Ananth Shankar

Pediatric and Adolescent Lymphoma: Comparison of Whole-Body STIR Half-Fourier RARE MR Imaging with an Enhanced PET/CT Reference for Initial Staging

PURPOSE To compare the diagnostic performance of rapid whole-body anatomic magnetic resonance (MR) staging of pediatric and adolescent lymphoma to an enhanced positron emission tomographic (PET)/computed tomographic (CT) reference standard. MATERIALS AND METHODS Ethical permission was given by the University College London Hospital ethics committee, and informed written consent was obtained from all participants and/or parents or guardians. Thirty-one subjects (age range, 7.3-18.0 years; 18 male, 11 female) with histologically proved lymphoma were prospectively recruited. Pretreatment staging was performed with whole-body short inversion time inversion-recovery (STIR) half-Fourier rapid acquisition with relaxation enhancement (RARE) MR imaging, fluorine 18 fluorodeoxyglucose PET/CT, and contrast agent-enhanced chest CT. Twenty-six subjects had posttreatment PET/CT and compromised our final cohort. Eleven nodal and 11 extranodal sites per patient were assessed on MR imaging by two radiologists in consensus, with a nodal short-axis threshold of >1 cm and predefined extranodal positivity criteria. The same sites were independantly evaluated by two nuclear medicine physicians on PET/CT images. Disease positivity was defined as a maximum standardized uptake value >2.5 or nodal size >1 cm. An unblinded expert panel reevaluated the imaging findings, removing perceptual errors, and derived an enhanced PET/CT reference standard (taking into account chest CT and 3-month follow-up imaging) against which the reported and intrinsic performance of MR imaging was assessed by using the kappa statistic. RESULTS There was very good agreement between MR imaging and the enhanced PET/CT reference standard for nodal and extranodal staging (kappa = 0.96 and 0.86, respectively) which improved following elimination of perceptual errors (kappa = 0.97 and 0.91, respectively). The sensitivity and specificity of MR imaging (following removal of perceptual error) were 98% and 99%, respectively, for nodal disease and 91% and 99%, respectively, for extranodal disease. CONCLUSION Whole-body STIR half-Fourier RARE MR imaging of pediatric and adolescent lymphoma can accurately depict nodal and extranodal disease and may provide an alternative nonionizing imaging method for anatomic disease assessment at initial staging.

Resection Alone in 58 Children With Limited Stage, Lymphocyte-predominant Hodgkin Lymphoma-Experience From the European Network Group on Pediatric Hodgkin Lymphoma

Lymphocyte‐predominant Hodgkin lymphoma (LPHL) is a rare, CD20‐positive, good prognostic lymphoma in children. Patients with early‐stage LPHL who underwent successful surgical lymph node resection alone have been reported. To clarify the optimum treatment strategy in children, European study groups were asked to report their experience of surgery alone used in the treatment of pediatric LPHL.

Local therapy and other factors influencing site of relapse in patients with localised Ewing's sarcoma

Relapse patterns have been documented in 191 children with localised Ewings sarcoma treated with the United Kingdom Childrens Cancer Group (UKCCSG) Ewings Tumour regimen ET2. All received chemotherapy comprising ifosfamide, vincristine, doxorubicin and actinomycin D. Local treatment modality was excision and or radiotherapy depending on tumour site and response to primary chemotherapy. Although not strictly comparable, due to the clinical indications used for each modality, local relapse rates were very low and were similar, irrespective of the type of local treatment modality: radiotherapy (3/56), surgery (7/114) or a combination (0/20). Combined relapse (local + distant) rates were similarly low irrespective of the type of local therapy: radiotherapy (4/56), surgery (4/114) or a combination (0/20). Overall survival was lower in females (P = < 0.04), older children (P = < 0.002) and those with primaries at sites other than long bones (P = < 0.02). It is concluded that with effective intensive chemotherapy combined with either radiotherapy or surgery, local control in this study was excellent at sites other than the pelvis. Preventing distant relapse, predominantly to lung and bone, remains the major challenge.

Does histology influence outcome in childhood Hodgkin's disease? Results from the United Kingdom Children's Cancer Study Group.

