; however, females predominate in the early adulthood peak.7–9

HL is a predominantly nodal disease, and typically disseminates in a predictable manner to contiguous nodal sites.10,11 Patients most often present with supradiaphragmatic lymphadenopathy, and mediastinal involvement is frequent.12 When extranodal sites are involved, the spleen, lungs, liver, and bone marrow are most common.10,11 However, extranodal presentation is uncommon, occurring in only rare reported cases. Systemic, or “B,” symptoms are present in approximately 1/3 of patients and factor into clinical staging schemes.

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Nodular Lymphocyte Predominant HL

NLPHL can occur at all ages; however, in contrast to CHL, NLPHL shows a single incidence peak in the fourth decade of life.13 Males are affected 2 to 3 times as often as females. Patients most commonly present with isolated cervical or axillary lymphadenopathy, often of long duration. Involvement of mediastinal lymph nodes and extranodal organs such as the spleen are rare, again distinguishing this entity from CHL.13 Bone marrow involvement is also extremely uncommon and occurs in <5% of cases.13 Systemic symptoms are present in only 10% of cases.13

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Classical Hodgkin Lymphoma

The morphologic hallmark of CHL is the binucleate RS cell present in a mixed inflammatory background (Figs. 1, 2). Classic RS cells are large with prominent nuclear membrane accentuation and large, inclusion-like, eosinophilic nucleoli. Typically, these RS cells comprise the minority of neoplastic cells, with the majority being mononuclear variants showing similar cytologic features. Lacunar cells, whose name comes from cytoplasmic retraction that occurs as an artifact of formalin fixation, as well as “mummified” cells with dark, condensed nuclear chromatin, may also be found throughout the infiltrate. Of course, the distinctive morphologic appearance of CHL comes not only from the presence of these unusual neoplastic cells, but also from the brisk inflammatory background. The composition of this background, as well as the nodal architecture provides the basis for the current morphologic subclassification of CHL by the World Health Organization.6

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Nodular Sclerosis

NS CHL is the most common subtype of CHL accounting for 50% to 80% of cases6–9 and, as mentioned previously, accounts for the peak incidence in young adulthood. This subtype is characterized morphologically by dense bands of collagen fibrosis that thicken the lymph node capsule and dissect through the nodal parenchyma imparting a nodular appearance that is often evident grossly as well as microscopically (Fig. 2). These collagen bands separate nodules of cellularity that are typically composed of scattered RS cells and variants, as well as numerous small lymphocytes, plasma cells, neutrophils, eosinophils, and macrophages in varying proportions. Lacunar cells showing cytoplasmic retraction are most often seen in this morphologic subtype. Occasionally, cases may show large aggregates or sheets of neoplastic cells with a surrounding rim of inflammation. These cases are termed “syncytial variant” and are significant mainly because of the potential for misdiagnosis of a “non-Hodgkin” large cell lymphoma, particularly anaplastic large cell lymphoma, or other nonhematologic malignancy.

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Mixed Cellularity

Mixed cellularity (MC) CHL is the second most common subtype of CHL (20% to 30% of cases)6–9 and is characterized by diffusely effaced lymph node architecture and a lack of collagen fibrosis (Fig. 2). In some cases, especially in the early phases of disease, this subtype may grow in an interfollicular pattern and some residual lymphoid follicles may be present within the node. As the name implies, the background infiltrate is composed of a heterogeneous population of small lymphocytes, eosinophils, plasma cells, and macrophages. MC CHL often presents at higher stages than NS CHL,19 and is more likely to be associated with Epstein Barr virus (EBV) and HIV infection.

