Feasibility of upfront dose-intensive chemotherapy in children with advanced-stage Hodgkin's lymphoma: preliminary results from the Children's Cancer Group Study CCG-59704.

BACKGROUND: Treatment strategies involving dose intensification have recently demonstrated improvements in cure compared with older trials. However, dose-intensive therapy is associated with increased acute and long-term toxicities, particularly in pediatric patients. The Children's Cancer Group initiated this pilot study to assess the feasibility and toxicity of a moderate dose-intensive regimen, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone), in children and adolescents with advanced-stage Hodgkin's lymphoma (HL). PATIENTS AND METHODS: Children with stage IIB or IIIB with bulk disease, or stage IV were eligible. Induction consisted of four cycles of escalated dose BEACOPP. The rapidity of response, defined as >70% reduction in disease burden, was assessed after two and four cycles. Rapid responders then received consolidation therapy as per gender-specific guidelines to reduce the risk of gender-specific long-term toxicities of therapy, i.e. females received four cycles of COPP/ABV (cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin and vinblastine) without radiation therapy and males received two cycles of ABVD (doxurubicin, bleomycin, vinblastine and dacarbazine) with involved field radiation therapy (IFRT). Slow responders received four cycles of BEACOPP and IFRT. RESULTS: Ninety-nine patients were enrolled. Myelosuppression was frequent. Non-hematological grade 4 toxicities included allergic reaction (two patients), hypotension (one), mucositis (four), infection (three), seizure (one) and elevated transaminases (one). Typhlitis developed in four patients; three recovered and completed dose-modified chemotherapy, while one died of sepsis associated with grade 4 neutropenia. A rapid response was achieved by 45 and 72% of patients after two and four cycles, respectively. There are no disease progressions or secondary malignancies to date. There is only one reported relapse to date. Median follow-up for the cohort is 6 months. CONCLUSIONS: BEACOPP chemotherapy is feasible and generally well tolerated in children with advanced-stage HL. The absence of reported progressive disease and only one relapse to date is encouraging.

Post-transplant lymphoproliferative disorder after autologous peripheral stem cell transplantation in a pediatric patient.

Post-transplant lymphoproliferative disorder (PTLD) is a complication of allogeneic bone marrow transplantation (BMT). Rare cases of PTLD after autologous BMT have been reported only in adults. This case report is the first to describe PTLD in a pediatric patient after autologous peripheral stem cell transplantation (PSCT). This 2-year-old male with stage IV neuroblastoma underwent autologous PSCT. The post-PSCT course was complicated by fever with hematochezia and a lung mass. On day 94 post PSCT, colonoscopy revealed an ulcer due to a PTLD, monomorphic type, B cell phenotype, associated with Epstein-Barr virus. Fine needle aspiration identified the lung mass as neuroblastoma. PTLD can occur in pediatric autologous PSCT recipients, and may occur more frequently in autologous grafts manipulated by T cell depletion or CD34+ cell selection.

Large-cell lymphoma arising in the mediastinum in children and adolescents is associated with an excellent outcome: a Children's Cancer Group report.

PURPOSE: Large-cell lymphoma (LCL) arising in the mediastinum (LCL-M) is a heterogeneous group of non-Hodgkin's lymphoma (NHL) that includes B-cell lymphomas as well as T-cell lymphomas, including anaplastic LCL. LCL-M is well recognized in young adults but is less well characterized and infrequent in children and adolescents. METHODS: A retrospective review of Children's Cancer Group therapeutic studies for nonlymphoblastic lymphomas (CCG-551, CCG-503, CCG-552, and CCG-5911) identified 20 patients with LCL-M, representing 7.2% of all LCLs classified by central pathology review. RESULTS: The patients ranged in age from 4 to 19 years (median, 12.5 years; mean, 12 years); 55% of the patients were male. Although a variety of chemotherapy regimens were used, response was excellent, with all 20 patients (100%) achieving a complete response. Four patients (20%) experienced relapse locally or in distant sites including brain and kidney. One patient died of sepsis during therapy. For the 20 patients with LCL-M, the product-limit estimated 5-year event-free survival (EFS) and 5-year overall survival (OS) rates are 75% +/- 10% and 85% +/- 8%, respectively. For disseminated LCLs (192 cases), the EFS and OS rates were 50% +/- 4% and 63% +/- 4%, respectively, which differ significantly from the those of the LCL-M cases (EFS, P =.025; OS, P =.034). The 5-year EFS and OS rates for patients with localized LCL (67 cases) were 92 +/- 3% and 97 +/- 2%, respectively. CONCLUSION: LCL-M is a heterogeneous group of NHLs that makes up approximately 7.2% of LCL in children and adolescents. Response to therapy and OS in this young age group seems excellent and superior to that of disseminated LCLs but inferior to that of other localized LCL. Future studies of LCL-M will evaluate short intense chemotherapy administered without radiation therapy.

