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Primary follicular lymphoma of the testis in childhood
Abstract
BACKGROUND
Follicular lymphoma in childhood is rare. The authors present four unusual primary follicular lymphomas of the testis in children.METHODS
Tumor tissue was evaluated using light microscopy, immunohistochemistry, flow cytometry, and polymerase chain reaction (PCR) for immunoglobulin heavy chain (IgH) and bcl-2 gene rearrangements. Southern blot and immunohistochemical analyses were used to detect bcl-6 gene rearrangements and protein expression, respectively.RESULTSFour young boys ranging in age from 3 to 10 years were diagnosed with Stage IE follicular large cell lymphoma (Grade 3). A B-cell phenotype was documented in all four cases; monoclonality was confirmed in three cases by demonstration of light chain restriction or clonal IgH gene rearrangement. None of the lymphomas expressed Bcl-2 or p53 protein, and bcl-2 gene rearrangements were not found in the three lymphomas studied. In contrast, Bcl-6 protein was expressed by all three lymphomas studied, and a bcl-6 gene rearrangement was detected in the one case analyzed by Southern blot. All four boys were treated by orchiectomy and combination chemotherapy and are alive with no evidence of disease 18–44 months following their initial diagnoses.CONCLUSIONS
Follicular lymphomas may rarely occur as primary testicular tumors in prepubertal boys and, when localized, appear to be associated with a favorable prognosis. In contrast to follicular lymphoma in adults, pediatric follicular lymphomas of the testis are usually of large cell type (Grade 3) and lack bcl-2 or p53 abnormalities. The identification, in one case, of a bcl-6 gene rearrangement suggests an alternate molecular pathogenesis for pediatric follicular lymphoma. Cancer 1999;85:1626–35. © 1999 American Cancer Society.
... Además del LDCBG, otros LNH pueden afectar de manera primaria al testículo; hay casos informados de LPT de células T, de estos la mayoría corresponden a linfomas anaplásicos de células grandes (LACG), linfomas periféricos de células T y linfomas de células T/NK (LCTNK) 6,7 . ...
... La gran mayoría de los LPT son LDCGB; sin embargo, se han informado otros tipos histológicos que incluyen: linfoma del manto, linfoma de la zona marginal extranodal, linfoma folicular (particularmente en población pediátrica); así como linfoma periférico de células T, LACG y LCTNK 6,7 . ...
... La expresión de CD56 se ha observado en 90% de los casos. Prácticamente todos los casos son positivos para EBER ISH y muestran índices de proliferación celular por arriba del 50% 6,7,9,12 . ...
Natural killer/T cell lymphomas chiefly involving the midline facial structures including the nasal cavity or nasopharyns are a relatively rare type of non-Hodgkin's lymphoma. Apart from the upper respiratory tract, the disease occasionally presents in certain extranodal sites, such as the central nervous system, skin, gastrointestinal tract, or testes. We report a case of natural killer NK/T cell lymphoma as a testicular tumor in a 36-year-old man with a history of progressive swelling of his right testicle. Histologically, the testicular mass showed a diffuse infiltrate of medium-sized and atypical large lymphoid cells with angiocentric infiltration and areas of coagulative necrosis. Immunohistochemical studies demonstrated tumor cells staining positively with CD3, TIA-1, and Granzyme B. The Epstein-Barr virus genoma was detected by in situ hybridization. There were no abnormal findings in the nasal and nasopharyngeal regions. Classified as stage IEA, the patient received involved-field irradiation to contralateral testis (45 Gy), followed by systemic chemotherapy with a combination regimen ofL-asparaginase, methotrexate and dexamethasone. Relevant literature is reviewed, and the clinicopathologic features, natural history, and treatment options for primary testicular NK/T cell lymphoma are discussed.