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Lymphocyte Rich

Lymphocyte rich (LR) CHL is less frequent and accounts for approximately 5% of all CHL cases.6–9 This subtype demonstrates neoplastic RS cells and variants in a background of predominantly small lymphocytes, with a distinct absence of eosinophils and neutrophils (Fig. 2). This infiltrate may take on a nodular, or less commonly diffuse, pattern within the node. The nodularity in this subtype, however, is created not by bands of fibrosis, but by an association with residual normal lymphoid follicles. Often a residual, eccentrically located germinal center can be found within the nodule. Neoplastic cells are typically found outside of these germinal centers. This subtype of CHL is the one which most frequently enters into the morphologic differential diagnosis of NLPHL. As discussed below, this distinction can be easily made using immunohistochemistry (IHC). Interestingly, similar to NLPHL, the LR subtype more often presents at low stage and demonstrates a less-aggressive course than the other subtypes of CHL.13

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Lymphocyte Depleted

The lymphocyte depleted (LD) subtype of CHL is the least common (<1% of CHL) and most morphologically distinct subtype.6–9 It is characterized by a diffuse architectural obliteration of the lymph node with a relative predominance of neoplastic cells, often in a fibrotic background (Fig. 2). This diffuse fibrosis can lend a sarcomatoid appearance to the tumor, which brings a number of other lymphoid and nonlymphoid malignancies into the differential. There are typically few reactive lymphocytes in the background. This subtype has a predilection for retroperitoneal lymph nodes and abdominal organs. It is more common in patients with HIV.20 However, LD CHL is less commonly diagnosed nowadays; it is unclear if this represents a true decreased incidence or whether such cases are now being classified as other entities.

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Immunophenotype of CHL

Although the different subtypes of CHL show distinct morphologic features, and in some cases, clinical behaviors, they are still ultimately considered one disease. The immunophenotype of the neoplastic cells in all subtypes of CHL is similar (Table 1 and Fig. 3). RS cells, as well as their multinucleated and mononuclear variants (together known as Hodgkin cells), are the neoplastic element of CHL and have been proven to derive from a germinal center B cell (Fig. 3).3,4,21,22 In accordance with their B-cell origin, RS cells and variants express the B-cell transcription factor Pax5 albeit at lower levels than non-neoplastic B cells. This marker, however, is often the only sign of B-cell derivation, as these cells are typically negative for CD20 (expressed in up to 40% of cases in some series, and when positive, is expressed by only a subset of the neoplastic cells), CD19, CD79a, and the transcription factors OCT-2 and BOB.1 (Fig. 4). In addition, despite their proven cell of origin, Hodgkin cells generally lack expression of common germinal center antigens such as CD10 and BCL6. Interestingly, newer markers such as LMO2 and HGAL, which are also characteristically expressed in germinal center B cells, are positive in 100% and 75% of CHL cases, respectively.26,27 Further contributing to the mystery of these cells is their negativity for CD45, a pan-hematopoietic marker, which has the potential for raising the question of a nonhematopoietic neoplasm. CD30 is strongly positive with a distinct membrane and Golgi staining pattern in virtually all cases, whereas CD15 stains a smaller majority (75% to 85% of cases). Other markers which may be occasionally helpful to distinguish CHL from other entities in the differential diagnosis include positivity for MUM1 and fascin, and negativity for EMA.28,29

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Nodular Lymphocyte Predominant Hodgkin Lymphoma

Similar to CHL, NLPHL is characterized by a paucity of large, neoplastic cells in a reactive background. However, in NLPHL, the characteristic architecture is the macrofollicle formed by expanded follicular dendritic cell (FDC) meshworks surrounding a mixture of residual small lymphocytes (follicle-derived B and T cells) and scattered neoplastic cells (Fig. 5). The neoplastic cells of NLPHL are termed lymphocyte predominant (LP) cells (also previously L&H cells) and have been descriptively called “popcorn cells” because of their multilobated or folded nuclei. LP cells are typically smaller in size than RS cells and instead of a single prominent nucleolus, usually display several smaller, more basophilic nucleoli. However, more classic RS cells can be found in cases of otherwise typical NLPHL and certainly do not preclude the diagnosis.

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Although the macrofollicular or nodular architecture is typical for NLPHL, a number of morphologic patterns of NLPHL have been described. These patterns include, classic B-cell–rich nodular, serpiginous nodular, nodular variant with prominent extranodular LP cells, T-cell–rich nodular, and T-cell–rich diffuse large B-cell like.30 Most cases present with an admixture of several patterns. Although it is widely recognized that NLPHL can have areas of diffuse growth, at least a focus of nodularity within the neoplastic infiltrate is required to diagnose NLPHL. In cases with prominent diffuse growth, the differential diagnosis of TCRLBL may arise, and underscores the need for adequate tissue sampling for proper diagnosis,6,31 and the potential limitations of limited needle biopsies.