Anaplastic large cell lymphoma arising in bone: report of a case of the monomorphic variant with the t(2;5)(p23;q35) translocation.

Anaplastic large cell lymphoma (ALCL) represents approximately 2% of all non-Hodgkin lymphomas according to the recent Non-Hodgkin Lymphoma Classification Project. As defined in the revised European-American classification of lymphoid neoplasms (REAL), ALCL is a neoplasm of T-cell or null-cell lineage; 20% to 60% of cases are associated with the t(2;5)(p23;q35) translocation. ALCL commonly involves nodal as well as a wide variety of extranodal sites, although primary or secondary involvement of bone is rare. We describe the case of a 71-year-old man with stage IE T-cell ALCL, monomorphic variant, arising in the left anterior fifth rib and involving adjacent soft tissue without other sites of disease. The monomorphic histologic features hindered the initial recognition of this neoplasm as ALCL. However, strong uniform CD30 antigen expression and subsequent demonstration of the t(2;5)(p23;q35) translocation and anaplastic lymphoma kinase (ALK) immunoreactivity led to the correct diagnosis. We identified only 5 reported cases of T-cell and null-cell ALCL arising in bone and only 2 of these cases involved a single bone site. All 5 previously reported cases were ALCL of the classic type. We report a case of ALCL that is unique to our knowledge. This case of monomorphic ALCL was localized to bone and tumor cells contained the t(2;5)(p23;q35) translocation.

T-cell-rich large B-cell lymphoma in children and adolescents: a clinicopathologic report of six cases from the Children's Cancer Group Study CCG-5961.

BACKGROUND: T-cell-rich large B-cell lymphoma (TCRLBCL) is a morphologic subset of diffuse large B-cell lymphoma that has been confused with Hodgkin disease and reactive lymphadenopathies. To the authors' knowledge the majority of reports of TCRLBCL are from adults, and it is not widely recognized as occurring in the pediatric population. The current study reports a cohort of six cases of TCRLBCL from the Children's Cancer Group CCG-5961 study. METHODS: Biopsies from patients entered on CCG-5961 were submitted for central pathology review and immunophenotyping. Six cases of TCRLBCL were identified and correlated with clinical characteristics. RESULTS: Of 86 cases centrally reviewed to date on CCG-5961, 20 (23%) were diagnosed as diffuse large B-cell lymphomas. Of these, 6 cases (7% of total cases and 30% of large B-cell cases) were TCRLBCL, based on a diffuse growth pattern with a minor population of neoplastic large B cells and an associated extensive reactive T-cell infiltrate. All patients with TCRLBCL were males ages 12-16 years. Three patients with TCRLBCL had advanced stage disease. No bone marrow or central nervous system involvement was detected in any case. CONCLUSIONS: TCRLBCL is a morphologic subtype of diffuse large B-cell lymphoma that may be difficult to recognize due to the extensive infiltrate of reactive T cells. This entity is not well recognized in pediatric patients, but in the current study represented 7% of all cases and 30% of large B-cell lymphomas received for central review from the ongoing CCG-5961 protocol. Because TCRLBCL may be confused with Hodgkin disease and reactive lymphadenopathies, it is essential that this entity be recognized in the pediatric age group.

Mature B-cell lymphoma/leukemia in children and adolescents: intergroup pathologist consensus with the revised European-American Lymphoma Classification.

