Pathology of Hodgkin's Lymphoma

330

HISTORY

In 1832, Dr. Thomas Hodgkin, working at Guy’sHospital in London, reported a series of seven casesof enlargement of the lymph nodes and spleen,which he speculated might represent a primary dis-order of those tissues rather than reactive enlarge-ment.1 Hodgkin’s observations on these cases maywell have slipped into permanent obscurity had theynot been resurrected some 30 years later by anotherGuy’s Hospital physician, Dr. Samuel Wilks, who, ina paper published in 1865, was the first to attach thename “Hodgkin’s disease” to this clinical entity.2

The first descriptions of the microscopic appearanceof the affected tissues appeared in the late 1800s.3

However, it was not until the seminal observationsby Sternberg in 18984 and Reed in 19025 that wide-spread attention was drawn to the curious giant cellpresent in many such cases, which would later cometo bear their names and which would soon becomeregarded as a morphologic hallmark of Hodgkin’sdisease (HD) (Figure 20–1). Interestingly, neitherSternberg nor Reed felt that this disorder repre-sented a neoplasm. Sternberg believed that it was avariant of tuberculosis,4 whereas Reed felt it to be anindependent entity of inflammatory origin.5

The work by Sternberg and Reed gave the worldits first pathologic definition of HD: the identifica-tion of diagnostic Reed-Sternberg (RS) cells in anappropriate cellular environment. This essentiallymorphologic definition of HD proved useful in sepa-rating cases of HD from other inflammatory and neo-plastic conditions that might mimic HD clinicallyand provided the basis for the diagnosis of HD formost of the twentieth century.6–8 In this definition, a

diagnostic RS cell was defined as a giant cell withmultiple (frequently two) nuclear lobes, each con-taining a prominent inclusion-like acidophilic nucle-olus that itself approached the size of a small lym-phocyte (Figure 20–2). Mononuclear variants of RScells (sometimes termed Hodgkin’s cells) also wererecognized to be present in most cases but were notfelt to be diagnostic of HD in the absence of the morecharacteristic multinucleate forms. The appropriatecellular background was considered a generally het-erogeneous mixture of cytologically benign inflam-matory cells, which could include small lympho-cytes, histiocytes, eosinophils, neutrophils, andplasma cells (see Figure 20–2). This era of morpho-logic diagnosis of HD culminated in the Rye Classi-fication (Table 20–1), produced at a meeting ofhematopathologists in Rye, New York, in 1966.9 TheRye Classification, with its four familiar categoriesof lymphocyte predominance (LP), mixed cellularity(MC), lymphocyte depletion (LD), and nodular scle-rosis (NS) types, provided the standard for the diag-nosis and classification of HD for over three decades.

A further refinement in the definition of HDcame in the 1980s, when immunohistochemistrywas used to demonstrate that the RS cells typicallydisplayed a characteristic immunophenotype. TheRS cells and variants could usually be shown toexpress both CD30 and CD15 (typically in a mem-brane-and-Golgi staining pattern) (Figure 20–3) butusually lacked markers associated with non-Hodgkin’s lymphomas, such as leukocyte commonantigen (LCA; CD45/CD45RB), B-cell antigens(eg, CD20), and T-cell antigens (eg, CD3) (Table20–2).7 CD30 and CD15 were hardly specific to HD.CD30, although originally identified on RS cells,

20

The Pathology of Hodgkin’s DiseasePATRICK A. TRESELER, MD, PHD

The Pathology of Hodgkin’s Disease 331

had also been shown to be expressed by activated Tand B lymphocytes, some non-Hodgkin’s lym-phomas, monocytes/macrophages, certain carcino-mas, and some malignant melanomas.10,11 CD15 hadbeen identified on activated T lymphocytes, inter-digitating reticulum cells, myeloid cells, and manyadenocarcinomas.10,11 But the combined expressionof these two antigens on cells resembling RS cells

(and lacking T-cell and B-cell markers) had not beenobserved in other neoplasms. It served as a relativelyspecific method of diagnosis and provided the sec-ond pathologic definition of HD. This combinedmorphologic and immunophenotypic diagnosis ofHD was reflected in the 1994 Revised European-American Lymphoma (REAL) Classification11

(Table 20–3) and is still widely used today.

Figure 20–1. Reed-Sternberg cell from case 2 of Thomas Hodgkin’s original 1832 seven-caseseries. (Courtesy of Dr. W. Rosenau, Dept. of Pathology, University of California, San Francisco.)(Hematoxylin and eosin; ×1,000 original magnification.)

Figure 20–2. Diagnostic Reed-Sternberg cells. A, The classic bilobed cell is no more diagnostic than B, cells having multiple nuclear lobes.Background cells are benign inflammatory cells and typically include mature small lymphocytes, histiocytes, large lymphocytes, eosinophils,and plasma cells. (Hematoxylin and eosin; ×1,000 original magnification.)

A B

332 MALIGNANT LYMPHOMAS

Although an important milestone in diagnosis,this use of immunophenotyping in diagnosis alsomade it clear that HD, defined morphologically, washeterogeneous and included many entities in whichthe candidate RS cells were CD30 and/or CD15-negative. Lymphocyte predominance HD, in particu-lar, fell out as a distinct entity, whose unusual RScells (Figure 20–4) were usually CD30- and CD15negative but positive for LCA and B-cell antigens,thus appearing more closely related to the non-Hodgkin’s lymphomas than to the other subtypes ofHD12 (Table 20–4). (The non-LP subtypes of HD arenow frequently referred to as “classic” HD to distin-guish them from this less reputable family mem-ber.13,14) Other cases previously diagnosed as HDalso were found immunophenotypically to be betterclassified as non-Hodgkin’s lymphomas.15 This prob-lem was particularly acute among cases diagnosed asLD HD by morphology alone, where at least one ret-rospective analysis revealed most of these cases to be

entities other than HD—most typically non-Hodgkin’s lymphomas.15,16 The non-Hodgkin’s lym-phomas most frequently misdiagnosed as HD by mor-phology alone were anaplastic large cell lymphoma,T-cell-rich large B-cell lymphoma, mediastinal largeB-cell lymphoma, and pleomorphic peripheral T-celllymphoma.17 For a time in the late 1980s and early1990s, disease entities such as these were removedfrom the category of HD with such frequency thatone could wonder whether anything would remain ofHD once all the morphologic imitators had beenstripped away. The differentiation of these mimicsfrom classic HD will be considered in more detail inthe section on differential diagnosis below.

PATHOGENESIS

The etiology of HD remains unknown. Epstein-Barrvirus (EBV) has been suspected of playing a role inthe pathogenesis of HD, beginning with epidemio-logic studies showing an apparent link with EBVinfection.18,19 Epstein-Barr virus subsequently hasbeen found to latently infect the RS cells in themajority of cases of classic HD. Because latentinfection by EBV can cause up-regulation of thebcl-2 gene, thereby allowing the cell to avoid apop-tosis, the virus has long been suspected of playing a

Figure 20–3. Reed-Sternberg cells showing positive staining for CD30 in the characteristic mem-brane-and-Golgi staining pattern. (CD30 immunoperoxidase; ×1,000 original magnification.)