PURPOSE Histology has been identified as an important prognostic factor in Hodgkins disease (HD) in adults. Information regarding the impact of histology on outcome in childhood HD is scarce. This study determines the effect of histology on the overall survival (OS) or progression-free survival (PFS) in a national series of children treated in a standardized manner. PATIENTS AND METHODS The results of treatment of 331 assessable patients, treated between January 1, 1982 and June 30, 1992, in the United Kingdom Childrens Cancer Study Group (UKCCSG) Hodgkins study I were reviewed to evaluate OS, PFS, and deaths according to stage and histology. Treatment was either involved-field radiation alone (stage IA) or chlorambucil, vinblastine, procarbazine, and prednisolone (ChlVPP) chemotherapy with or without mediastinal radiation. All were clinically staged at diagnosis. RESULTS Nodular sclerosing (NS) HD was the most common histologic subtype (155 of 331 patients [47%]) and was uniformly distributed through all stages. Lymphocyte-depletion (LD) HD was extremely uncommon (< 1%). Mixed-cellularity (MC) HD had the highest relapse rate, but this was only significant (P < .05) in stage I patients who received local irradiation alone. There was no other statistically significant difference in OS and PFS between the various histologic subtypes. Multivariate analysis for PFS and OS confirmed that stage was the most important prognostic factor and that histology did not have an effect after stratification by stage. CONCLUSION This study demonstrates that with effective multiagent chemotherapy, histologic subtype does not influence outcome. The high relapse rates in stage I MC subtype indicates that MC HD is biologically aggressive and systemic treatment with or without local irradiation may be indicated. The high relapse rate in stage IV patients appeared to be independent of histology.

Treatment outcome after low intensity chemotherapy [CVP] in children and adolescents with early stage nodular lymphocyte predominant Hodgkin's lymphoma - an Anglo-French collaborative report.

PURPOSE To examine whether three cycles of a low-intensity chemotherapy consisting of cyclophosphamide [500 mg/m(2) - day 1], vinblastine [6 mg/m(2) - days 1 and 8] and prednisolone [40 mg/m(2) - days 1-7] (CVP) is safe and therapeutically effective in children and adolescents with early stage nodular lymphocyte predominant Hodgkin lymphoma [nLPHL]. PATIENTS AND METHODS Fifty-five children and adolescents with early stage nLPHL [median age 13 years, range 4-17 years] diagnosed between June 2005 and October 2010 in the UK and France are the subjects of this report. Staging investigations included conventional cross sectional as well as 18 fluro-deoxyglucose [FDG] PET imaging. Histology was confirmed as nLPHL by an expert pathology panel. RESULTS Of the 45 patients, who received CVP as first line treatment, 36 [80%, 95% Confidence Interval [CI]: (68; 92)] either achieved a complete remission [CR] or CR unconfirmed [CRu], the remaining nine patients achieved a partial response. All nine subsequently achieved CR with salvage chemotherapy [n=7] or radiotherapy [n=2]. Ten patients received CVP at relapse after primary treatment that consisted of surgery alone and all achieved CR. To date, only three patients have relapsed after CVP chemotherapy and all had received CVP as first line treatment at initial diagnosis. The 40-month freedom from treatment failure and overall survival for the entire cohort were 75.4% (SE ± 6%) and 100%, respectively. No significant early toxicity was observed. CONCLUSIONS Our results show that CVP is an effective chemotherapy regimen in children and adolescents with early stage nLPHL that is well tolerated with minimal acute toxicity.

Quantitative diffusion weighted MRI: A functional biomarker of nodal disease in Hodgkin lymphoma?

PURPOSE This study explores the relationship between MRI Apparent Diffusion Coefficient (ADC) and PET Standardized Uptake Value (SUV) measurements in pediatric Hodgkin lymphoma. METHODS Sixteen patients (mean age 15.4 yrs, 8 male) with proven Hodgkin lymphoma were recruited and staged using PET-CT, anatomical MRI and additional 1.5T diffusion weighted imaging (DWI) prior to and following chemotherapy. Pre-treatment lymph nodes and anatomically paired post-treatment residual tissue located on MRI were matched to the corresponding PET-CT. Region of interest (ROI) analysis was used to extract quantitative measurements. Mean ADC (ADC(mean)) and maximum SUV (SUV(max)) were recorded and correlation assessed using Spearman statistics. RESULTS Fifty-three ROIs were sampled. Pre- and post-treatment ADC(mean) ranged from 0.77 × 10(−3) to 1.79 × 10(−3) (median 1.15 × 10(−3) mm(2)s(−1)) and 1.08 × 10(−3) to 3.18 ×10(−3) (median 1.88 × 10(−3) mm(2)s(−1)), and SUV(max) from 2.60 to 25.4 (median 8.85 mg/ml) and 1.00 to 3.50 mg/ml (median 1.90 mg/ml). Median post-treatment ADC(mean) was higher, and median SUV(max) lower than pretreatment values (p < 0.0001). There was an inverse correlation between pre-treatment ADC(mean) and SUV(max) (p = 0.005) and between fractional change ([post-treatment – pre-treatment]/pre-treatment)in ADC(mean) and SUV(max) (p =0.002). CONCLUSION Our results confirm a strong reciprocal relationship between nodal ADC(mean) and SUV(max) in Hodgkin lymphoma;supporting the potential application of quantitative DWI as a functional biomarker of disease.