BACKGROUND: The Revised European-American Lymphoma (R.E.A.L.) Classification criteria were evaluated in the international protocol FAB LMB 96 Treatment of Mature B-cell Lymphoma/Leukemia: A SFOP LMB 96/CCG-5961/UKCCSG NHL 9600 Cooperative Study. This includes B-lineage lymphomas: Burkitt's lymphoma (including ALL-L3); high-grade B-cell lymphoma, Burkitt-like; diffuse large B-cell lymphoma (excluding anaplastic large cell Ki-1 lymphoma). PATIENTS AND METHODS: Cases were independently reviewed by eight hematopathologists from the three cooperative national groups (two SFOP, two CCG, four UKCCSG), without prior discussion of classification criteria or guidelines for case rejection. Consensus diagnosis was determined by each national cooperative group, and final consensus diagnosis established when at least two national consensus diagnoses were in agreement, or following group agreement at a multiheaded microscope. RESULTS: Two hundred eight cases were reviewed, with final consensus diagnosis established in two hundred three. The percent agreement of each group's national consensus diagnosis with final consensus diagnosis was 86%, 86% and 71%. The percent agreement of the group's national consensus diagnosis with final consensus diagnosis for Burkitt's and diffuse large B-cell lymphoma were 88% and 80%, respectively, but only 42% for Burkitt-like lymphoma. CONCLUSIONS: International panel review of mature B-cell lymphoma/leukemia in children and adolescents highlighted difficulties in subclassification, particularly with Burkitt-like, which is a 'provisional entity' in the R.E.A.L. Classification. The absence of previous discussion of classification and guidelines for case rejection may in part explain the discrepancy between pathologists. These results underline that morphology may need to be complemented by other studies, such as molecular genetic and cytogenetics, to discriminate between the mature B-cell lymphomas.

Posttransplant lymphoproliferative disorder in pediatric bone marrow transplant recipients: disseminated disease of donor origin demonstrated by fluorescence in situ hybridization.

BACKGROUND: Posttransplant lymphoproliferative disorders in bone marrow transplantation are typically rapidly progressive and fatal B-cell lymphoid proliferations associated with Epstein-Barr virus, and are mostly of donor origin. We report three pediatric bone marrow transplant cases in which posttransplant lymphoproliferative disorder was diagnosed at postmortem examination. Epstein-Barr virus in these cases was identified by a combined in situ hybridization-immunoperoxidase technique and donor origin was identified by fluorescence in situ hybridization. METHODS: Tissues obtained from postmortem examination were evaluated by light microscopy, immunohistochemistry, combined in situ hybridization-immunoperoxidase technique with Epstein-Barr virus-encoded RNA probe, and fluorescence in situ hybridization with X and Y centromeric probes. RESULTS: Three pediatric patients underwent sex-mismatched, T-cell-depleted bone marrow transplants complicated by graft versus host disease, rapidly progressive multiple organ failure, and postmortem diagnosis of posttransplant lymphoproliferative disorder. Histologic examination and immunohistochemistry studies demonstrated immunoblastic lymphoma (one case) or polymorphic B-cell lymphoma (two cases). In all cases, Epstein-Barr virus-encoded RNA was detected by a combined in situ hybridization-immunoperoxidase technique. Fluorescence in situ hybridization for X and Y chromosomes in paraffin sections demonstrated donor origin in two cases (one case was indeterminate). CONCLUSION: Fluorescence in situ hybridization was used to prove donor derivation of Epstein-Barr virus-associated posttransplant lymphoproliferative disorders in pediatric bone marrow transplant recipients. Many features of posttransplant lymphoproliferative disorders in pediatric bone marrow transplant recipients are very similar to adult cases, although a higher proportion of children appear to be diagnosed postmortem and have a fatal outcome.

Detection of Epstein-Barr virus in the L & H cells of nodular lymphocyte predominance Hodgkin's disease: report of a case documented by immunohistochemical, in situ hybridization, and polymerase chain reaction methods.