Unlike CHL in which transformation is exceedingly rare, NLPHL transforms to diffuse large B-cell lymphoma (DLBCL) in approximately 5% of cases,32,33 and a clonal relationship between the NLPHL and the large cell component has been convincingly shown.34,35 In these instances, sheets or large aggregates of large B cells are typically found, generally precluding a diagnosis of TCRLBL simply based on the number of large B cells.35

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Immunophenotype of Nodular Lymphocyte Predominant Hodgkin Lymphoma

Although some morphologic overlap may be present, NLPHL is easily distinguished from typical cases of CHL based on immunophenotype (Table 1). B-cell–specific markers such as CD20, CD79a, Pax5, OCT-2, BOB.1, and J-chain are strongly positive in NLPHL (Fig. 5).36 In addition, LP cells are negative for CD30 and CD15 and positive for CD45. Supporting their derivation from an intermediate stage between germinal center and memory B cells,37 BCL6 is strongly positive in LP cells, although CD10 is negative and MUM1 expression is variable. Other helpful immunohistochemical features of NLPHL include identifying the expanded CD21+ FDC meshworks in association with the macrofollicles. Identifying these meshworks is critical for the distinction from TCRLBL (discussed further below), as even a small focus of nodularity in association with FDC meshworks that precludes a diagnosis of TCRLBL in an otherwise diffuse infiltrate.6,31 In NLPHL, the neoplastic cells are rimmed by small, follicular helper T cells that show expression of CD4, CD57, and PD1 (CD279). However, the majority of small lymphocytes within the macronodules, at least in the early phases of the disease, are residual IgD-positive/IgM-positive mantle zone B cells (as the disease evolves, small T cells predominate).

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As discussed above, CHL and NLPHL may in some cases enter into each other’s differential diagnosis, but most often are easily distinguished based on immunophenotype. The main differential diagnostic considerations for CHL include other lymphomas such as DLBCL and anaplastic large T-cell lymphoma (ALCL). Again, IHC provides the most reliable method of distinguishing these entities. The majority of DLBCLs will show preserved expression of CD45 as well as an array of B-cell markers such as Pax5, CD79a, CD20, OCT-2, and BOB.1.6 DLBCLs may be CD30+, especially certain subtypes such as primary mediastinal large B-cell lymphoma (PMBL); however CD30 in this entity is typically weaker and more variable than in CHL.6

ALCL is another large cell lymphoma in which neoplastic cells may be accompanied by a brisk inflammatory background. In addition, the cells of ALCL are often multinucleated with prominent nucleoli, and thus morphologic distinction between ALCL and CHL may be challenging. CD30 is strongly expressed in ALCL, and these cells, like CHL, show downregulation of most lineage-specific antigens.6 However, ALCL is of T-cell origin, and thus will be negative for Pax5, and will most often express at least one marker of T-cell lineage. Other useful markers include positivity for EMA and negativity for CD15 in ALCL. A subset of cases of ALCL is positive for the ALK protein, and thus detection of this protein in the setting of a CD30+ lymphoma without other lineage markers is essentially diagnostic of that entity.6

Finally, in rare cases, especially in LD CHL and the syncytial variant of NS CHL, carcinoma, melanoma, or sarcoma may enter into the differential diagnosis. Knowledge of the possible morphologic overlap of CHL with these entities should enable one to readily distinguish them using an appropriate IHC panel.

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Gray Zone Lymphoma

The World Health Organization currently recognizes the category B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and CHL, which covers this aspect of the “gray zone.”6 The overlap between these 2 entities most often occurs in the mediastinum between PMBL and CHL. Both entities occur in young women with a similar disease distribution, and share some morphologic and immunophenotypic, as well as gene expression-based features,38–44 and tend to have a favorable prognosis. By contrast, this gray zone lymphoma is more common in men, and has a poor outcome. Histopathologic features that favor placing a lymphoma in this category include sheets of pleomorphic, RS-like cells in a background of fine fibrosis with a phenotype that is intermediate between the 2 entities (positive for CD30 and CD15, as well as CD45 and B-cell lineage antigens).6,31

