Guidelines for the investigation and management of nodular lymphocyte predominant Hodgkin lymphoma

Abstract

The guideline group was selected to be representative of UK-based medical experts. Ovid MEDLINE, Ovid EMBASE and DYNAMED were searched systematically for publications in English from 1980 to 2014 using the key words Hodgkin disease, Hodgkin lymphoma and lymphocyte predominant Hodgkin lymphoma. References from relevant publications were also searched. Editorials, studies with <8 cases, letters and conference abstracts were excluded. The writing group produced the draft guideline, which was reviewed by the British Committee for Standards in Haematology (BCSH) Haemato-oncology Task Force. Further comments were invited from a sounding board of the British Society for Haematology (BSH) and patient representatives identified through the Lymphoma Association. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations (Atkins et al, 2004). The objective of this guideline is to provide healthcare professionals with guidance on the investigation and management of patients with nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). Individual patient circumstances may dictate an alternative approach. This is the first BCSH guideline on this topic and is in date at time of publication. Any updates will be posted on the BCSH website (http://www.bcshguidelines.com/). Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare disease accounting for 3–8% of all Hodgkin lymphoma (HL) in adolescents and adults and 10–20% in pre-pubertal children. It is more common in males (3:1) with peak incidence in children of 13–14 years and adults of 30–35 years. Patients usually present with early stage, non-bulky disease affecting predominantly peripheral nodal sites with few adverse prognostic factors (Diehl et al, 1999). The clinical, biological, morphological and immunophenotypic features of NLPHL differ from classical Hodgkin lymphoma (cHL) (Swerdlow et al, 2008). The clinical course in NLPHL is more indolent and the prognosis is favourable, especially for patients with early stage disease, although late and occasionally multiple relapses do occur (Diehl et al, 1999; Nogova et al, 2008; Farrell et al, 2011). Transformation to high-grade B non-Hodgkin lymphoma (B-NHL), namely diffuse large B-cell lymphoma (DLBCL), is reported in 3–5% of cases (Hansmann et al, 1989). The outcome of DLBCL evolved from NLPHL in adults is similar to that encountered with de novo disease with an overall survival of 60% at 10 years (Biasoli et al, 2010). Deaths from NLPHL are uncommon whilst toxicities related to treatment are a significant cause of mortality (Tsai & Mauch, 2007). Late toxicity from treatment is therefore an important factor to consider in determining the optimal management plan. There is no doubt that this condition has historically been misclassified, with difficulties differentiating NLPHL from both lymphocyte rich classical HL (LRcHL) and reactive conditions. It is now recognized as a B-cell neoplasm characterized by the presence of CD20+ lymphocyte predominant (LP) or popcorn cells (Mason et al, 1994; Nguyen et al, 1999; Swerdlow et al, 2008) and has been more clearly defined in recent pathological and molecular genetic studies (Brune et al, 2008). There are no prospective randomized controlled trials in NLPHL to compare the merits of different treatment approaches. Many published studies are retrospective reviews or single arm phase 2 trials. Frequently, patients with this disease have been included in cHL trials and these studies have not been powered to give reliable outcome data on this subset. Given the limited scientific evidence base there has been little consistency in approach to management except in paediatric clinical trials in Europe and the US (EuroNet paediatric Hodgkin lymphoma [PHL]–L1 and Children's Oncology Group [COG]). International multi-centre collaboration will be required to establish prospective randomized controlled trials to assess the optimal management of this rare disease. The guidance offered here is pragmatic, based on the best evidence available. The architecture of the lymph node is totally or partially effaced by a nodular or a nodular and diffuse lymphoid infiltrate (Swerdlow et al, 2008). The nodular pattern is characterized by large lymphoid aggregates composed of small, predominantly B-lymphocytes supported by expanded spherical meshworks of follicular dendritic cells (FDC). Within the lymphoid aggregates, large atypical cells known as lymphocyte predominant (LP) or popcorn cells are characteristically seen. These cells, which have scant cytoplasm, polylobated nuclei and distinct nucleoli, may also be found outside the nodular areas surrounded by follicular helper T cells (Nam-Cha et al, 2008; Swerdlow et al, 2008). In the diffuse form, the LP cells are embedded in a diffuse background predominantly composed of follicular helper T cells (Nam-Cha et al, 2008) and some histiocytes. FDC meshworks are absent. In contrast to cHL, sclerosis is not a frequent feature in diagnostic biopsies but may be seen at relapse. Six histological variants of NLPHL have been described (Fan et al, 2003) but due to its complexity this approach has not been widely adopted. The German Hodgkin Lymphoma Study Group has shown that patients with a histological variant pattern have a poorer