Outcome of children with nodular lymphocyte predominant Hodgkin lymphoma – a Children's Cancer and Leukaemia Group report

This report describes the clinical outcomes and follow‐up records of 42 children with nodular lymphocyte predominant Hodgkin lymphoma (LPHL) treated on United Kingdom Childrens Cancer Study Group (UKCCSG) HD1 (1982–1992) and HD2 protocols (1992–2000). The clinical records of 42 children with LPHL treated between 1982 and 2000 were reviewed retrospectively. All 42 had histology reviewed centrally and confirmed as LPHL by an expert panel. In both trials, only patients with stage IA disease had the option of being treated with either involved field radiation alone or combination chemotherapy consisting of chlorambucil, vinblastine, procarbazine and prednisolone (ChlVPP). Patients with all other stages were treated with ChlVPP chemotherapy. Thirty‐five patients (83%) presented with early stage disease (Stages I & II). All 42 patients achieved a complete remission (CR). Six children relapsed after primary therapy. The 5‐ and 10‐year relapse‐free survival rates were 87% and 82% respectively. Forty‐one are currently alive in CR. In conclusion, children with low‐stage LPHL treated between 1982 and 2000 according to the UK strategy for classical Hodgkin lymphoma (HL) had an excellent prognosis. There have been no second malignancies or transformations to B‐cell non‐Hodgkin lymphoma.

Role of FDG PET in the management of childhood lymphomas – case proven or is the jury still out?

Positron emission tomography (PET) is a novel non invasive functional imaging modality that is increasingly used for the primary staging of lymphomas and assessment of therapeutic response. This review evaluates the published reports of its use in childhood lymphomas, particularly in the primary staging, response assessment and monitoring after completion of treatment. Specific attention is focused on the clinical circumstances in which FDG PET is most likely to have an impact on management and some indications for its use in childhood lymphomas are suggested.

Outcome after autologous hemopoietic stem cell transplantation in relapsed or refractory childhood Hodgkin disease

Objectives: To determine the clinical outcome and prognostic factors for overall survival in children with recurrent and/or primary refractory Hodgkin disease (HD) after high-dose therapy and autologous hemopoietic stem cell transplantation (AHSCT). The survival outcome of this treatment was compared with conventional salvage therapy without stem cell transplantation. Methods: Clinical records of 51 patients with relapsed or refractory HD who underwent AHSCT were reviewed. The source of the stem cells was bone marrow (n = 22) or peripheral blood (n = 29). At the time of high-dose therapy, 39 patients were in complete remission and 1 was in partial remission, while the remaining 11 had refractory disease. The records of 78 patients from the HD 1 trial who underwent conventional salvage treatment but without AHSCT for relapsed or refractory HD were also reviewed. All patients received HDTwithout radiation for conditioning. Results: Overall survival from diagnosis of patients treated with AHSCT did not differ significantly from that of those treated with conventional salvage therapy (hazard ratio = 1.5; 95% confidence interval = 0.9-8.2; P = 0.4). There were also no statistically significant differences in survival data between the two approaches for patients whose duration of first remission was less than or greater than 1 year (P = 0.5; stratified log-rank). Of the 11 patients who received AHSCT for refractory disease, 9 remain alive and well with followups ranging from 2 to 18 years. No deaths due to treatment-related complications were seen in the AHSCT group. Conclusions: Stem cell transplantation does not offer any significant survival advantage over conventional salvage therapy in children with relapsed HD, although it may be of benefit for patients with primary refractory disease.

Nodular lymphocyte predominant Hodgkin lymphoma in children and adolescents – a comprehensive review of biology, clinical course and treatment options

Nodular lymphocyte predominant Hodgkin lymphoma (nLPHL) is a unique variant of Hodgkin lymphoma with an overall good prognosis. It is conspicuously different from classical Hodgkin lymphoma (cHL) and is now recognized as distinctive form of B cell lymphoma. Although it has an indolent clinical course, it has a propensity for multiple and often late relapses. Although the majority of children present with early stage disease and without B symptoms, treatment strategy has, until recently, been identical to that used for cHL. This approach is excessively toxic as it predisposes these children and adolescents to serious late effects including end organ damage to heart, gonads, lungs, thyroid and second malignant neoplasms. The aim of this article is to review the published literature on the treatment outcomes of nLPHL in affected children and adolescents, and discuss the options for treatment including surgery, chemotherapy, radiotherapy and targeted anti‐CD 20 antibody therapy.