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Progressive transformation of germinal centers (PTCG) is a nonspecific reactive pattern in which mantle zone B cells infiltrate and expand a follicle.45 This expansion may, at low power, resemble the macronodules seen in NLPHL. In addition, PTGC has been associated with a variety of lymphomas, most notably NLPHL.46 The association of NLPHL with PTCG is both a useful feature and a frequent source of anxiety among pathologists. However, PTCG does not show large, transformed LP cells as seen in NLPHL. PTCG is most often seen focally in association with reactive follicular hyperplasia, but can rarely be the primary reactive feature within an enlarged lymph node. Although the presence of PTGC should alert one to the possibility of a concurrent or future NLPHL, the vast majority of lymph nodes with PTCG are seen in patients without lymphoma.45,46 In addition, no study has conclusively demonstrated an increased risk of NLPHL in patients who have focal PTCG in the setting of a reactive lymph node.47

The distinction between NLPHL and TCRLBL is critical because of the rather different clinical courses and treatment strategies.48,49 As the name implies, TCRLBL is characterized by scattered large B cells, most often with centroblastic morphology, in a diffuse background of small T cells and histiocytes. TCRLBL lacks underlying follicular architecture, and thus lacks CD21+ FDC meshworks. However, in small biopsies, areas of diffuse NLPHL can appear identical to TCRLBL. Thus, excisional lymph node biopsy is paramount to making this distinction. By IHC, the large B cells of TCRLBL may show a similar immunophenotype to LP cells, although LP cells may be more often BCL6+/MUM1, whereas TCRLBL is more often BCL6/MUM1+. The background T cells in TCRLBL are typically CD8 predominant, whereas in NLPHL CD4+ follicular helper T cells are characteristic.50 However, neither of these features is specific enough to be reliable in every case.

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Classical Hodgkin Lymphoma

Studies on the genetics of HL were historically limited by the relative rarity of neoplastic cells within the tumor. In the early 2000s, comparative genomic hybridization studies in CHL uncovered recurrent gains in chromosomes 2p, 7p, 9p, 11q, and Xq with losses of 4q and 11q.51–53 Since then, studies on microdissected RS cells have definitively proven B-cell lineage and furthermore have demonstrated that CHL arises from a germinal center B-cell harboring, in a subset of cases, a “crippling” immunoglobulin heavy chain gene mutation that would normally target the cell for apoptosis.36,54–57 Several studies have gone on to further implicate activation of the NF-κB pathway, via mutations in a number of genes including NFKBIA, NFKBIE, TNFAIP3, CREL, among others58–62 (Table 2 and Fig. 6). Of note, these mutations are far less frequent in EBV-positive CHL, suggesting that the virus may replace the role of mutations in NF-κB pathway activation.62 Activation of NF-κB leads to both inhibition of apoptosis as well as enhanced proliferation in the neoplastic cells of HL.58 A key feature of CHL, the loss of a B-cell phenotype, is directly reflected in its genetic and epigenetic profile which shows downregulation of almost all B-cell–specific genes by various mechanisms.36,54–57,69–72 Hypermethylation, a well-established modality of tumor suppressor gene inactivation, has been shown to be consistently present in the promoter regions of several key B-cell–specific transcription factors such as BOB.1 and PU.1.71,72 Silencing of these “master transcription factors” then likely leads to a complex cascade of inactivation of genes involved in the B-cell receptor (BCR) signaling pathway including CD19, CD20, SYK, and CD79B through various mechanisms including additional promoter methylation.73 Furthermore, aberrant expression of genes involved in T-cell and NK-cell differentiation such as NOTCH1 and ID2 may cooperate with the aforementioned mechanisms to mask the B-cell gene signature of these cells.63,74 In conjunction with downregulation of the B-cell gene signature, several other pathways including MAP/ERK and JAK/STAT pathways also promote survival and proliferation in CHL51,64–66,75 (Fig. 6 and Table 2). Finally, genetic aberrations that modulate the tumor microenvironment, for example genomic gains in PD-L1(CD274) and PD-L2(CD273) and translocations of CIITA, are being uncovered using massively parallel DNA sequencing techniques and are thought to promote tumor cell survival23,76 (Table 2).