Table 20–1. HODGKIN’S DISEASE

RYE CLASSIFICATION (1966)

• Lymphocyte predominance• Mixed cellularity• Lymphocyte depletion• Nodular sclerosis


role in the pathogenesis of HD.20,21 The major prob-lem with invoking EBV as etiologic in HD is the factthat the virus is absent in approximately 50 percentof cases, even when analyzed by sensitive tech-niques such as in polymerase chain reaction(PCR).20,21 Some have speculated that EBV couldtransiently infect RS cells in such virus-negativecases but then be eliminated from the cell in a mech-anism termed “hit-and-run.”22 It is equally possiblehowever, that an etiologic agent other than EBV isinvolved in such cases, or that EBV is not etiologicin any cases of HD.22,23 Latently infected B cells maysimply provide better targets for the true transform-ing agent, causing EBV to be carried along in prog-eny cells as a “passenger” virus. A detailed discus-sion of the complex relationship between EBV and

HD is beyond the scope of this chapter, but the inter-ested reader is referred to several excellent recentreviews of this subject.22–24

Many lymphoid neoplasms have been found tohave consistent chromosomal translocations involv-ing cellular oncogenes, which appear to be etio-logic.25–30 Such characteristic karyotypic abnormal-ities have not been described in HD, however.31 Thestudy of chromosomal abnormalities in HD hasbeen hindered by the difficulty in obtaining purepopulations of RS cells and propagating them in tis-sue culture. The few studies describing successfulkaryotyping of RS cells report complex hyper-diploid to near-tetraploid karyotypes with numer-ous structural abnormalities, but few consistent pat-terns.31–34 A recent study using the technique

Table 20–2. REED-STERNBERG CELL PARAFFIN SECTION

IMMUNOPHENOTYPE (CLASSIC HODGKIN’S DISEASE)

CD30 +CD15 +/– CD45 –CD20 –/+T-cell antigen -

Proportion of cases showing positive staining at least focally:+ >90%;+/– 50–90%; –/+ 10–50%; – <10%.


REAL CLASSIFICATION (1994)

• Lymphocyte predominance• Mixed cellularity• Lymphocyte depletion• Nodular sclerosis• Lymphocyte-rich classic*

*Provisional entity.

Figure 20–4. L&H Reed-Sternberg variants from a case of nodular lymphocyte predominanceHodgkin’s disease. These cells characteristically show much less nuclear atypia than the RS cells ofclassic Hodgkin’s disease. Their lobate appearance leads to their colloquial designation as “popcorncells.” (Hematoxylin and eosin; ×1,000 original magnification.)


multicolor fluorescence in situ hybridization (“spec-tral karyotyping”) of RS cell lines has demonstratedchromosomal structural rearrangements clusteringin ribosomal DNA regions of chromosomes 5q and9p.35 These rearranged areas frequently appearedexported to other chromosomal sites in the form of“jumping translocations.”35 Such involvement oftransposable DNA elements could explain the com-plexity and lack of uniformity seen in standard RScell karyotypes.

A final area of investigation in the pathogenesis ofHD is the relationship between the RS cells and thesurrounding reactive and inflammatory cells. Noother malignant neoplasm features such a prominentinflammatory cell component, and there is some evi-dence to implicate these cells in both the developmentand maintenance of the neoplastic RS cell popula-tion.36–41 These cell-cell interactions are highly com-plex and are only now becoming well understood, butappear to involve antigen presentation by RS cellsresulting in an exuberant but essentially anergic hostresponse, permitting the neoplastic cells to evadeimmune destruction. A complete review of this sub-ject is beyond the scope of this chapter, but severalexcellent recent reviews of the subject are avail-able.36–42 Recent reports describing frequent muta-tions of the IκBα gene (which plays a central role inthe normal regulation of inflammatory responses) inHD cases may represent the first recurrent molecularabnormality identified in RS cells.43–45

MOLECULAR PATHOLOGY AND THE MYSTERY OF THE CELL OF ORIGIN

The era of immunophenotyping that began in the1980s, and the occasional difficulty encountered indistinguishing HD from its morphologic mimics,emphasized that there was little to define the entityof HD other than the peculiar immunophenotype ofits characteristic RS cells. Even the cell of originremained undetermined for classic HD, and therewas continued speculation that it may represent areactive condition (at least in some cases) ratherthan a true neoplasm.46,47 A B-cell or T-cell lym-phoid origin had long been suspected, given thatCD30 and CD15 could be expressed by activatedlymphocytes in some cases, and B-cell and T-cell

antigens could be demonstrated on RS cells in rarecases, however convincing proof was lacking.47

In the 1980s and early 1990s, much attentionfocused on attempts to demonstrate clonal B- and T-cell lymphoid antigen receptor (ie, immunoglobu-lin and T-cell receptor) gene rearrangements in casesof HD.48 Such attempts, if successful, could simulta-neously confirm a lymphoid origin and a clonal/neo-plastic nature for the cells in HD. Studies using stan-dard Southern blotting to detect lymphoid antigenreceptor gene rearrangements generally demon-strated clonal rearrangements, usually of immuno-globulin genes, in a small percentage of cases (typi-cally < 10%).48 But it remained unclear whether thelarge percentage of negative cases were true nega-tives or merely reflected the use of an insufficientlysensitive method (given that Southern blotting canonly detect clonal cells down to a level of about 1 percent of total cells, which is approximately theproportion of RS cells in many cases of HD). Thisled to subsequent investigations using the more sen-sitive PCR technique to look for immunoglobulingene rearrangements in tissue sections. By usingPCR, several groups of investigators have demon-strated clonal immunoglobulin gene rearrangementsin 32 to 50 percent of cases of classic HD, with evenhigher rates seen in cases where B-cell antigenexpression could be detected on the RS cells.49–53

The negative cases in these studies could potentiallybe explained as false negatives, given thatimmunoglobulin PCR typically employs “consen-sus” primers, which may fail to detect a significantproportion of rearrangements. However, these stud-ies, which used DNA extracted from whole tissuesections, could not confirm that the rearrangements

Table 20–4. CLASSIC HODGKIN’S DISEASE VS.

LYMPHOCYTE PREDOMINANCE HD

PARAFFIN SECTION IMMUNOPHENOTYPE

CHD LP HD

CD30 + –/+CD15 +/– –CD45 – +CD20 –/+ +T-cell Ag – –Epithelial membrane antigen – +

Proportion of cases showing positive staining at least focally: + >90%;+/– 50–90%; –/+ 10–50%; – <10%.


were localized to the RS cells and could not excludethe possibility that the positive cases might representcontamination (a frequent and vexing problem inPCR studies).

In an attempt to definitively resolve the issue ofclonal gene rearrangements in RS cells, a group ofresearchers at the University of Cologne led by KlausRajewsky undertook the Herculean task of pluckingmultiple individual CD30-positive RS cells from his-tologic sections of classic HD and subjecting theindividual cells to PCR for immunoglobulin heavychain (IgH) gene rearrangements (Figure 20–5). Ineach case where a PCR product was obtained from acell (indicating the presence of a rearrangement), itwas sequenced to determine whether it was identicalto other such rearrangements found in the same case(indicating clonality of the RS cells) or whether eachwas different (indicating polyclonal rearrangements).In a series of cases reported in five separate publica-tions,54–58 clonal IgH rearrangements were detectedin 16 of 17 cases (94%) of classic HD. Other investi-

gators using similar single-cell PCR assays have alsofound clonal IgH rearrangements, with the largestsuch series reported by a group led by Harald Steinat the Free University of Berlin59 and a smaller num-ber of cases reported from the University ofNebraska.60 At least initially, these two latter groupsreported a lower proportion of cases with clonal IgHrearrangements, as well as some cases with poly-clonal IgH rearrangements.59,60 In addition, a fewother groups failed to detect any rearrangements atall.61,62 It now appears that the lower rate of detectionof clonal IgH by these groups was due to the use ofless specific “consensus” PCR primers, rather thanthe multiple family-specific primers used by theCologne group, and that their polyclonal re-arrange-ments were due to contamination by free DNAleached from polyclonal B cells in the histologic sec-tions.63–66 When Stein’s Berlin group repeated theiranalyses using family-specific primers and tech-niques to avoid PCR product contamination, theyreported finding clonal IgH rearrangements in 24 of

Figure 20–5. A CD30-stained Reed-Sternberg cell removed by micromanipulation from a histologic tissue sec-tion for use in single-cell IgH gene rearrangement studies by PCR. (Reproduced with permission from KuppersR, et al. Hodgkin’s disease: Hodgkin and Reed-Sternberg cells picked from histologic sections show clonalimmunoglobulin gene rearrangements and appear to be derived from B cells at various stages of development.Proc Natl Acad Sci U S A 1994;91(23):10962–6.)