outcome (in terms of relapse risk) than those with typical nodular histology (Hartmann et al, 2013). Progressive transformation of germinal centres (PTGC) is a benign condition that may mimic NLPHL or may precede or co-exist with NLPHL in the same lymph node (Hicks & Flaitz, 2002; Ioachim & Medeiros, 2009). In PTGC it is common to find a single nodule of NLPHL, therefore careful examination is essential. On histology, PTGC is characterized by single or multiple follicles with distorted residual germinal centres separated by expanded mantle zones. Large B-lineage cells (with the morphology of centroblasts) are present, scattered within and outside the PTGC and are usually not surrounded by T cells. Though PTGC might precede NLPHL, it is not a conditio sine qua non for the development of NLHPL. Lymphocyte rich classical Hodgkin lymphoma (LRcHL) has particularly been confused with NLPHL in the past. In one study, approximately 30% of cases previously diagnosed as NLPHL were found to be LRcHL on review (Anagnostopoulos et al, 2000). Detailed immunophenotyping (Table 1) is required to distinguish these entities (Tedoldi et al, 2006; Swerdlow et al, 2008). Unlike the Hodgkin Reed‒Sternberg (HRS) cells of cHL, LP cells strongly express B-cell markers, are nearly always negative for Epstein‒Barr virus (EBV) and are surrounded by rosetting follicular helper T cells (CD3, CD4, CD57 and PD-1 positive). Distinguishing NLPHL with a diffuse pattern from T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) may also cause some difficulty. At least one nodular lymphoid aggregate showing the characteristic features of NLPHL is required to exclude the diagnosis of THRLBCL (Swerdlow et al, 2008). Furthermore, LPHL nodules may be missed in the limited tissue obtained with some needle biopsies. Though a number of criteria are used to differentiate these entities (Boudova et al, 2003) they are not specific enough to be reliable in every case and the two histologically different areas may represent a biological continuum of the same disorder (Harris, 2013). Histological transformation of NLPHL to DLBCL has been reported to occur in approximately 3–5% of cases and may be concurrent or consequent on the development of NLPHL (Hansmann et al, 1989). Higher rates of transformation (14%) were reported in a large series from the British Columbia Cancer Agency (BCCA) (Al-Mansour et al, 2010) with a median time to transformation of 8·1 years. Molecular studies have conclusively demonstrated the clonal relationship between the two diseases (Greiner et al, 1996). Biopsy specimens containing more than 5% NLPHL nodules with diffuse large B-cell areas should be regarded as NLPHL with progression to DLBCL and distinguished from NLPHL with diffuse areas (Fan et al, 2003). Full blood count (FBC), erythrocyte sedimentation rate (ESR), renal function, liver function, lactate dehydrogenase, calcium, phosphate, urate, immunoglobulins and screening for human immunodeficiency virus, hepatitis B and hepatitis C are recommended. A contrast-enhanced computerized tomography (CT) scan of the neck, chest, abdomen and pelvis is recommended at diagnosis for all adult patients to determine the extent of disease. For patients with cHL, functional imaging with 18-F fluoro-deoxy-glucose positron emission computerized tomography (FDG-PET/CT) has become a routine investigation for the staging and subsequent assessment following treatment. There is emerging interest in this modality in NLPHL; two small retrospective series suggested excellent sensitivity of FDG-PET/CT when compared with CT and up to a third of patients are upstaged when studied with FDG-PET (Ansquer et al, 2008; Grellier et al, 2014). The impact of this on clinical outcomes of patients with limited stage disease determined by CT is unknown. However, in common with other indolent lymphomas where radiotherapy may be applied at diagnosis to achieve long-term disease control, accurate staging of NLPHL is of utmost importance to clinicians treating this disease. Those patients with disease confined to an area that can be safely and effectively treated with radiation should undergo PET/CT imaging as this may affect management. It is also an option for patients with advanced stage disease by CT scan and may obviate the need for a bone marrow biopsy (BMB). In children and teenagers, staging is usually via PET/CT with magnetic resonance imaging (MRI) and/or ultrasound as required. There is anecdotal evidence (case reports) that PET/CT may be useful in identifying areas of high-grade transformation and in targeting biopsies but this aspect needs further evaluation. In cHL there is evidence to suggest that in patients staged with PET/CT, BMB rarely alters management and is not routinely indicated (El-Galaly et al, 2012; Hamilton et al, 2014). Whether this also applies to NLPHL is uncertain, despite the fact that the series reported by El-Galaly et al (2012) included 24 patients with NLPHL. Of these, 23 patients had no evidence of bone marrow infiltration on PET/CT and none of these patients had disease involvement as demonstrated by BMB (personal communication: T.C. El-Galaly, Department of Haematology, Aalborg University Hospital, Aalborg, Denmark). Akin to patients with early stage cHL, patients with early stage NLPHL and a normal FBC do not usually require a BMB. A BMB is recommended