... The true incidence of TFL is unknown owing to its rarity; nevertheless, about 25 cases have been reported in the literature. Nearly all cases occur in children and young adults [1,2,[4][5][6][7][8][9]. Patients typically present with a unilateral painless testicular mass or testicular enlargement, without systemic manifestations [1,2]. ...
... Nearly all cases occur in children and young adults [1,2,[4][5][6][7][8][9]. Patients typically present with a unilateral painless testicular mass or testicular enlargement, without systemic manifestations [1,2]. On testicular ultrasound, TFL appears as diffuse or well-delineated hypoechoic unilateral testicular lesions with increased vascularity [1,[4][5][6]. Comprehensive staging investigations almost invariably show stage 1E, defined as extranodal and organ-confined disease [1,2]. ...
... Gross examination of orchiectomy specimens shows architectural disruption by tan/white/pink, discrete or ill-defined fleshy tumors primarily located in the testicular parenchyma with frequent extension to the epididymis [4][5][6][7][8][9]. Microscopically, TFL shows predominantly follicular or combined follicular and diffuse growth patterns [1][2][3][4][5][6][7][8][9]. ...
Background
Primary testicular follicular lymphoma (TFL) is a rare extranodal variant of follicular lymphoma confined to the testis, almost exclusively occurring in children and young adults. TFL has unique clinicopathologic features and excellent prognosis. Distinction of TFL from other neoplasms involving testis and from systemic follicular lymphoma is essential due to major differences in management and outcome.
Aim
We aimed to review and summarize the existing literature describing clinical, histopathologic, immunophenotypic and genetic features of TFL. We also include distinguishing characteristics of potential morphologic mimickers of TFL, including usual follicular lymphoma involving the testis as part of systemic disease.
Methods
PubMed was searched for relevant studies before December 1, 2021, using keywords “primary testicular lymphoma”, “primary testicular follicular lymphoma” and “follicular lymphoma”. We selected and summarized the results of relevant studies. We also reviewed the latest WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues.
Conclusions
Primary testicular follicular lymphoma (TFL) is a unique extranodal variant of follicular lymphoma mainly presenting in children and young adults as stage 1E disease. Microscopically, TFL has a follicular or follicular and diffuse growth pattern and is composed predominantly of centroblasts. TFL characteristically lacks the t(14;18)/IGH-BCL2 and BCL2 protein overexpression. Optimal management is not well defined. Nevertheless, after unilateral orchiectomy combined with chemotherapy, TFL has shown excellent prognosis without recurrence. A focal diffuse large B-cell component does not appear to confer adverse prognosis.
... They are of germinal center B-cell derivation; and have a relatively good prognosis in contrast to other forms of diffuse large B-cell lymphoma seen in young patients [1,16,21]. [16] Finally, there is testicular follicular lymphoma, which is a rare condition seen in young boys; these patients have a very good prognosis and in the vast majority of cases appear to be cured by simple orchiectomy [22,23]. Systemic chemotherapy is not required. ...
... Systemic chemotherapy is not required. Finally, there is testicular follicular lymphoma, which is a rare condition seen in young boys; these patients have a very good prognosis and in the vast majority of cases appear to be cured by simple orchiectomy [22,23]. Systemic chemotherapy is not required. ...
The definitions of follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are evolving in the era of personalized medicine. Early stages of the evolution of FL have been recognized. Two histological manifestations of early lesions are in situ follicular neoplasia and duodenal type FL. Additionally, FL frequently undergoes histological transformation, the most common form being DLBCL. High-grade B-cell lymphoma with double hit, with translocations involving BCL2 and MYC are important clinically. Rarer forms of transformation include classic Hodgkin lymphoma (CHL) and histiocytic sarcoma. In addition to conventional FL associated with the BCL2 translocation, alternative forms of BCL2-negative FL have been observed. These are heterogenous clinically and genetically. A distinctive group of B-cell lymphomas of follicle cell derivation arise in young patients and include pediatric type FL, testicular FL and a large B-cell lymphoma with IRF4 rearrangement. Historically DLBCL was separated into only two histological variants, centroblastic and immunoblastic. In 2017 the WHO classification recommended (1) the segregation of activated B cell and germinal center B cell derived DLBCL, (2) the identification of high-grade B-cell lymphoma with double hit, and (3) the recognition of an aggressive lymphoma that may resemble Burkitt lymphoma, currently designated in the International Consensus Classification as Large B-cell lymphoma with 11q aberration. Today we appreciate greater genomic complexity among aggressive B-cell lymphomas. Recent studies with NGS and mutational profiling have identified clinically significant genetic subgroups. It is hoped that these data ultimately will lead to targeted therapy based on the genetic profile.
