Annals of Oncology Advance Access originally published online on November 10, 2005
Annals of Oncology 2006 17(1):141-145; doi:10.1093/annonc/mdj037
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© 2005 European Society for Medical Oncology
Lymphocyte-rich classical Hodgkin lymphoma (LRCHL): clinico-pathological characteristics and outcome of a rare entity
1 The Netherlands Cancer Institute, Amsterdam, the Netherlands; 2 Institut Gustave Roussy, Villejuif, France; 3 St. James's University Hospital, Leeds, UK; 4 Hôtel-Dieu, Paris, France; 5 Centre François Baclesse, Caen, France
* Correspondence to: Dr D. de Jong, The Netherlands Cancer Institute, Department of Pathology, Plesmanlaan 1211066 CX Amsterdam, The Netherlands. Tel: +31-20-512-752; Fax: +31-20-512-2759; E-mail: d.d.jong{at}nki.nl
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Abstract |
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Background: To investigate the proportion, clinical characteristics and outcome of lymphocyte-rich classical Hodgkin lymphoma (LRCHL) in relation to nodular lymphocyte predominant HL (NLPHL) and classical HL (cHL).
Patients and methods: A series of 2743 HL patients of all stages enrolled into three EORTC trials (H7, H8, H34) conducted between 1988 and 2000 and forming an unbiased series of HL patients was studied.
Results: Detailed histological classification after panel review was available in 96% of the cases to allow selection of all cases with features potentially compatible with the WHO-definition of LRCHL for this study. Cases with dominance of lymphocytic infiltrate and relative paucity of eosinophils and fibrosis could be selected for re-classification. Twenty-one (0.8%) LRCHL cases were identified of which three were originally classified as NLPHL, seven as nodular sclerosis HL (NSHL) and 11 as mixed cellularity (MCHL), indicating that LRCHL is a rare disease.
Conclusions: Clinical evaluation of the unselected series of patients (n = 2743) showed that LRCHL and NLPHL cases more often presented with favorable features. Clinical outcome adjusted on ab initio patient prognosis did not differ between the three histological entities. These results strongly suggest that LRCHL corresponds to an early stage in the spectrum of cHL rather than a biologically different disease entity.
Key words: lymphocyte-rich classical Hodgkin lymphoma, lymphoma classification, clinical trial, prognosis
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introduction |
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In the World Health Organization (WHO) classification for lymphoid malignancies, five subtypes of Hodgkin lymphoma (HL) are recognized [1
]. An important dichotomy is made between nodular lymphocyte predominant HL (NLPHL) and the group of classical HL (cHL). These two entities differ essentially in their clinical course with a significantly more indolent behavior associated with NLPHL, less frequent adverse clinical features, late relapses and deaths more often due to late effects of treatment than to the disease itself. Therefore, patients with NLPHL are currently treated with protocols that fundamentally differ from those applied to patients with cHL. Four different subtypes of cHL are now recognized with the introduction of the novel entity lymphocyte-rich classical HL (LRCHL) [1]. This variant was only recently defined as a subtype of cHL [2–4].
In a combined study based on data from 17 European and American centers, diagnostic criteria were set for LRCHL: scattered Hodgkin-Reed-Sternberg cells with a classical immunophenotype in a background of small lymphocytes without admixture of eosinophils and neutrophils and without sclerosis [4]. Two morphological variants are identified (nodular versus interfollicular and diffuse). Clinical characteristics and outcome were analyzed based on 512 patients diagnosed as NLPHL between 1970 and 1994 and heterogeneously treated [3]. The results suggested that LRCHL may be associated with early stage disease and favorable prognostic factors compared with nodular sclerosis (NS) and mixed cellularity (MC) subtypes, leading to better overall survival. In this series, LRCHL patients more often presented with stage I than NS and MC patients (46% versus 10% and 21%, respectively), infrequent B-symptoms (11% versus 54%/40%) and infrequent mediastinal involvement (15% versus 80%/40%). Data was originally collected to study the differential diagnosis of NLPHL and T cell-rich B-cell lymphoma. This selection may have resulted in a significant bias, precluding strong conclusions on its clinical relevance.
Few well-documented, well-collected and uniformly treated patient series are available that may be less biased. The European Organization for Research and Treatment of Cancer (EORTC) HL Pathology Review Panel had the opportunity to study the histological material of three series of patients enrolled onto three prospective controlled clinical trials to study the incidence and clinical features of the WHO-HL entities [5–8].