in patients with advanced stage NLPHL unless the patient has had a PET/CT scan with normal BM appearances. If the BM is abnormal on PET/CT a BMB may be justified, particularly if high-grade transformation is considered likely. Semen cryopreservation should be offered to male patients receiving combination chemotherapy. The possibilities for females are more limited but if commencement of treatment is not imminent patients may wish to discuss their options (oocyte, embryo or ovarian strip cryopreservation) with an assisted conception unit. The role for prophylactic use of gonadotropin-releasing hormone analogues to preserve female fertility remains uncertain (Behringer et al, 2012; Wong et al, 2013). There is no current evidence to support early interim PET/CT imaging to either escalate or de-escalate treatment during first line therapy. Although there are emerging reports of the value of modulating therapy in cHL on the basis of interim PET/CT imaging, these studies either specifically excluded patients with NLPHL or have yet to report any data (Gallamini et al, 2011; Raemaekers et al, 2014). Contrast enhanced CT should be performed on completion of first line therapy. MRI or ultrasound assessment should be considered as an alternative in children. The achievement of a partial remission (PR) is often considered satisfactory in this indolent disease and is not an indication for PET/CT scan or further therapy. There are no published series or guidelines specifically addressing the use of PET/CT in NLPHL to confirm remission status at the end of first line therapy and this investigation is not routinely recommended. If PET/CT is used in this situation, careful comparison should be made with the staging PET/CT scan if available and levels of residual uptake should be reported according to Deauville criteria (Meignan et al, 2009). Second line treatment should not be initiated on the basis of a residual PET-positive lesion alone. Biopsy is recommended to confirm the presence or absence of viable lymphoma and to assess for high-grade transformation (Gyorke et al, 2011; Banzo et al, 2012). If biopsy is not performed, clinical follow-up and early re-assessment is recommended. In any patient, consider possible alternative causes of PET positivity such as infections, sarcoidosis and inflammatory disorders. Careful review of scans by radiologists with expertise in PET/CT reporting in the context of a multidisciplinary team (MDT) is advised. The BCSH transfusion guidelines (Treleaven et al, 2011) recommend irradiated blood products for patients with HL and, as NLPHL is classified as a form of HL, irradiated blood products continue to be recommended despite the lack of evidence that they are necessary (1B). Whilst specific factors associated with inferior outcomes in NLPHL have been identified (Nogova et al, 2008; Hartmann et al, 2013) there is currently no evidence to support a risk-stratified approach to therapy in localized NLHPL. Treatment options include watchful waiting, usually following diagnostic surgical excision, radiotherapy (RT), chemotherapy, immunotherapy and combined modality treatment (CMT). Comparing the effectiveness of each treatment modality is difficult due to lack of clinical trial data. In patients with localized nodal involvement and no detectable disease following excision biopsy, there is no overall survival (OS) benefit from additional therapy at that time. Retrospective analysis of French registry data of 164 patients with NLPHL (83% localized) did show an improved 10 year progression-free survival (PFS) for the 106 patients who received additional treatment (RT alone (27%), CT alone (9%) and CMT (29%); chemotherapy was MOPP (mechlorethamine, vincristine, procarbazine and prednisolone) +/−AVD (doxorubicin, vinblastine and dacarbazine) or compared to the patients who were but there was no in not (Biasoli et al, 2010). A French et al, 2003) similar for patients in remission following excision, the was similar in both additional outcomes for patients with localized NLPHL who received no treatment following excision with of and of et al, 2007). A number of studies support the use of alone as treatment for early stage NLPHL (Table years years years years There have been no prospective randomized controlled trials to the of the optimal or in NLPHL. in cHL have included small of patients with NLPHL and there is limited long-term outcome data specifically to NLPHL Treatment have been from the cHL approach. reports of first line treatment of NLPHL have therefore used radiotherapy between and in et al, et al, 2010). The used radiation in CMT of cHL is and, in the absence of alternative is currently the recommended for single modality treatment of NLPHL. radiotherapy of in 2 has been reported in small of patients at or in relapse et al, with rates and The patient are small to The of CMT for cHL has radiation with radiotherapy by and this in radiation has been applied to treatment of NLPHL where alone rates the need for additional chemotherapy. in imaging and radiotherapy and further of radiotherapy using radiotherapy et al, 2013) and node radiotherapy et al, are in the treatment of cHL as a of effectiveness radiation and late these may also be used in the treatment of NLPHL although when used as a single with is recommended in to et al, 2014). of the is the of late associated with