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Genome-wide expression studies on RS cells have uncovered heterogeneity and complexity among CHL that was not previously recognized. When supervised clustering is performed, RS cells of NS and LD CHL map more closely to PMBL, whereas those of MC and LR CHL subtypes map with NLPHL.70 These results are intriguing in that they suggest the relatedness of PMBL and CHL, shown in prior GEP studies,42 is a reflection of the neoplastic cells themselves.77 Somewhat surprisingly, there were not significant differences between expression profiles of RS cells with and without EBV, suggesting that similar mechanisms of oncogenesis are at play regardless of EBV status.70 Most interestingly, unsupervised clustering of all subtypes of CHL revealed 2 distinct subgroups which differed with respect to their expression levels of MYC/NOTCH1 and MUM1 (IRF4) target genes, which involve pathways not previously known to be involved in CHL oncogenesis.70 These 2 subgroups did not reflect either histologic CHL subtype or EBV status.70 The significance of these findings, and whether or not they reflect a truly significant dichotomy among CHL cases, is currently unclear.

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Nodular Lymphocyte Predominant HL

Until recently, very little was known about the molecular pathogenesis of NLPHL. Unlike in CHL, where recurrent translocations involving oncogenes are rare, BCL6 gene rearrangements are found in approximately 50% of NLPHLs78 (Table 2). A large percentage of these translocations involve the IGH@ gene at 14q32; however, other translocation partners include 2q23, 5q31, 6q22, 9q22, and 17p21.79 Additional cytogenetic abnormalities found in NLPHL include chromosome 1q gain and losses or rearrangements of chromosomes 4, 7, and 13.79 In most cases, the genes involved at these sites and their roles in oncogenesis have not been elucidated.

Ongoing somatic hypermutation in LP cells may target various protooncogenes contributing to tumorigenesis.80 When gene expression profiles of microdissected LP cells are analyzed, NLPHL is confirmed to be a distinct entity, albeit with a close relationship to CHL and TCRLBL.37 As in CHL, NLPHL is characterized by constitutive activity of the NF-κB pathway, however, the mechanisms underlying this activation are distinct between the 2 entities.37,67 Specifically, the inactivating mutations found in genes such as NFKBIA and TNFAIP3 in CHL are not present in most cases of NLPHL.67 Genomic gains in CREL, also common in CHL, are not seen in NLPHL, and EBV infection, which is known to drive NF-κB activation in some cases of CHL, is also not a factor in this tumor. The ERK pathway, implicated in malignant transformation in several types of cancer, also shows evidence of dysregulation at several levels in at least a subset of NLPHL cases.37

Although not as extensive as what is found in CHL, gene expression profiling studies do confirm downregulation of several key B-cell–specific genes in NLPHL.37 These include signaling factors such as CD79a, CD22, and SYK, as well as transcription factors such as BOB.1, E2A, Pax5, and Ikaros, among others.37 In addition, upregulation of antiapoptotic genes and downregulation of proapoptotic genes appear to be key in promoting tumor cell survival in NLPHL.37 Finally, as with CHL, alterations in the tumor microenvironment help LP cells escape from recognition by cytotoxic T and NK cells.37

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EBV, a gamma-herpes virus implicated in the pathogenesis of a number of lymphoid neoplasms, is found in 40% of CHL cases with the highest proportion of these being the MC subtype.68,81 In contrast, no convincing association with EBV has been found for NLPHL. A number of features of EBV suggest that its presence likely plays a critical role in CHL pathogenesis. First, LMP1, a viral latency protein, acts to mimic the activity of an activated CD40 receptor on B cells.68 In addition, this same protein upregulates BCL2 and activates the NF-κB pathway, thereby promoting proliferation and survival, while inhibiting apoptosis.68 A second latency protein, LMP2a serves to mimic the signaling portion of the BCR.68 In fact, studies have shown that cases of CHL that lack a functional BCR are EBV positive at a higher rate than those with functional BCR.82