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patients and methods |
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In all EORTC HL trials since 1964, pathology review by an international panel of expert pathologists has been part of the protocol. Cases have been diagnosed according to the Rye classification using a standardized protocol and criteria. Histological material from patients treated in two trials on supradiaphragmatic stages I and II (H7, 1988–1993, 833 patients; H8, 1993–1998, 1578 patients) and in one trial on stages III and IV (H34, 1989–2000, 739 patients) was re-analyzed. Material was collected for 2869 cases and the diagnosis of HL confirmed in 2743 (96%) including 83 (3%) NLPHL, 2267 (83%) NSHL and 386 (14%) MCHL; seven (<1%) cases were unclassified.
At the initial central pathology review, detailed morphological and immunohistochemical parameters were recorded. Detailed classification in NSHL cases included information on the extent of fibrosis (minimal sclerosis/cellular phase, well-formed collagen bands and extensive sclerosis) and subclassification according to the BNLI-guidelines (BNLI-type 1 and type 2) in all reviewed cases. MCHL cases are subclassified as classical, interfollicular and as ‘by exclusion of other subtypes’ according to set criteria in all reviewed cases. For NLPHL cases, the extent of nodularity and diffuse components was recorded as well as the presence of a component of so-called progressive transformation of germinal centers (PTGC). According to the current definition of LRCHL the presence of extensive fibrosis and/or a component of eosinophils in the background pattern excludes this classification. Cases that were previously classified as NSHL with well-formed collagen bands or extensive fibrosis and cases classified as BNLI-type 2, as well as cases classified as classical type MCHL that includes an eosinophilic infiltrate as a defining criterion, do not fit the definition of LRCHL and were therefore excluded from re-review in this study. According to morphological parameters assessed by the panel, cases classified as ‘NSHL with minimal sclerosis’ (n = 386), MCHL interfollicular and MCHL by exclusion of other subtypes (n = 382) and NLPHD (n = 83) may include LRCHL. These 851 cases were selected for re-classification and corresponding material retrieved. Immunohistochemical stainings on paraffin-embedded biopsy samples was performed according to standard antigen retrieval procedures to include CD20, CD3, CD30 and CD15 (all from DAKO, Glostrup, Denmark) if lacking, or repeated if of insufficient quality. Each case was evaluated by the full panel of pathologists (DdJ, JB, KAML, JD, JA) without knowledge of corresponding clinical data. Data was prospectively collected and centrally computerized at Centre François Baclesse, Caen, France. Data was updated by 1 June 2002, at the latest. Relapse-free survival (RFS), event-free survival (EFS; including treatment failure, relapse or death of any cause) and overall survival (OS) were estimated using the Kaplan–Meier method and compared using the log-rank test. Ninety-five per cent confidence limits (95% CL) of rates were estimated using the Rothman method [9]. The Stata statistical software was used to analyze data [10]. Cases classified as LRCHL or NLPHL on review and cHL cases (reviewed and non-reviewed) were compared.
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results and discussion |
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TopAbstractintroductionpatients and methodsresults and discussionReferences |
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Of the 2743 available cases, 21 (0.8%) fulfilled the criteria for LRCHL as set in the WHO classification (Table 1). Three cases were originally classified as NLPHL, seven as NSHL and 11 as MCHL. A nodular growth pattern was seen in 18/21 cases with a varying extent of the presence of eccentrically located atrophic germinal centers in nodi. This growth pattern was combined with a component with a diffuse pattern in two cases, while three cases showed only the diffuse growth pattern. The distribution of the two growth patterns is comparable to previously reported findings [4
]. Cases diagnosed as LRCHL showed a classical immunophenotype with positivity for CD30 in all cases and CD15 in 15/21 (71%). CD20 expression was observed in one of 18 cases. No signs of progressive transformation of germinal centers (PTGC) were observed.
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In addition, nine cases originally classified as NLPHL were re-classified as cHL (NSHL and MCHL) and two cases of cHL as NLPHL. A majority of these 11 cases were originally diagnosed without immunohistochemical data and additional immunophenotypical information collected for the present study was the dominant parameter for re-classification.