25 cases, with no evidence of polyclonal re-arrange-ments in any case.65–67 Their results appear to provideimportant confirmation that classic HD is a trueclonal neoplasm derived from B lymphocytes innearly all cases. In addition, there are at least threereported cases of classic HD where single-cell IgHPCR assays have demonstrated the same IgH clonepresent in clinical specimens from different sites inthe same patient (eg, primary and relapsedtumor).57,68,69 If one accepts the standard definitionof a malignancy as a neoplasm that either locallyinvades or distantly metastasizes, then classic HDhas been proven to be a malignant tumor of B-cellorigin in at least these cases, solving a century-oldmystery as to the cell of origin. For these reasons, theWorld Health Organization (WHO) committeesdrafting a new lymphoma classification system haverecommended a name change to “Hodgkin’s lym-phoma”70 (a term appearing with increasing fre-quency in the literature),66,71 although the synonymof “Hodgkin’s disease” will continue to be recog-nized as an acceptable alternative.72 (Several excel-lent reviews of this fascinating subject are availablefor the interested reader.)73–76

Beyond indicating a B-cell origin, the above-described single-cell IgH PCR studies have pro-vided evidence to suggest that the RS cells of clas-sic HD are derived from germinal center B cells thathave undergone unusual “crippling” mutations oftheir immunoglobulin genes, rendering them non-functional—providing a fascinating clue as to whythis B-cell neoplasm appears so different from allothers.54 During normal B-cell development, naïveB lymphocytes (which have few or no mutations intheir immunoglobulin genes) enter germinal centerswhere, upon exposure to antigen, they undergo highrates of mutation of their immunoglobulin genevariable regions.76,77 This process, termed somatichypermutation, is a key process in generating adiverse antibody repertoire and serves to increasethe likelihood that high-affinity antibody is pro-duced against a foreign antigen.77 Only B cells thatare successful in creating immunoglobulin withhigh affinity for the antigen presented are permittedto leave the germinal center to become eitherplasma cells or memory B cells. B cells that cannotmake antibody, or make antibody with no or low

affinity for the antigen in question, undergo apop-tosis and die. Indeed, it appears likely that a defaultcell-death program is activated as the B cells enterthe germinal center, and cells are “rescued” fromapoptosis only if they produce high-affinity anti-body; this rescue appears to involve activation ofthe bcl-2 anti-apoptosis gene. Sequence data fromthe single-cell IgH PCR assays from Rajewsky’sgroup indicate that the RS cells in their studies ofclassic HD have high levels of immunoglobulingene mutations, indicating that they have beenexposed to the germinal center environment.54–56,77

However, in a high proportion of cases studied, theIgH genes appear to have undergone “crippling”mutations (eg, the creation of a stop codon in themiddle of the gene), which would make it impossi-ble for the cells to synthesize immunoglobu-lin.54–56,77 In further support of this, studies haveshown that IgH messenger ribonucleic acid (mRNA)cannot be detected in RS cells even if their IgHgenes are found to be rearranged.78 This lack of IgHmRNA production due to gene mutation was con-firmed by Stein’s Berlin group, who found in theircases that this genetic “crippling” could be due toeither structural gene mutations or functionaldefects in Ig gene regulatory elements.67 How ger-minal center B cells incapable of immunoglobulinproduction escape apoptotic death is uncertain, andelucidation of this mystery may provide importantinsights into the pathogenesis of HD.

Similar single-cell IgH PCR assays performed incases of LP HD have led to near-universal consensusthat the peculiar RS variants (termed “L&H vari-ants”) in this disorder contain clonal immunoglobu-lin gene rearrangements,56,79–81 confirming earliersuspicions based on immunophenotyping that LPHD is a B-cell neoplasm. Like classic HD, the IgHgenes in LP cases show evidence of somatic hyper-mutation, which appears to be ongoing in the lives ofthese cells (ie, there is apparent acquisition of addi-tional mutations at high rates in subsequent tumorcell generations, leading to the development of tumorsubclones).80,81 Unlike classic HD however, theseIgH rearrangements appear productive (ie, no “crip-pling” mutations), and, indeed, IgH mRNA and evensurface immunoglobulin have been detected in amajority of cases of LP HD in some studies.78,82,83


The apparent common origin from germinal center Bcells of both classic and LP HD appears to re-estab-lish some ties of kinship between these two disor-ders, which otherwise had appeared to have little incommon in recent years (Figure 20–6).

Controversy and mysteries persist in the field ofHD, however. The same German investigators whodemonstrated nonfunctional IgH gene rearrange-ments in most HD cases recently described a case ofclassic HD in which the RS cells harbored unmu-tated, potentially functional immunoglobulin heavyand light chain immunoglobulin genes, suggestingderivation from a naïve, pre-germinal center B cell.84

Although these authors suggest the possibility thatsuch cases could represent germinal center “foundercells” that have yet to acquire somatic mutations(thus preserving the possibility of a germinal centerorigin for all cases of HD), it raises questions ofwhether such a tumor would differ biologically fromits more common “crippled” cousins, and how it

would differ from B-cell non-Hodgkin’s lymphomas.The same group also has recently reported a case ofclassic HD in which the RS cells, although morpho-logically typical and positive for both CD30 andCD15, contained clonally rearranged T-cell receptorβ-chain genes, with no rearrangement of immuno-globulin chain genes.84 They use this evidence toargue for a T-cell origin of HD in some cases. Otherauthorities, however, state that evidence of T-cell ori-gin can be used to exclude the diagnosis of classicHD, restricting that diagnosis only to cases with RScells consistent with germinal center B-cell origin.13

In addition, reports continue to be published of HDcases in which the RS cells appear to have more incommon with dendritic cells than lymphocytes.85,86

Arguments concerning which genetically differententities should be included in the category of classicHD may be largely semantic. However, such contro-versies make it clear that, even today, we still lack auniversally accepted definition of HD, and biologic

Figure 20–6. B-cell lymphomas of both Hodgkin’s and non-Hodgkin’s and the stages of normal B-cell development fromwhich they are thought to derive. Both classic and lymphocyte predominance types of Hodgkin’s disease are thought tobe derived from germinal center B cells. (Reproduced with permission from Kuppers R. Identifying the precursors ofHodgkin and Reed-Sternberg cells in Hodgkin’s disease: role of the germinal center in B-cell lymphomagenesis. J AcquirImmune Defic Syndr 1999;21 Suppl 1:74–9.)


differences, if any, between these genetically differ-ent contenders to the title remain unknown.

HISTOPATHOLOGY AND DIAGNOSIS

The current pathologic classification schemes forHD have changed little from the widely acceptedRye Classification first proposed in 1969. The 1994REAL Classification of Lymphoid Neoplasms (seeTable 20–3) and the 2001 WHO Classification ofHematopoietic and Lymphoid Tumors87,88 (Table20–5) both add only the entity of lymphocyte-richclassic (LRC) HD (designated a “provisionalentity” in the REAL) to the four Rye categories ofLP, MC, LD, and NS HD.9 Lymphocyte-rich classicHD was added to emphasize that a predominance ofbackground small lymphocytes is one of the leastimportant features in the diagnosis of LP HD. Asdiscussed above, LP HD has many significant dif-ferences from the other “classic” forms of HD, andits distinction from these other subtypes is of pri-mary importance.