Although Epstein-Barr virus (EBV) is commonly present in the neoplastic Reed-Sternberg and Hodgkin cells of the mixed cellularity, nodular sclerosis, and lymphocyte depletion types of Hodgkin's disease (HD), EBV is rare in the neoplastic cells of the nodular lymphocyte predominance type of HD, particularly in the United States. We describe a 19-year-old Hispanic man in whom nodular lymphocyte predominance HD involved a cervical lymph node. Epstein-Barr virus was identified in the neoplastic L & H cells by using in situ hybridization for EBV RNA and immunohistochemical staining for EBV latent membrane protein-1. Polymerase chain reaction studies demonstrated the type A strain of EBV. The presence of EBV in this case may be related to drainage of the virus from the oropharynx to the cervical lymph node. The presence of EBV also may be related to this patient's Hispanic ethnic origin.

Donor origin of posttransplant lymphoproliferative disorder localized to a liver allograft: demonstration by fluorescence in situ hybridization.

SETTING: Posttransplant lymphoproliferative disorders in solid organ transplantation are mostly of recipient origin. We report an unusual case of posttransplant lymphoproliferative disorder following liver transplantation with localized limited involvement of the solid organ allograft. DESIGN: Tissues were obtained at the time of surgery and evaluated by immunohistochemistry, in situ hybridization, and fluorescence in situ hybridization with chromosome X and Y centromeric probes. PATIENT: A 53-year-old Hispanic man with hepatic failure due to hepatitis C virus who underwent orthotopic liver transplant from a female donor and developed posttransplant lymphoma in the transplanted liver. INTERVENTION: Withdrawal of immunosuppression, resection of liver allograft, and second transplant. RESULTS: This posttransplant lymphoproliferative disorder was clearly shown to be derived from Epstein-Barr virus-infected donor lymphoid cells. This was demonstrated by fluorescence in situ hybridization for X and Y chromosomes in paraffin sections in a sex-mismatched transplant. Despite aggressive histology (monoclonal B-cell immunoblastic lymphoma) and lack of response to withdrawal of immunosuppression, the posttransplant lymphoproliferative disorder was successfully managed by repeat liver transplantation without recurrence. CONCLUSION: Fluorescence in situ hybridization was used to prove donor derivation in a posttransplant lymphoma of the liver. Allograft-localized donor posttransplant lymphoproliferative disorder may represent a unique category with more favorable prognosis requiring different clinical management from other cases.

Posttransplant lymphoproliferative disorder in liver allograft biopsies: a comparison of three methods for the demonstration of Epstein-Barr virus.

Posttransplant lymphoproliferative disorder (PTLD) is associated with Epstein-Barr virus (EBV), and may clinically resemble acute allograft rejection. Three methods to show EBV in tissue were evaluated in 15 liver allograft biopsies from 12 patients including four with PTLD: (1) semiquantitative polymerase chain reaction (PCR) for EBV DNA; (2) in situ hybridization for EBV RNA (EBER); and (3) immunoperoxidase for EBV latent membrane protein (LMP). Index cases had a PCR dot blot result of "positive" or "weak positive." Findings were correlated with histology, clinical data, therapy, and outcome. All four PTLD patients had a clinical diagnosis of acute rejection. All four showed EBV: PCR 4, EBER 4, LMP 3, Liver function tests were elevated in three, but EBV viral capsid antigen (VCA) IgM was not increased in three, but EBV viral capsid antigen (VCA) IgM was not increased in three. Immunosuppression was withdrawn and all four patients underwent a second transplantation. One died 4 days posttransplant with disseminated PTLD, two died of sepsis at 1.5 and 14 months, and one is well at 3 years without PTLD. Eleven biopsies without PTLD showed: acute rejection 7, acute rejection and hepatitis 1, hepatitis B 1, and non-inflammatory changes 2. In this group, EBV results included: PCR weak positive in 10 and 1+ in one, EBER negative in ten and rare positive cells in one, LMP negative in 11. Liver function tests were elevated in 10, whereas VCA IgM was not increased in three and increased in one. Patients with acute rejection were treated with increased immunosuppression: none developed PTLD, with follow-up of at least 6 months in nine cases. Two patients died within 4 months of biopsy. One patient with PTLD in tonsils had a liver biopsy showing both acute rejection and EBV (PCR 1+, rare EBER + small cells). Histological studies combined with special EBV detection methods, can be useful to evaluate atypical lymphoid infiltrates in liver allograft biopsies and confirmation of a diagnosis of PTLD. All three methods are useful; EBER and PCR are the most sensitive. EBER and LMP can use paraffin sections.