While intriguing from a pathogenetic standpoint, until recently, the presence of EBV in CHL was not thought to be of prognostic significance. Typically, EBV-encoded RNA in situ hybridization is used to demonstrate the presence of EBV in paraffin tissues. A number of studies have shown concordance between these tissue results and the presence of EBV DNA in plasma.83,84 Interestingly, a recent study in patients with CHL, found that higher plasma EBV DNA levels both pretreatment and 6 months posttherapy were predictive of poor outcomes independent of other factors.84 Although EBV-encoded RNA staining showed good concordance with plasma DNA levels, the relationship to prognosis was more consistent for the plasma EBV levels, perhaps suggesting a role for this assay in CHL patients.84

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Staging of HL is performed using the Ann Arbor Staging system which takes advantage of HL’s propensity for predictable spread through adjacent lymph node sites.10,11 From a prognostic and therapeutic decision-making standpoint, patients are divided into either early-stage (stage I or II) or advanced-stage (stage III or IV) disease. Prognostic factors for patients within each of these groups have been delineated. In advanced-stage HL, the International Prognostic Factors Project Score (IPS) score is the current standard for stratification of risk.85 The IPS score, as well as similar scoring systems for limited stage HL include primarily clinical and laboratory features such as age, disease bulk, and white blood cell count. However, even with risk-adapted therapy, the 5-year survival for HL is only 81%. In addition, some patients are likely overtreated for their disease, resulting in unnecessary secondary complications of therapy. Thus, studies continue in attempt to further refine prognostic classifications and more appropriately tailor therapy (Table 3).

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Classical Hodgkin Lymphoma

Much attention has been paid to the role of the tumor microenvironment in supporting the growth of HL. It is clear that cross-talk between the neoplastic cells and the abnormal immune response it incites is critical for tumorigenesis (Fig. 1).14,86,99–103 As such, several groups have focused on evaluating the composition of the tumor microenvironment from both a gene expression profile and histopathologic perspective. Steidl and colleagues showed that a macrophage gene expression signature is associated with primary treatment failure in CHL.14,103 This group and others have confirmed that increased numbers of tumor-associated macrophages as evaluated by CD68 and CD163 IHC are associated with poor prognosis,14,86,103 although other studies have not found such significance99–101; even if their significance was agreed upon, it might be challenging to adopt a standardized manner to enumerate these cells in the clinical-diagnostic scenario. As a corollary to this, one group evaluated the peripheral blood (PB) absolute lymphocyte count/absolute monocyte count ratio (ALC/AMC) at diagnosis in patients with CHL, and subsequently NLPHL, and demonstrated a correlation with survival.88,89 In patients with limited and advanced-stage CHL, an ALC/AMC ratio of >1.1 was associated with superior overall survival, progression-free survival, and time to progression and outperformed other variables, including the IPS score, in a multivariate analysis.88 Finally, investigation of the PB absolute neutrophil count/ALC ratio, revealed an inverse correlation with survival in a different cohort of patients with CHL.90

With the ease and relative low cost of IHC, several groups have evaluated the prognostic utility of various markers in HL. Given that CHL is thought to arise from a BCR-nonfunctional germinal center B cell that has escaped apoptosis, it has been postulated that expression of BCL2, an antiapoptotic protein, may hold prognostic significance. Although a few groups have found high levels of BCL2 protein expression by IHC to correlate with decreased survival,91–93 this evaluation has not made its way into routine clinical practice. CD20 is another example of a marker that has been exhaustively studied and found to have variable effects on prognosis.91,104,105 Aberrant T-cell antigen expression, especially CD2 and CD4, on RS cells is present in a subset of CHL cases and has been shown in 1 study to be independently associated with shorter overall and event-free survival as compared with T-cell antigen-negative cases.94

As discussed above, genomic and proteomic analysis have furthered our understanding of both the underlying mechanisms that lead to development of HL and also factors which may affect response to therapy. High expression of galectin-1, an immune-modulating protein that promotes the Th2/Treg predominant tumor microenvironment in CHL, correlates with shorter survival in CHL when assessed by proteomic analysis and by IHC.95 More recently, a serum assay for galectin-1 has been developed and the results shown to correlate with high tumor burden in newly diagnosed CHL patients.96 Although gene expression profiling technologies have not reached widespread clinical use, Scott et al97 have established a gene expression-based predictor of increased death risk among advanced-stage CHL patients that is potentially amenable to routine clinical use. Their assay uses RNA extracted from formalin-fixed, paraffin-embedded tissue and evaluates expression of 23 genes, many of which are related to a Th1 cytokine profile.97 Finally, another group has identified an miRNA signature that integrates both tumor and microenvironmental factors and is associated with shorter overall survival in patients with advanced CHL.98 In this same study, MIR30D and MIR21 were shown to have a direct functional role in chemoresistance.98