In the following discussion of the histopathologyand differential diagnosis of the various subtypes ofHD, extensive references will not be given as thefeatures mentioned are described in detail in thestandard references of these disorders,6,7,11,70,87,88 aswell as recent authoritative reviews of the sub-ject,13,42,71,89,90 which, in turn, contain references tothe original literature reports. Details concerningthe immunophenotype of HD and its morphologicmimics are available in these standard references aswell as in a number of excellent comprehensivereviews of hematopoietic markers that have beenpublished recently.91–94

Classic Hodgkin’s Disease

The appellation of classic Hodgkin’s diseaseincludes all forms of HD containing morphologi-cally typical diagnostic RS cells and mononuclearvariants that display the characteristic CD30-posi-tive and (usually) CD15-positive immunopheno-type. It excludes only the category of LP HD. In theproposed WHO classification, there are four sub-types of classic HD: MC, LRC, LD, and NS.

Mixed Cellularity Hodgkin’s Disease and Lymphocyte-Rich Classic Hodgkin’s Disease

Mixed cellularity Hodgkin’s disease (MC HD) occursmost commonly in adults, and is rare in children. Anylymphoid body site may be involved, and advanced-stage presentations are more common than in LP HDor NS HD, with tumor not infrequently involving thespleen, liver, and bone marrow. Purely extranodal pre-sentations are uncommon, however. The overall prog-nosis is also worse than in LP or NS HD but varieswith stage, and the disease can be cured in manypatients. Mixed cellularity HD is the most commondiagnosis made in cases of classic HD that do notshow the distinctive features of the NS subtypedescribed below.

At low power, the involved tissue in both of theseforms of classic HD appears diffusely effaced by amixed cellular infiltrate consisting of scattered diag-nostic RS cells and mononuclear variants in a back-ground of benign inflammatory cells, which consistsof varying proportions of mature small lympho-cytes, large lymphocytes, histiocytes, eosinophils,and plasma cells (see Figure 20–2). Typically, smalllymphocytes and eosinophils are the most numer-ous, but the proportions vary widely from case tocase, and even common constituents such aseosinophils may be completely absent in a givencase. Cases in which the background cells are virtu-ally all small lymphocytes are termed LRC HD (Fig-ure 20–7), but, as previously noted, this serves prin-cipally to draw a distinction between this form ofclassic HD and true LP HD. There is little evidenceto suggest a biologic difference from MC HD, andmost of these cases were likely diagnosed as MCHD in the past by most hematopathologists. As inthe LP subtype, the histiocytes may aggregate toform granulomas, which may be quite prominent inparticular cases. In lymph nodes showing early or


WHO CLASSIFICATION (2000)

• Nodular lymphocyte predominance HD• Classic HD

Mixed cellularityLymphocyte depletionNodular sclerosisLymphocyte rich classic


partial involvement by HD, tumor cells tend to accu-mulate in the interfollicular regions, sparing thelymphoid follicles and producing the illusion of nor-mal nodal architecture at low power. Such caseshave been termed “interfollicular HD” by someauthors, but most cases likely represent simply earlyor partial nodal involvement by MC HD or otherforms of classic HD.95

Except perhaps in some cases of NS HD,immunophenotyping is required to confirm the diag-nosis of classic HD and exclude morphologic mim-ics, as will be discussed in more detail in the sectionon differential diagnosis below. In most cases of clas-sic HD, the RS cells and mononuclear variants willexpress both CD30 and CD15, often in a characteris-tic membrane-and-Golgi staining pattern, althoughin some individual cases either the membrane patternor Golgi pattern may predominate (see Table 20–2).The majority of classic HD cases also lack evidentexpression of LCA (CD45) and T-cell or B-cellmarkers. CD30 expression is seen in virtually allcases and is taken by many to be a required elementfor the diagnosis of any form of classic HD. CD15,on the other hand, is recognized to be absent inroughly 20 percent of classic HD cases. Approxi-

mately 20 percent of classic HD cases will also showexpression of B-cell markers, such as CD20, by theRS cells, but in contrast to B-cell non-Hodgkin’slymphomas, the CD20 expression in classic HDtends to be relatively weak and focal. Expression ofT-cell antigens such as CD3, however, appears to bedistinctly unusual in classic HD. Some authoritieshold that such expression can be used as grounds toexclude the diagnosis,13 whereas others believe thatHodgkin’s disease may truly be of T-cell origin inrare cases.96 A variety of other antigens are expressedby RS cells, but few offer any advantages in speci-ficity or sensitivity over those described above.91–94

Lymphocyte Depletion HD

Lymphocyte depletion Hodgkin’ disease (LD HD) isthe least commonly diagnosed form of HD, at least inindustrialized nations. This may reflect a lack of clearcriteria to separate it from other forms of classic HD,as well as a high standard imposed by many patholo-gists for the diagnosis, given the history of misdiag-nosis of other entities as LD HD in the pre-immuno-phenotyping era (see below). It is more common inpatients infected with HIV than in the general popu-

Figure 20–7. Hodgkin’s disease, lymphocyte-rich classic type. The phenotype and distribution of theReed-Sternberg cells are similar to that in mixed cellularity Hodgkin’s disease, but virtually all thebackground cells are small lymphocytes. The phenotype of the RS cells and their marked nuclearatypia distinguish this entity from lymphocyte predominance Hodgkin’s disease. (Hematoxylin andeosin; ×1,000 original magnification.)


lation and more common in industrialized societiesthan in developing countries. Patients with LD HDare also more likely to be elderly and present withinvolvement of abdominal lymph nodes, liver,spleen, and bone marrow. They often lack peripherallymphadenopathy. Overall, the prognosis is poor butstage for stage appears similar to that of MC HD.

Morphologically, LD HD resembles the MC sub-type, but has a significantly higher proportion of RScells and mononuclear variants relative to inflamma-tory cells. The RS cells and variants may be presentin sheets resembling a diffuse large cell non-Hodgkin’s lymphoma or other poorly differentiatedlarge-cell neoplasm (Figure 20–8). The tumor cellsmay also be elongated, resembling at least focally thespindled cells of a malignant sarcoma (Figure 20–9).Given this resemblance to other large-cell malignan-cies, it is perhaps not surprising that retrospectivereview of cases diagnosed as LD HD by morphologyalone in the pre-immunophenotyping era haverevealed that the majority of such cases actually rep-resented entities other than classic HD (most com-monly diffuse large B-cell lymphomas).15,16

The distinction between MC HD with numerousRS cells and LD HD is sometimes an arbitrary one.

There are no established criteria concerning the pre-cise proportion of RS cells at which MC HDbecomes LD HD. This fact, combined with the skep-ticism with which the diagnosis of LD HD becameviewed at the onset of the immunohistochemical era,has led some hematopathologists to diagnose mostcases of classic HD not showing the characteristicfeatures of the NS subtype as MC HD.

Nodular Sclerosis Hodgkin’s Disease

Of all the subtypes of classic HD, NS is the most dis-tinctive. Patients tend to be younger, with mostpatients presenting as adolescents or young adults.However, the disease can occur at any age. In contrastwith both the LP and MC subtypes, the disease occurspredominantly in females, with the mediastinumbeing the single most common site of involvement.Prognosis depends on the stage of disease at presenta-tion, but many patients can be cured.