The European Taskforce on Lymphoma first described LRCHL in a series of cases that were originally diagnosed as NLPHL or considered as possible mimics [4]. The majority of LRCHL, therefore, were originally classified as NLPHL (67/115, 58%). Immunohistochemical information at the time of diagnosis was mostly lacking. Since in the absence of immunohistochemical information NLPHL is the major morphological mimic of LRCHL, a relatively high percentage of LRCHL may be expected in this selection. Our selection of cases is essentially different, but obviously also resulted in a cohort that is enriched for cases with dominance of a lymphocytic infiltrate and paucity of eosinophils and well-formed collagen bands. However, since in our series immunohistochemical data was available at the time of original classification in 81% of cases, a classical immunophenotype could be recognized and, therefore, the majority of our cases of LRCHL were already recognized as cHL and classified as NS or MC (18/21, 86%). This further underlines the importance of immunohistochemical information as an integral component of the modern approach to lymphoma classification according to the WHO classification.
The relatively unbiased EORTC series of all stage disease can be used to estimate the actual frequency of LRCHL. It shows that among all assessable cases, this variant is significantly less frequent than previously suggested with <1% LRCHL compared with 3% NLPHL and 96% cHL. The much lower frequency of LRCHL in our series compared with the findings of the European Taskforce may be fully explained by the strong bias in their series of difficult NLPHL cases and the above-mentioned effects of immunohistochemical information. It should be noted that the distribution of clinical stage is highly comparable in both series (for stage I/II versus II/IV the distribution was 76.6%/23.3% and 76.5%/23.4%, respectively) and will not account for the different findings.
Clinical features of patients corresponding to all reviewed and non-reviewed cases are listed in Table 2. Compared with patients having other types of cHL, LRCHL patients presented significantly less frequently with mediastinal involvement, enlarged mediastinum, bulky disease and elevated ESR. Consequently, patients with LRCHL early stage disease more frequently belong to the (very) favorable prognostic group despite their male predominance and older age. Reviewed cases were selected for dominance of lymphocytes and lack of eosinophils and fibrosis, while non-reviewed cHL, per definition, showed higher numbers of eosinophils and well-formed fibrotic bands. With respect to clinical parameters, reviewed cases showed significant differences with male dominance, less elevated ESR and less frequent mediastinal involvement and mediastinal enlargement compared with the non-reviewed cases (Table 2). In contrast, no differences in age distribution, stage, proportion of B-symptoms and bulky disease were seen. Von Wasielewski and co-workers described a new grading system for nodular sclerosing HL, in which eosinophilia and lymphocyte depletion constitute dominant parameters and are predictive for adverse clinical course [11]. This is fully in line with the distribution of prognostic features of the present series of cHL that showed a gradient of the eosinophilic component and inverse gradient of the lymphocytic component with established clinical prognostic stratification, including mediastinal involvement. Since in these EORTC trials, treatment was stratified on ab initio prognosis, this is not reflected in clinical outcome in terms of RFS, EFS and OS for LRCHL as well as for NSHL and MCHL (Table 3).
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Taken together, a spectrum of patterns with nodular and interfollicular disease and varying density of Hodgkin cells, components of hyaline fibrosis and eosinophilic granulocytes are recognized. Within this spectrum, the different subtypes of cHL can be placed morphologically as well as clinically as stated above. Therefore, one may suggest that cHL is one single disease that evolves through a spectrum of morphological changes, that largely also follows the progression of clinical features. In the initial phase, Hodgkin cells start to appear within the periphery of the follicular mantle zone with subsequent expansion of the mantles. This pattern has been previously recognized as ‘cellular phase of nodular sclerosis’ (although this term may have included many cases that would now be recognized as different entities of both HL and non-Hodgkin lymphoma) [12
]. During the next phase, increasing numbers of proliferating Hodgkin cells either migrate into the follicular nodules or expand interfollicularly. At this stage, early fibrosis and induction of eosinophils and other constituents such as epitheloid cells are first appreciated. The first pattern results in nodular disease, diagnosed as NS according to classical and WHO criteria; the second pattern fits the criteria of MC disease. The earlier stages are fully compatible with LRCHL, nodular and interfollicular, and diffuse variants, respectively. Others have shown a similar infection rate with EBV and similar molecular features with the lack of ongoing immunoglobulin gene mutations and the presence of crippling mutations compatible with pre-apoptotic germinal center derived B-cells in LRCHL and the other types of cHL [4, 13]. We conclude that LRCHL is a rare variant of cHL that fully fits into the morphological and biological spectrum of cHL. |
Acknowledgements |
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The authors thank Drs E. M. Noordijk, P. Carde, C. Fermé, H. Eghbali, B. M. Aleman and J. M. Raemaekers for their support to this study as principal clinical investigators of the H7, H8 and H34 trial. Dr F. Berger has contributed to the diagnostic reviewing procedure for these trials.
Received for publication July 7, 2005. Revision received September 6, 2005. Accepted for publication September 9, 2005.
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