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Nodular Lymphocyte Predominant Hodgkin Lymphoma

Given the biological differences between CHL and NLPHL, it is intuitive that prognostic features and predictive markers would differ between the 2 groups. Despite this, as mentioned above, the PB ALC/AMC ratio may be applicable as a predictor of superior survival in both the diseases.89 There is a notable paucity of literature on the subject of predictive markers in NLPHL, likely a reflection of its overall favorable prognosis as well as the relative rarity of the disease. Although a significant minority of cases will transform to DLBCL, features which may be predictive of this transformation at diagnosis are not well established.32–35

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First-line therapy for a diagnosis of HL is determined by a combination of factors including subtype (CHL vs. NLPHL), stage of disease, and clinical risk factors (IPS score).48,106,107 A combination of multiagent chemotherapy, most commonly ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) and involved field radiotherapy is typical for CHL, with PET/CT imaging being used to monitor disease response during therapy.48 In NLPHL, there is less standardization of therapy because of the rarity of the disease and the generally favorable outcomes, especially in early stages of disease.108 Given the interesting similarities between CHL and NLPHL, but also the obvious biological differences (late relapses in NLPHL and tendency to progress to DLBCL) there is a lack of consensus on whether therapy should resemble that of CHL or not.108 However, current guidelines suggest that some combination of multiagent chemotherapy, plus rituximab, in addition to involved field radiotherapy is appropriate.48

As with all areas of oncology, the search for novel, less cytotoxic, and targeted therapeutic agents is ongoing in HL. Although a detailed discussion of therapeutics is beyond the scope of this review, it is critical for the pathologist to be aware of emerging targeted therapies and our role in detecting these biologic targets. Not surprisingly given the strong CD30 expression that is one of the hallmarks of RS cells, anti-CD30 agents have entered the clinics in the form of predominantly second-line agents for relapsed/refractory disease as an alternative to autologous stem cell transplant.48,107,109 Brentuximab vedotin, an anti-CD30 monoclonal antibody conjugated to an antitubulin agent, has shown excellent response in phase II trials and has been FDA approved as a second-line agent in CHL.110 Rituximab, a chimeric anti-CD20 monoclonal antibody used widely in B-cell lymphomas, is also being investigated as an adjunct to first-line therapy for both CD20+ and CD20 cases of HL.111 Finally, novel agents such as chimeric antigen receptor-modified T cells with specificity for CD19, which have shown efficacy in both acute and chronic B-cell malignancies,112,113 might someday be applicable in HL cases, especially those with CD19 expression.

As discussed above, it is clear that the pathogenesis of CHL relates in part to epigenetic silencing of genes critical to normal B-cell differentiation. As such, histone deacetylase inhibitors have been investigated and have shown some efficacy in patients who have failed autologous stem cell transplant.114 Lenalidomide, an immunomodulatory agent, has shown modest efficacy in a subset of patients as well.115

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Ongoing investigation into the pathogenesis of HL has lead to a rich literature on novel diagnostic and prognostic markers. From uncovering the B-cell origin of the RS cell, to investigating the role of anti-CD30 agents, the past 20 years have seen great strides made in our understanding of this intriguing disease. With the use of next-generation sequencing technologies, and continued efforts to understand the epigenetics of neoplasia, it is likely that the pace of new studies demonstrating relevant mutations and genetic features of HL, as well as their application to diagnosis and prognostication will continue to increase. Hopefully as these studies increase numerically, so too will their validation and clinical applicability, so that we as pathologists can provide the most clinically relevant set of information to our oncology colleagues.

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The authors thank Dr Dale Frank (Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA) for providing cases used for the photomicrographs.

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Hodgkin lymphoma; classical Hodgkin lymphoma; nodular lymphocyte predominant Hodgkin lymphoma; genetics; prognosis

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