Like other forms of classic HD, diagnostic RScells and mononuclear variants are present and oftenrelatively numerous. However, the hallmark of NSHD is the presence of dense bands of sclerosis,which tend to divide the cellular infiltrate into nod-

Figure 20–8. Hodgkin’s disease, lymphocyte depletion type. Reed-Sternberg cells and mononuclearvariants outnumber background inflammatory cells, and can mimic large cell non-Hodgkin’s lym-phomas as well as other poorly differentiated large-cell malignancies. (Hematoxylin and eosin; ×1,000original magnification.)


ules of varying size (Figure 20–10). When these scle-rotic bands and nodules are well developed, the diag-nosis of NS HD can be suspected even at low powerexamination. When the sclerotic bands and nodulararchitecture are poorly developed, caution should beexercised to prevent mistaking a residual lymph nodetrabecular sinus or band of fibrinous exudate as scle-rosis. Polarized light examination will reveal refrin-gent collagen in areas of true sclerosis.

In NS HD, however, other distinctive histologicfeatures are also generally present to suggest thediagnosis. These include a relatively high proportionof neutrophilic inflammation (which may includemicroabscesses) and scattered apoptotic (or “mum-mified”) RS cells. One will also typically observe,in formalin-fixed tissues, apparent retraction of thecytoplasm of RS cells and variants to produce so-called lacunar variants of RS cells (Figure 20–11).Although none of these features is specific for NSHD, their presence should spur the search for bandsof sclerosis. Some pathologists term cases of classicHD showing these latter features, but lacking obvi-ous sclerosis, as the “cellular phase” of NS HD, par-ticularly when it occurs in a clinical setting charac-teristic of NS HD. However, there is little evidenceto indicate a natural progression of NS HD fromnonsclerotic to sclerotic phases in most cases.

Another distinctive morphologic feature thatoccurs in some cases of NS HD is the presence ofRS cells and variants in diffuse sheets (at leastfocally), producing the so-called syncytial variant(Figure 20–13). In addition to causing confusionwith large cell non-Hodgkin’s lymphomas and otherlarge-cell malignancies, the presence of RS cells insheets appears to be associated with a worse prog-nosis.13 The syncytial variant of NS HD appears tooverlap significantly with the high-grade or grade 2category of NS HD as defined by the BritishNational Lymphoma Investigation, which has alsobeen associated with poor clinical outcome.97

Lymphocyte Predominance Hodgkin’s Disease

The MC, LD, NS, and LRC subtypes are collectivelytermed classic HD, in recognition of the presence inall four of highly pleomorphic diagnostic RS cellsthat typically display the characteristic CD30-positiveand CD15-positive immunophenotype. In contrast,LP HD contains few, if any, diagnostic RS cells.Instead, scattered among the background small lym-phocytes is a peculiar form of giant cell termed“L&H” RS variants (a name taken from the 1966Lukes-Butler classification,98 in which this entity was

Figure 20–9. Hodgkin’s disease, lymphocyte depletion type. Reed-Sternberg cells and mononuclearvariants are present in vaguely spindled shapes, mimicking a malignant sarcoma. (Hematoxylin andeosin; ×400 original magnification.)


Figure 20–10. Hodgkin’s disease, nodularsclerosis type. Bands of dense sclerotic colla-gen separate the cellular infiltrate into nodulesof varying size. (Hematoxylin and eosin; ×40original magnification.)

Figure 20–11. Hodgkin’s disease, nodularsclerosis type. In formalin-fixed tissue sections,the Reed-Sternberg cells and mononuclear vari-ants frequently demonstrate artifactual retrac-tion of their cytoplasm from surrounding cells toproduce “lacunar variants.” (Hematoxylin andeosin; ×1,000 original magnification.)

Figure 20–12. Hodgkin’s disease, nodularsclerosis type, syncytial variant. Reed-Sternbergcells and mononuclear variants are present inlarge aggregates and sheets, mimicking diffuselarge cell non-Hodgkin’s lymphoma. (Hema-toxylin and eosin; ×400 original magnification.)


termed the lymphocytic and/or histiocytic subtype ofHD). Morphologically, these giant cells resemblelobate histiocytes more than typical RS cells, and theirmultiple nuclear lobes display relatively finely dis-persed chromatin and small, inconspicuous nucleoli(see Figure 20–4). This characteristic nuclear lobationresults in their being colloquially termed “popcorncells.” Their bland nuclear cytology and scant cyto-plasm make them relatively inconspicuous, and theymay not be readily apparent at screening magnifica-tion, but a diligent search at high power will revealtheir presence. The great majority of cases of LP HDwill have a nodular architecture at low power, withaggregation of the background small lymphocytesinto densely packed nodules resembling those of fol-licular lymphoma (see Figure 20–13). These cases areoften termed nodular LP HD (NLP HD). Lack of anynodular architecture in a large biopsy should call thediagnosis of LP HD into question.99 Histiocytes arealso frequently present in the cellular background ofLP HD and not uncommonly form scattered granulo-mas, which can be a clue to the diagnosis.

Lymphocyte predominance HD can present at anyage, including childhood, although most cases occurin adults. Generally, peripheral lymph nodes areaffected, and involvement of the mediastinum isuncommon. Involvement of extranodal sites is dis-tinctly uncommon. Disease is usually localized at

presentation, and the prognosis is excellent in low-stage cases, although late relapses may occur. Pro-gression of LP HD to large B-cell lymphoma mayalso occur in some cases.

Immunophenotyping is not necessary to confirmthe diagnosis of LP HD if the above-described char-acteristic morphologic features are present. Ifimmunohistochemical stains are performed, a num-ber of differences from classic HD will be observed.The peculiar L&H variants of LP HD will be posi-tive for CD30 only in a minority of cases, and gen-erally not in the membrane-and-Golgi staining pat-tern seen in cases of classic HD. CD15 expression isseen only rarely and should raise some doubt as tothe accuracy of the diagnosis. Repeated studies havedocumented expression of both LCA and B-cellmarkers such as CD20 by the L&H RS variants, butthese stains can be difficult to interpret in routinepractice, given that the majority of the surroundingsmall lymphocytes are B cells that will also expressthese antigens. The B-cell nature of the backgroundsmall lymphocytes is another feature, however, thatdistinguishes the LP subtype from classic HD,where the majority of the non-neoplastic lymphoidcells are T cells. The few small T lymphocytes pre-sent in LP HD are described by some authors as fre-quently forming rings or rosettes around the L&Hcells; CD57 expression by these T cells has been

Figure 20–13. Hodgkin’s disease, lymphocyte predominance type. At low power, a nodular architecturewill be found at least focally in virtually all cases. (Hematoxylin and eosin; ×400 original magnification.)


advocated by some as a diagnostic aid, but othershave reported it to be of limited utility. L&H RSvariants are also reported to stain for epithelialmembrane antigen (EMA) in the majority of cases,another feature distinguishing these cells from theRS cells of classic HD.

DIFFERENTIAL DIAGNOSIS

Many entities can mimic HD pathologically. Tumorgiant cells histologically indistinguishable from theRS cells of classic HD can be observed in tumors asvaried as diffuse large cell non-Hodgkin’s lymphomas,malignant melanoma, large cell carcinomas, and pleo-morphic sarcomas. Thus, morphologic RS cells,although necessary for the diagnosis of classic HD, arehardly sufficient. The problem is compounded by thepresence of rare cases of bona fide classic HD inwhich the RS cells and variants may appear relativelybland cytologically, raising the question of whetherthey represent benign reactive large lymphocytes (centroblasts or immunoblasts) rather than neoplasticlymphoid cells. The distinctive subtype of LP HD alsoraises its own particular differential diagnosis.