... 3,6,[8][9][10] There are several recent reports of extranodal pediatric FL with a striking propensity for testicular involvement. 1,2,11,12 In many of these cases, testicular involvement was the initial manifestation of clinically occult nodal disease rather than true primary extranodal disease. 1 Ghislanzoni et al 10 recently reported the first case of primary cutaneous follicular center cell lymphoma arising on the nose and the left nasolabial fold of a 16-yearold adolescent boy. ...
... Strict criteria must be used in the diagnosis of FLs in children, to differentiate them from the much more frequently occurring reactive follicular hyperplasia (Figure 1, A and B). Frizzera and Murphy 3 based their diagnosis of FL on the following architectural and cytologic features: (1) total or extensive replacement of nodal structure; (2) even distribution of nodules throughout the node or lesion, as opposed to the predominantly cortical distribution of follicles in reactive hyperplasia; (3) crowding of nodules with little interposed lymphoid tissue; (4) overall uniformity in size and shape of nodules as compared with that seen in follicles of reactive hyperplasia; (5) paucity of reactive lymphoid cells (immunoblasts and plasma cells) in the interfollicular areas, strikingly demonstrable by immunoperoxidase staining; and (6) the cytologic composition of the nodules. Winberg et al 4 found that the most helpful features were effacement of nodal architecture, the presence of cytologically atypical cells in the interfollicular areas identical to those in the neoplastic follicles, and the monomorphous appearance of these cells in the follicles. ...
Follicular lymphoma, although common in adults, is rare in children. Pediatric follicular lymphoma has a more favorable prognosis than adult follicular lymphoma, even though it is often of higher grade. Children with follicular lymphomas are generally at a lower clinical stage, respond well to less aggressive therapy, and have a better survival than adults. Follicular lymphoma must be distinguished from reactive follicular hyperplasia, which it may mimic. Immunohistochemical and molecular markers serve to facilitate this distinction, as well as careful attention to clinical and morphologic details. It is important to recognize pediatric follicular lymphoma as a unique clinicopathologic entity to properly diagnose and manage these patients. It may represent a subset of follicular lymphoma with a particularly good prognosis.
... To our knowledge, only 5 cases have been reported in the literature to date, 4 with molecular genetic analysis. 6,7 In these studies, none of the 4 cases evaluated expressed BCL-2 or had evidence of bcl-2 gene rearrangement. However, BCL-6 was expressed in all 3 cases studied, and bcl-6 gene rearrangement was found in the one case evaluated by Southern blot analysis. ...
... However, BCL-6 was expressed in all 3 cases studied, and bcl-6 gene rearrangement was found in the one case evaluated by Southern blot analysis. 7 Herein, we report another case of primary follicular large cell lymphoma in a 6-year-old boy. ...
Primary follicular lymphoma of the testis in childhood is extremely rare. To our knowledge, only 5 cases have been reported to date. We report a case in a 6-year-old boy who presented with painless right scrotal enlargement. Right radical orchiectomy revealed a follicular large cell lymphoma with diffuse areas confined to the testis and epididymis, clinical stage IE. Immunohistochemical stains demonstrated that the neoplastic cells were of B-cell lineage, positive for CD10, CD20, CD79a, and BCL-6. Staining for CD21 accentuated networks of dendritic reticulum cells within the nodules. The cells were negative for BCL-2, p53, and T-cell antigens. There was no evidence of the t(14;18) detected by polymerase chain reaction. The data suggest that follicular lymphoma of the testis in children has a different pathogenesis than follicular lymphoma in adults.