Multilocular thymic cyst. A novel thymic lesion associated with human immunodeficiency virus infection.

Thymic involvement is an important feature of human immunodeficiency virus-related disease in the pediatric population. The most common lesions are thymic involution or atrophy, thymitis (thymic lymphoid hyperplasia), and dysinvolution with loss of Hassall's corpuscles. We report a case of an unusual form of thymic enlargement in a human immunodeficiency virus-infected boy. In addition to lymphoid hyperplasia similar to that associated with human immunodeficiency virus infection in lymph nodes and other sites, the thymus was characterized by multilocular cysts with squamous epithelial lining (multilocular cystic lesion of the thymus).

Changes in tonsils and adenoids in children with posttransplant lymphoproliferative disorder: report of three cases with early involvement of Waldeyer's ring.

Posttransplant lymphoproliferative disorder (PTLD) is an infrequent complication of transplantation in children, and this report emphasizes the value of tonsil and adenoid biopsy in the early management of this potentially life threatening condition. In all three cases biopsy specimens of tonsils and adenoids were diagnostic of polymorphic diffuse B-cell hyperplasia (PBCH). Immunophenotyping showed no immunoglobulin (Ig) light chain restriction, although immunoglobulin heavy chain (IgH) gene rearrangement was monoclonal in two cases. Despite an absence of serological evidence for acute Epstein-Barr virus (EBV) infection, EBV was detected in all cases by semiquantitative polymerase chain reaction (PCR) for EBV DNA, by in situ hybridization for EBV mRNA (EBER), and by immunoperoxidase for EBV latent membrane protein (LMP). All three patients were treated with reduced immunosuppression and acyclovir and are well (19, 28, and 28 months' follow-up) with no recurrence. Children without previous EBV exposure may develop PTLD localized to the tonsils/adenoids, and biopsy specimens of these tissues may permit early diagnosis and clinical intervention. Despite monoclonal gene rearrangement in two cases, overall features were not indicative of malignancy. Strong association with EBV is helpful in confirming the diagnosis of PTLD and is consistent with initial presentation in the tonsils/adenoids.

Clinical-pathologic features of humoral rejection in cardiac allografts: a study in 81 consecutive patients.

BACKGROUND: Humoral rejection is an infrequently reported, poorly understood form of cardiac allograft rejection. METHODS: We reviewed 81 consecutive heart transplant recipients followed up to 3 years after transplantation to evaluate the frequency and significance of humoral rejection in this population. Histologic features evaluated included capillary endothelial cell swelling, interstitial edema and hemorrhage, and neutrophilic infiltration. Immunofluorescence studies with antibodies to immunoglobulin G, immunoglobulin A, immunoglobulin M, Clq, C'3, HLA-DR, and fibrinogen and immunoperoxidase staining for endothelial cells (factor VIII-related antigen) and macrophages (KP1 [CD68]) were performed. Minimal criteria for the diagnosis of humoral rejection were capillary endothelial cell swelling and any immunoglobulin and complement staining in capillaries. Findings were graded and compared with concurrent hemodynamic measurements. RESULTS: Immunoperoxidase staining showed that most swollen cells in capillaries were macrophages and fewer were endothelial cells. Humoral rejection was detected in 102 biopsy specimens from 42 patients (52%), within 3 weeks of transplantation in 28, and 3 weeks to 4 months later in the other 14 patients. One patient had evidence of humoral rejection almost 3 years after transplantation. A third of biopsy specimens with humoral rejection were associated with abnormal hemodynamics; of these 33 specimens only five had significant (grade 3 or 4) coexisting cellular rejection. Histologic findings most often associated with hemodynamic abnormalities were diffuse capillary endothelial cell swelling and any interstitial hemorrhage or edema. Three patients died of humoral rejection; only 1 had coexisting cellular rejection (grade 3A). CONCLUSIONS: In our experience humoral rejection (1) is not uncommon (52% of patients), (2) is often (33% of cases) associated with hemodynamic abnormalities, and (3) may be fatal.