Although a differential diagnosis can be gener-ated for each of the five subtypes of HD, it is simplerand more practical to consider the entities that mostcommonly mimic HD in its three basic morphologic

patterns: classic HD with scattered single RS cells,classic HD with aggregates of RS cells, and LP HD.

Classic Hodgkin’s Disease with Scattered Single Reed-Sternberg Cells

Most cases of HD appear histologically as scatteredsingle diagnostic RS cells or mononuclear variantsin a background of benign-appearing inflammatorycells. Reed-Sternberg cells in these cases may varyin density from area to area and form rare smallclusters but are not present in large aggregates orsheets. Forms of HD with this appearance wouldinclude MC HD, LRC HD, and the nonsyncytialforms of NS HD. Many entities other than HD arecapable of producing this pattern, some of whichmay mimic classic HD to perfection morphologi-cally. Each of these entities should be carefully con-sidered in the differential diagnosis before a diagno-sis of classic HD is rendered.

Several non-Hodgkin’s lymphomas may, on occa-sion, be histologically indistinguishable from MCHD or other forms of classic HD with scattered RScells (Figure 20–14). Principal among these isanaplastic large cell lymphoma (ALCL). Anaplasticlarge cell lymphoma has had a long and colorful his-tory. Originally described as Ki-1-positive large celllymphoma,100 it was characterized by pleomorphic

Figure 20–14. Anaplastic large cell lymphoma. Atypical giant cells resembling the Reed-Sternbergcells of classic Hodgkin’s disease are present. (Hematoxylin and eosin; ×1,000 original magnification.)


date cannot be tested in paraffin sections) appearsrelatively specific to HD. Morphologic clues withALCL include the presence of so-called hallmarkcells (with eccentrically placed horseshoe or kidney-shaped nuclei) (Figure 20–15), the presence of tumorgiant cells with wreath-like nuclei (Figure 20–16),104

nucleoli that appear less prominent than in HD, andtumor cells that grow in cohesive sheets, often with asinusoidal pattern apparent at least focally. Clinicalclues with ALCL would include tumor presenting ina child or young adolescent and an extranodal pre-sentation. Even with extensive immunophenotyping,however, rare cases cannot be clearly classified aseither ALCL or HD; these will be discussed in thesection on gray zone lymphomas below.

If the pattern of dense sclerosis and nodule for-mation is well developed, and the RS cells and vari-ants express the characteristic CD30/15-positiveimmunophenotype, few other entities need be con-sidered in the differential diagnosis of NS HD. In theearly 1990s, there were reports of cases of ALCL thatcould mimic the characteristic morphology andimmunophenotype of NS HD105; these were includedin the category of “ALCL, Hodgkin’s-like” thatappeared as a provisional entity in the 1994 REALclassification.11 This category has been dropped fromthe proposed WHO classification, however,87 andthere appears to be a consensus among experts thatmost cases of ALCL and CHD can be distinguishedusing the guidelines outlined above.13,25

Diffuse large B-cell lymphoma (DLBCL) mayalso mimic MC HD and other forms of classic HDwith scattered RS cells, particularly when it containsnumerous admixed inflammatory cells in the variantknown as T-cell/histiocyte-rich large B-cell lym-phoma. In these cases, the large B cells cited aboveas potential mimics of the L&H cells of LP HD canalso resemble classic RS cells and thus mimic MCHD. Lack of CD30 and CD15 staining, combinedwith the strong uniform CD20 expression that wouldbe expected of large B cells in such cases, will helpto exclude classic HD.106

Peripheral T-cell lymphoma (PTCL) can con-tain pleomorphic large cells present in a backgroundof small lymphocytes and thus mimic MC HD. Mor-phologically, one may note a so-called continuum ofatypia in such PTCL cases, that is, a spectrum of

CD30-positive tumor giant cells resembling RS cellsand variants that lacked CD15 and frequentlyexpressed T-cell antigens. The resemblance to RScells extended to the CD30 staining pattern, whichfrequently marked both cell membrane and Golgiregion. These tumors were often found to displayother features not typically observed in HD, such ascohesive growth of tumor cells in lymph nodesinuses, although such sheet-like growth is not seenin all cases. Later, it was discovered that a subset ofALCL cases, which were virtually always of T-cellorigin genetically, contained a distinctive t(2;5)translocation that caused expression of a NPM-ALKfusion protein that could, in turn, be recognized bythe ALK1 antibody and predicted a favorable clinicaloutcome in systemic cases.101–103 With these findingsfocusing attention on this distinctive T-cell form ofALCL, and few data to suggest biologic differencesbetween B-cell large cell lymphomas that expressedCD30 versus those that did not, the term ALCLbecame largely restricted to tumors of T-celltype.13,101 With the discovery that most cases of clas-sic HD were of probable germinal center B-cell ori-gin (see above), a further wedge was driven betweenthese two entities. Today most authorities suggestthat classic HD can be distinguished from ALCL inmost cases by application of immunoperoxidasestains that exploit the above-described differ-ences13,71 (Table 20–6). Positive staining of the can-didate RS cells for CD15 or CD20 (if weak andfocal) favors classic HD. Positive staining of the largecells for the ALK protein, T-cell antigens, or LCA(CD45) favors ALCL. Epithelial membrane antigenexpression is also found more commonly in ALCLthan in HD, whereas expression of fascin (which to

Table 20–6. CLASSIC HODGKIN’S DISEASE VS.

ANAPLASTIC LARGE CELL LYMPHOMA

PARAFFIN SECTION IMMUNOPHENOTYPE

CHD ALCL

CD15 + –CD20 –/+ –CD45 – +/–T-cell antigen – +/–Epithelial membrane antigen – +ALK/t(2;5) – +/–

Proportion of cases showing positive staining at least focally: + >90%;+/– 50–90%; –/+ 10–50%; – <10%.


atypical small, atypical intermediate, and atypicallarge lymphoid cells, rather than the sharp distinctionbetween the atypical large RS cells/variants and thebenign-appearing background inflammatory cellscharacteristically observed in classic HD. Immuno-phenotyping will generally reveal the T-cell nature of

the neoplastic cell population in such cases. Severalfacts about the immunophenotype of PTCLs that maytrip up the unwary should be kept in mind, however.First, loss of one or more pan-T-cell antigens byPTCLs is not uncommon, and thus the tumor mayappear to have a “null cell” phenotype if only one

Figure 20–15. Anaplastic large cell lymphoma. Sheet-like growth and the presence of tumor cellswith reniform to horseshoe-shaped nuclei (“hallmark cells”) provide clues that this is not classicHodgkin’s disease. (Hematoxylin and eosin; ×1,000 original magnification.)

Figure 20–16. Anaplastic large cell lymphoma. A large atypical tumor cell is present with awreath-like nucleus, which is characteristic of anaplastic large cell lymphoma. (Hematoxylin andeosin; ×1,000 original magnification.)


T-cell antigen is assayed. Second, CD15 is expressedby up to 60 percent of peripheral T-cell lymphomas.Finally, CD30 can be expressed by a variety of T-celllymphomas in addition to classic ALCL. Whether a T-cell lymphoma co-expressing CD30 and CD15should be considered a T-cell variant of classic HD islargely an issue of semantics. But such a tumor wouldclearly differ from the more common germinal-centerB-cell type of CHD, a point that should be made clearin the pathology report in such rare cases. Mostauthorities at present would regard the expression ofone or more T-cell antigens as an argument against thecase being considered classic HD.