radiation these should and a recent et al, 2013) has shown rates of in patients treated with radiotherapy alone. NLPHL rarely the radiotherapy to this is usually not indicated and therefore late are not receiving radiotherapy affecting tissue may be for screening and should be in with guidelines The data in support of a approach from paediatric studies studies et al, 2006; et al, 2010) suggested for patients treated with chemotherapy alone and survival median up The LP cells of NLPHL are in nearly all cases et al, therapy with the has been studied in NLPHL in both limited and advanced and in the and However, recommendations are difficult on the basis of the small of the of the patients included in the studies and as to patients included in studies have been offered any treatment in the These studies are as evidence for benefit is present in other B-cell lymphomas and toxicity is an important in the management of this patient group where late relapse is a feature and due to lymphoma is In a phase et al, of for in diagnosed patients early the overall rate as by CT criteria was of the patients were to following a for every for 2 The reported median for patients treated with alone and by was and with no significant between the patients disease progression of in of in and at a median time of years patients during the study, 2 from disease that and from an et al reported the of a phase of patients with stage disease who received the same therapy. The rates were with a of at years. of patients and all were there were no reports of disease Although has single in NLPHL with an the and for patients with previously limited stage disease are inferior when compared historically with obtained with radiotherapy and combination chemotherapy. There is no evidence to support the use of CMT alone. are associated with long-term outcomes and whilst CMT may this may not the additional toxicity the indolent of the disease. A from progression rate of was reported in patients with localized NLPHL treated with a course of chemotherapy by et al, 2004). There was no The rate of was similar to that reported et al, 2010) for alone This group and et al, found no significant additional benefit for CMT alone. analysis of patients with localized NLPHL identified from the Cancer et al, 2011) that CMT might outcomes than alone. the first treatment patients received during the received two of and received alone. The was in the treatment than in the first with a to improved this may have been by other diagnostic and between the two time In a retrospective analysis of German Hodgkin Study Group trials and (Nogova et al, there was no significant in or from treatment between patients treated with or CMT or although follow-up was at A analysis of the NLPHL stage patients treated on the with alone or CMT by a improved at years in the CMT group but no in et al, 2007). The for stage patients and cHL for stage to of patients present with advanced stage NLPHL. Although stage 2 disease is common in NLPHL, B are rare and, if present, the of disease should always be considered (Al-Mansour et al, 2010). involvement is in NLPHL, but common in (Biasoli et al, 2010). bone marrow involvement is rare and the of a infiltrate in such circumstances always disease et al, 2004). the multiple in this an area of is that if treatment is required for advanced stage disease combination chemotherapy is The cHL is a B-cell lymphoma approach may be more using and prednisolone) or and prednisolone) on clinical In to the of treatment on the should also consider its on the which of a of B cells with of NLPHL has biological with follicular lymphoma and it is not to use this as a when treatment with a of and may be in particularly following an The guidelines suggest or with as used for advanced stage NLPHL. The vincristine, procarbazine and prednisolone) as an alternative therapy (Nogova et al, 2008) but this is to be to clinicians in of its toxicity is a approach in of the to and for disease and/or B The published for are excellent et al, as are the outcomes with et al, There is little published data on outcomes with but centres are using this There is with prednisolone) in the paediatric where the use of for early stage NLPHL has excellent et al, 2012). This an approach it is more than It is uncertain therapy the of or has any on the subsequent of high-grade A on management a careful assessment of patient circumstances and with patients and their It is not possible to be therapy recommendations for this rare disease. Whilst remains a and should be considered for patients combination chemotherapy and for those with evidence a of of high-grade There is no published to support the use of with chemotherapy has there been a prospective of the approach. The in this guideline to include in combination chemotherapy for the treatment of NLPHL is an from data in and that NLPHL is a lymphoma. In the absence of randomized controlled clinical of is to the on optimal therapy. The have produced a prognostic for NLPHL (Hartmann et al, 2013). Although not in prospective clinical and from retrospective analysis of outcome in trials using the histological (Fan et al, 2003) and has distinct and with significant in and The might be in the of the recommended histological This approach should be and may provide a useful of determining optimal therapy in the In the series et