Grade 2 cellular heart rejection: does it exist?

According to the International Society for Heart and Lung Transplantation, a single focus of lymphocytic infiltration associated with myocyte injury in a cardiac allograft endomyocardial biopsy is focal moderate cellular rejection (Grade 2). We reviewed 115 endomyocardial biopsy specimens that were completely negative (n = 17), had a Quilty A (n = 17) or Quilty B (n = 46) lesion, or had a lesion fulfilling the criteria of grade 2 rejection (n = 35). By studying step sections (mean = 18) or sections stained for elastic tissue and collagen, we showed continuity of the focus of grade 2 rejection with the endocardium in 32 of 35 cases; these results justify reclassification of these foci as Quilty B lesions, which are defined as endocardial infiltrates that encroach on the underlying myocardium and that may be associated with myocyte injury but are not generally considered to represent acute rejection. Immunohistochemical staining for T and B lymphocytes and histiocytes showed similar patterns in deeper zones of Quilty B lesions and lesions initially regarded as grade 2 rejection. Normal hemodynamics were observed with 16 of 17 completely negative biopsy specimens, 16 of 17 Quilty A biopsy specimens, 46 of 46 Quilty B biopsy specimens, and 35 of 35 grade 2 rejection biopsy specimens. No grade 2 rejection was treated; only 1 biopsy specimen progressed to grade 3A rejection in a subsequent biopsy 2 months later. Most, if not all, cases of grade 2 cellular rejection can be shown to be Quilty B lesions, are not associated with hemodynamic abnormalities, and do not require augmented immunosuppression.(ABSTRACT TRUNCATED AT 250 WORDS)

Bcl-2 oncogene protein is preferentially expressed in Reed-Sternberg cells in Hodgkin's disease of the nodular sclerosis subtype.

One hundred three cases of nodular sclerosis (NS) and mixed-cellularity Hodgkin's disease were evaluated for expression of bcl-2 oncogene protein, because previous studies have revealed expression of bcl-2 in these subtypes but only rarely in the nodular lymphocyte-predominance subtype. Reed-Sternberg (RS) cells and lacunar variants were positive for bcl-2 in 51 of 86 NS cases and 4 of 17 mixed-cellularity cases. In individual cases of NS, the percentage of RS cells and lacunar variants positive for bcl-2 ranged from minimal (in 5 cases) to 100% positive (mean, 34%). By univariate analysis, expression of the bcl-2 gene product in RS cells was observed in a significantly greater proportion of NS Hodgkin's disease cases than MC cases (P < .009), a finding that may have implications on the pathogenesis of this disorder.

Necrosis in thyroid nodules after fine needle aspiration biopsy. Report of two cases.

Two cases of infarction of thyroid neoplasms following fine needle aspiration (FNA) biopsy are reported. Histologic study of a 2.5 x 2.5 cm nodule excised 18 days after FNA had diagnosed a Hürthle-cell neoplasm showed mainly necrotic debris and granulation tissue. While FNA made the diagnosis of a papillary carcinoma in the second case, which had had an FNA biopsy of the same nodule six years earlier, most of the nodule was fibrotic and necrotic. These two cases demonstrate the potential problems in such cases: (1) post-FNA infarction may obscure the nature of a cytologically diagnosed neoplasm, making histologic confirmation difficult, and (2) FNA of an infarcted nodule may have difficulties in obtaining diagnostic material, potentially resulting in a false-negative diagnosis. Review of the literature on thyroid infarction shows it to be a rare event, with most reported cases occurring after FNA biopsy of a neoplasm. The finding of necrosis and fibrosis in an aspirate or surgical specimen should thus suggest the presence of a neoplasm.

Fatal hemorrhage in a cerebral pilocytic astrocytoma-adult type.

A 69-year-old female presented with a 6-week history of left-sided weakness and a large cerebral mass on computed tomographic scan and magnetic resonance imaging. The patient subsequently had an acute intracerebral hemorrhage with uncal and tonsillar herniation. Postmortem examination revealed an acute cerebral hemorrhage from a pilocytic astrocytoma-adult type. These cerebral neoplasms are rarely associated with hemorrhage.