Mixed cellularity HD and similar forms of classicHD can also be mimicked by an unusual type of B-cellproliferation known as post-transplant lymphopro-liferative disorder (PTLD). Post-transplant lympho-proliferative disorders are EBV-induced B-cell prolif-erations that may arise following either solid organ orbone marrow transplantation.107 They are an unusualclass of disorders that span the spectrum from benignto malignant, and their behavior is difficult to predictfrom their pathologic appearance.107 PolymorphicPTLDs are destructive lesions that efface the architec-ture of involved tissues, which may be lymph nodes orextranodal sites. Morphologically, they most closelyresemble a “diffuse mixed small and large cell lym-phoma” such as a marginal zone lymphoma. Somecases, however, may include scattered atypical largecells resembling RS cells, which may express CD30.Staining for CD20 or other B-cell markers will revealstrong uniform positive staining of both large andsmall cells, however, essentially excluding HD.

Lymph nodes responding to antigens that pro-voke T-cell immunity, such as viral infections andvaccinations, may undergo expansion of the interfol-licular areas, which on high-power microscopicexamination may contain numerous reactive largelymphocytes (centroblasts and/or immunoblasts), acondition known as interfollicular immunoblastichyperplasia. In its milder forms, the bland cytologyand general preservation of nodal architecture raiselittle concern of malignancy, but more florid casesmay include atypical large lymphoid cells and thusmimic either early “interfollicular” HD or MC HD.Contributing to this potential confusion is the not-infrequent expression of CD30 by reactive immuno-

blasts, particularly in response to viral infections.108

The cytologic atypia in such cases generally fallsshort of that typically observed in classic HD, andthe expression of CD30 and CD15 in a membrane-and-Golgi pattern is seldom observed. Consultationwith the clinician in such equivocal cases may yieldimportant clinical information, for example, that thepatient’s lymphadenopathy is resolving sponta-neously or that the patient has serologic evidence ofinfectious mononucleosis.

Finally, the possibility of LP HD must be con-sidered in cases of MC HD with relatively bland RScells and a predominance of small lymphocytes andhistiocytes in the inflammatory background. Thisparticular differential diagnosis between LP HD andclassic HD will be discussed in more detail below.

Classic Hodgkin’s Disease with Aggregates of Reed-Sternberg Cells

In two forms of classic HD, LD HD and the syncytialvariant of NS HD, RS cells and variants may be pre-sent in large aggregates or diffuse sheets. This maycause the diagnosis of classic HD to not be consid-ered in the initial differential diagnosis. The presenceof such subtypes and variants of CHD raises differen-tial diagnostic considerations not applicable to morecharacteristic forms of classic HD such as MC HD.

The differential diagnosis of LD HD is somewhatbroader than that of MC HD, but many of the sameentities must be considered. The closer resemblanceof LD HD to other poorly differentiated large-cellmalignancies such as non-small cell carcinoma,malignant melanoma, large cell non-Hodgkin’slymphoma, and pleomorphic sarcomas means thatsuch entities must generally be excluded by immuno-histochemical stains for epithelial, melanocytic, T/B-cell, and other mesenchymal antigens. Absence ofstaining for such lineage-associated markers, com-bined with characteristic membrane-and-Golgi stain-ing for CD30 and CD15, confirms the diagnosis.Morphologically, LD HD does not typically demon-strate the dense cohesion of tumor cells typical ofmany other poorly differentiated large-cell malignan-cies, but this is an unreliable feature. In CD15-nega-tive cases, anaplastic large cell lymphoma wouldneed to be excluded, following the guidelines estab-


lished in the discussion of MC HD above. The dif-ferential diagnosis would also have to include thesyncytial variant of NS HD, which will also have RScells present in diffuse sheets. The presence of scle-rotic bands of collagen excludes LD HD and con-

firms NS HD, which typically presents in youngerpatients. Cases lacking sclerosis but showing othercharacteristic features of NS HD could be consideredthe “cellular phase” of NS HD, particularly if presentin a young patient (see below).

Figure 20–17. T-cell-rich large B-cell lymphoma. This variant of diffuse large B-cell lymphomacontains scattered large B cells in a background of numerous mature small T cells, and may thusmimic classic Hodgkin’s disease. Immunophentotyping is required to confirm the diagnosis. (Hema-toxylin and eosin; ×1,000 original magnification.)

Figure 20–18. Peripheral T-cell lymphoma. Such lymphomas may contain pleomorphic large cellsresembling the Reed-Sternberg cells of classic Hodgkin’s disease and may show someimmunophenotypic features of that disorder. The continuum of atypical cells, from small to inter-mediate to large, helps distinguish this entity from Hodgkin’s disease. (Hematoxylin and eosin;×1,000 original magnification.)


In cases of presumed NS HD where the scleroticbanding pattern is poorly developed or the immuno-phenotype is not classic for HD (eg, lack of CD15expression), essentially all the entities described indiscussion of the differential diagnosis of MC HDshould be considered as outlined above. In the caseof a presumed syncytial variant of NS HD, the dif-ferential should be broadened further to include theother entities discussed in the differential diagnosisof LD HD, and the possibility of processes such asmetastatic melanoma or carcinoma might need to beexcluded. A particular problem is distinguishing NSHD from the subtype of diffuse large B-cell lym-phoma known as primary mediastinal (thymic)large B-cell lymphoma. Both commonly present asmediastinal masses in young women, so the clinicalsetting can be identical. Moreover, both tumors fea-ture large, atypical, lymphoid cells separated byfibrous bands. However, the pattern of fibrosis ismuch finer in mediastinal large B-cell lymphomathan in NS HD, surrounding small clusters of tumorcells in a pattern termed “compartmentalizing fibro-sis,” as opposed to the coarse fibrous bands and largetumor nodules seen in NS HD (Figure 20–19). Tofurther complicate matters, primary mediastinallarge B-cell lymphoma is frequently CD30 posi-tive.109 However, the strong uniform staining of theB-cell lymphoma for CD20 generally serves to dis-tinguish the two.

Lymphocyte Predominance Hodgkin’s Disease

Lymphocyte predominance HD can be confidentlydiagnosed on the basis of its morphologic appearancealone if all of the characteristic diagnostic featuresdiscussed above are present. Certain other conditions,both benign and malignant, may mimic LP HD insome instances, however, and care must be taken toexclude them from the differential diagnosis.

Cases of LP HD in which the L&H cells displayhigher degrees of nuclear atypia may be confusedwith classic Hodgkin’s disease, but the morpho-logic and immunophenotypic features describedabove usually suffice to exclude classic HD, whichrarely displays the regular, densely packed, smallcell-predominant, nodular architecture seen in most

cases of LP HD. The typical case of LP HD is muchmore likely to be confused with small cell B-cellnon-Hodgkin’s lymphomas, particularly follicularlymphoma. The low-power microscopic appearanceof LP HD in its most common nodular form canmimic a low-grade follicular B-cell lymphoma to per-fection (Figure 20–20), and both entities should beconsidered in the pathologic differential before eitheris diagnosed. B-cell immunostains will also demon-strate the majority of the cells in these nodular aggre-gates to be mature small B cells in both cases, addingto the confusion. Distinction between these entities ismade principally by high-power microscopic exami-nation, which will reveal the majority of the smalllymphocytes present to have round nuclear contours inLP HD, whereas a significant population of centro-cytes (small cleaved cells) will be evident in cases oftrue follicular lymphomas (Figure 20–21). Furtherhigh-power examination will reveal the presence ofthe characteristic lobate L&H cells in cases of LP HD.