al, the comparison of outcomes for patients with previously advanced stage disease receiving with outcomes for patients treated with combination chemotherapy found that for treated patients is on the basis of current alone be recommended for the treatment of diagnosed For patients who require therapy but who have significant that chemotherapy, might be some patients in the The management of patients with disease on a number of also paediatric stage at relapse and treatment. A biopsy is to exclude high-grade transformation For patients who had a excision, may be for For advanced stage chemotherapy is usually required for some a and may be as for other indolent The of chemotherapy will be by treatment and of Patients a remission with may have further treatment with this If there is evidence of high-grade transformation or the clinical is more is advised. is rarely indicated for NLPHL. Patients with NLPHL achieve similar outcomes as to those with de novo DLBCL (Biasoli et al, 2010) when using and in is not an indication for In patients with disease and to combination chemotherapy, an and might be A single et al, 2013) of patients with NLPHL treated with chemotherapy and a and of and The use of has been reported in the of disease. et al reported patients with a median of two relapses treated for at a of patients had previously received chemotherapy and/or patients a a and two patients disease. The median of for the patients was not at The follow-up on this was and identified a median of at a median follow-up of report et al, 2003) included patients with disease. patients with disease were treated with the same described The rate was a median follow-up of of 10 patients had and the was 10 the studies reported toxicities with the in small of The of in the recommendations The to at relapse are not and it currently be recommended except in those patients the use of combination chemotherapy. patients the of years are diagnosed with NLPHL in the each year & 2012). The is with A of to diagnosis is not patients have early stage disease that is disease with B is rarely encountered if and when it of disease is children and adolescents with NLPHL were treated using for outcome with cHL therapy was excellent but by the and, mortality associated with and often multiple of CMT et al, 2002; Nogova et al, et al, 2007). These are now considered for this predominantly early stage disease & 2012; et al, 2012). data that treatment can be et al, et al, 2003). The with alone by et al, and with chemotherapy et al, suggest that cHL are not required in the of patients with NLPHL. The Children's Oncology Group a approach and children with NLPHL with localized to one of chemotherapy on the presence of selected prognostic et al, 2012). Patients who were in chemotherapy were randomized to or no further treatment. a median follow-up of the and was and with no between patients who received and those who did In the et al found that chemotherapy alone in survival than alone in children with NLPHL treated on the Children's Cancer Study Group and patients stage received alone and with stage disease, with stage disease, and with advanced received chemotherapy alone. a median up of one patient of lymphoma and were The survival rates were in those treated with and treated with (cHL) chemotherapy alone. there are two prospective clinical trials for the treatment of early stage NLPHL in patients years of both of which of therapy. The trial offered surgical alone of stage disease and, for disease, of chemotherapy, (doxorubicin, vincristine, and and for those not in by The trial alone for stage disease and of chemotherapy, for stage & disease. The of has been reported in a of children and adolescents treated for localized NLPHL et al, with of at and of There is now a of using in children with no or long-term toxicity related to B-cell et al, 2012). The to use in patients with disease is its use in early stage disease remains difficult to due to the to a prospective randomized trial and excellent using chemotherapy alone. However, patients with more or advanced disease should be considered for such as or The late of radiotherapy this a treatment modality in this However, radiotherapy for localized stage disease should be considered in especially those in treatment with might in The current the of therapy that the overall of treatment and at a but for a of therapy or with if There is no the management of patients with advanced stage NLPHL in this Patients have on cHL treatment or with or Given that patients with disease may have disease, chemotherapy is an alternative & et al, to cHL combined with Late and/or multiple relapses may relapse or progression is of first line therapy either of diagnosis or lymphoma at The factors for relapse in this group are advanced disease et al, and early stage disease et al, 2007). disease should always be to Patients alone may chemotherapy than cHL therapy. Treatment for patients on stage at relapse and of include and For localized relapse with in the radiotherapy may be more Transformation rates in this group are not large clinical trials (in with long-term follow-up will provide more the of this disease in the and in these guidelines is to be and accurate at the time of to the the British Society for Haematology the any for the of these to writing the the There are no other relevant of interest to