Lymphocyte predominance HD must also be dis-tinguished from a form of florid reactive follicularhyperplasia of lymph nodes known as progressivetransformation of germinal centers (PTGC). Pro-gressive transformation of germinal centers may befound in the lymph nodes of patients with LP HDeither preceding, concurrent with, or subsequent to thediagnosis of HD, and in some cases LP HD appears toarise from a background of PTGC. However, a con-nection between these two entities is far from clear,and PTGC is too commonly found as a focal feature ofnonspecific reactive follicular hyperplasia to be a pre-cursor lesion to LP HD in all cases. Progressive trans-formation of germinal centers is characterized by thepresence, in a background of typical follicular lym-phoid hyperplasia, of scattered, strikingly enlargedlymphoid follicles four to five times the size of sur-rounding reactive follicles, which appear to consistmainly of small cells and lack a typical germinal cen-ter. Such “transformed” follicles resemble the individ-ual nodules of NLP HD, but in a typical case of PTGCthe transformed follicles are widely scattered, nottightly clustered with effacement of nodal architectureas is typically observed in NLP HD. In cases of PTGCwhere transformed follicles appear focally clusteredand the diagnosis of incipient NLP HD is considered,a diligent search for L&H cells is warranted.


Figure 20–19. Mediastinal diffuse large B-cell lymphoma. This variant of diffuse large B-cell lymphoma may mimic classic Hodgkin’sdisease its clinical presentation, its sheet-likegrowth (mimicking the syncytial variant of NSHD), and in its frequent expression of CD30.The pattern of fine “compartmentalizing” fibro-sis and the strong diffuse expression of CD20help to confirm the diagnosis. (Hematoxylinand eosin; ×1,000 original magnification.)

Figure 20–20. Low-grade follicular non-Hodgkin’s lymphoma. The low-power appear-ance of multiple, crowded, ill-defined folliclesmimics the nodular appearance of nodularlymphocyte predominance Hodgkin’s dis-ease. (Hematoxylin and eosin; ×40 originalmagnification.)

Figure 20–21. Low-grade follicular non-Hodgkin’s lymphoma. The presence of numer-ous small cleaved lymphocytes (centrocytes)and the absence of L&H variants excludes thediagnosis of LP HD. (Hematoxylin and eosin;×1,000 original magnification.)


Lymphocyte predominance HD may also be con-fused with diffuse small B-cell lymphomas, such assmall lymphocytic lymphoma, mantle cell lym-phoma, and marginal zone lymphoma (ie, MAL-Toma or monocytoid B-cell lymphoma), particu-larly if the characteristic nodular architecture of LPHD is not well developed. Small cell lymphoma willalmost invariably demonstrate its characteristic“pseudofollicular” architecture due to the presenceof proliferation centers containing larger prolympho-cytes and paraimmunoblasts, which are absent fromcases of LP HD. Mantle cell and marginal zone lym-phomas can be distinguished by the absence of thecharacteristic L&H cells at high power, but caution isurged, particularly in the case of marginal zone lym-phomas, which may contain large numbers of histio-cytes and large lymphocytes resembling L&H cellsto a certain extent. One can decrease the likelihoodof confusing mantle cell and marginal zone lym-phomas with LP HD if one is extremely cautious inthe diagnosis of LP HD in cases entirely lacking itscharacteristic nodular architecture. If biopsy materialis too limited to assess architecture with confidence,a definitive diagnosis is often best avoided.

Finally, the scattered large L&H cells presentamong the small lymphocytes and histiocytes of LPHD may mimic the morphologic variant of diffuselarge B-cell lymphoma known as T-cell/histiocyte-rich large B-cell lymphoma. As the name implies,this tumor features large numbers of admixed reactivesmall T lymphocytes or histiocytes (Figure 20–17).Several reports describe a relatively aggressive clini-cal course in these patients. The large B cells in thesecases may resemble L&H variants of LP HD; how-ever, the lack of nodular architecture and a paucity ofbackground small B cells would argue against thediagnosis of LP HD. A case of LP HD which isentirely diffuse should call into question the diagnosisof LP HD (ie, should make one suspect the diagnosisis incorrect).99

“Grey Zone Lymphomas”

In the vast majority of cases, the question of whethera tumor containing candidate RS cells represents HDcan be solved by routine paraffin section immuno-peroxidase staining, where a CD30-positive, CD15-

positive, and T/B-cell antigen-negative immunophe-notype will be found in most cases of true classic HD.Most cases of classic HD will also demonstrate a com-bination of characteristic clinical presentation, typicalmorphology, and characteristic immunophenotype. Asa general rule of thumb, the diagnosis of classic HDcan be made with relative confidence if at least twoof these three features are present. For example, acase of HD presenting in an extranodal site (anuncommon clinical presentation) is still classic HD,provided that it demonstrates diagnostic RS cells inan appropriate mixed inflammatory background andthese cells show the characteristic CD30/15-positivephenotype in a membrane-and-Golgi staining pat-tern. Any lack of the characteristic morphology orimmunophenotype in such a case, however, shouldcause the diagnosis of HD to be made only withextreme caution. Similarly, an adolescent femalewith a mediastinal mass showing microscopic densesclerosis and lymphoid nodules containing scatteredlarge lymphoid cells that are CD20 negative andCD30/15 positive in the characteristic pattern can beconfidently diagnosed with NS HD, even if the largelymphoid cells are relatively bland morphologically.But if the cells instead appear CD30 negative, itshould put the diagnosis of classic HD in doubt.

Ancillary markers can be employed in equivocalcases. For example, as discussed above, a case on theborderline between classic HD and ALCL can be sub-jected to stains for ALK protein expression andfascin, in the hope of tipping the scales toward one orthe other diagnosis. In addition, genetic studies can beemployed. Although PCR-based gene rearrangementstudies may be difficult to interpret (given that clonalB-cell populations could be detected in both classicHD and B-cell lymphomas), the presence of a strongclonal band in standard Southern blots for T- or B-cellantigen receptor genes can be used as evidence tosupport the diagnosis of a non-Hodgkin’s lymphomaas these are not generally found in classic HD.

In rare cases, however, even using all the strate-gies outlined above, it may be impossible to excludepathologic mimics and reach an unequivocal diag-nosis of HD. This may be due to lack of material forneeded studies (eg, lack of snap-frozen tissue forfascin stains or Southern blotting) or to completelyequivocal results. A classic example of the latter


would be a tumor with RS-like cells and mononu-clear variants, present both as single scattered cellsand in clusters, in which the neoplastic large cellsstain only with CD30 in a membrane-and-Golgi pat-tern. Such a tumor could reasonably be consideredeither a CD15-negative case of classic HD or anALK-negative case of ALCL. A Southern blot couldfail to yield a clonal gene rearrangement in eithercase: between 1 and 5 percent of lesional cells mustcarry the rearrangement to be detected by Southernblotting, and both classic HD and ALCL may havetoo few neoplastic cells in some cases.

Tumors such as those described above have beentermed “gray zone lymphomas”110 and, althoughrare, present a situation frustrating to both patholo-gists and clinicians. There is some evidence to sug-gest that such lymphomas may respond equally wellto therapy for HD and non-Hodgkin’s lymphomas,leaving clinicians free to treat such neoplasmsaccording to their best clinical judgment.111 Thewider availability of molecular biologic techniquesto look for the presence of the non-productively re-arranged, “crippled” immunoglobulin chain genestypically identified by research laboratories in mostcases of classic HD analyzed to date may helpresolve many such gray zone cases, but likely notall. The ability to distinguish between HD and itsmany morphologic mimics in all cases will require auniversally accepted genetic definition of HD andtechnology that is cost-effective and widely avail-able to diagnostic pathologists.

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Pathology of Hodgkin's Lymphoma

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