... Primary testicular follicular lymphoma (TFL) is a rare variant of FL that presents mainly in children, adolescent and young adults, as stage IE disease. [94][95][96][97] Morphologically, the atypical follicles are composed of a mixture of cells resembling classic centroblasts and centrocytes, usually associated with well-formed FDC meshworks. In contrast to PTFL, TFL cells are negative for surface immunoglobulins demonstrated by flow cytometry. ...
Follicular lymphoma (FL) is a neoplasm derived from germinal center B cells, composed of centrocytes and centroblasts with at least a focal follicular growth pattern. The t(14;18) translocation together with epigenetic deregulation through recurrent genetic alterations are now recognized as the hallmark of FL. Nevertheless, FL is a heterogeneous disease clinically, morphologically, and biologically. The existence of FL lacking the t(14;18) chromosomal alteration highlights the complex pathogenesis of FL, and indicates that there are alternative pathogenetic mechanisms that can induce a neoplasm with follicular center B-cell phenotype. According to their clinical presentation t(14;18)-negative FL can be divided in three broad groups; nodal presentation, extranodal presentation, and those affecting predominantly children and young adults. Recent studies have shed some light into the genetic alterations of t(14;18)-negative FL. Within the group of t(14;18)-negative FL with nodal presentation, cases with STAT6 mutations are increasingly recognized as a distinctive molecular subgroup, often co-occurring with CREBBP and/or TNFRSF14 mutations. FL with BCL6 rearrangement shows clinicopathological similarities with the t(14;18)-positive counterpart. In contrast, t(14;18)-negative FL in extranodal sites are characterized mainly by TNFRSF14 mutations in the absence of chromatin modifying gene mutations. FL in children have unique molecular landscape when compared to adults. Pediatric-type follicular lymphoma (PTFL) is characterized by MAP2K1, TNFRSF14 and/or IRF8 mutations, whereas large B-cell lymphoma with IRF4 rearrangement is now recognized as a distinct entity different from PTFL. Ultimately, the better understanding of FL biology and heterogeneity should help to understand the clinical differences and help guiding patient management and treatment decisions.
... Pediatric-type FL is characterized by recurrent mutations in the MAPK pathway, lack of BCL2 rearrangement, and an excellent prognosis FL [90][91][92], and has also been included as a new subtype in the 5th edition of the WHO Classification [83]. Furthermore, testicular FL, identified as a new FL entity in young boys, which confers good prognosis, is also characterized by the lack of BCL2 translocations [84,93]. ...
Follicular lymphoma (FL), a generally indolent disease that derives from germinal center (GC) B cells, represents around 20–25% of all new lymphomas diagnosed in Western countries. The characteristic t(14;18)(q32;q21) translocation that places the BCL2 oncogene under control of the immunoglobulin heavy-chain enhancer occurs in pro- or pre-B cells. However, additional secondary alterations are required for the development of overt FL, which mainly affects genes involved in epigenetic and transcriptional regulation, signaling and B cell differentiation, the BCR/NF-κB pathway, and proliferation/apoptosis. On the other hand, new insights into the FL pathogenesis suggest that FL lacking the BCL2 translocation might be a distinct biological entity with genomic features different from the classical FL. Although FL is considered an indolent disease, around 10–20% of cases eventually transform to an aggressive lymphoma, usually a diffuse large B cell lymphoma, generally by a divergent evolution process from a common altered precursor cell acquiring genomic alterations involved in the cell cycle and DNA damage responses. Importantly, FL tumor cells require interaction with the microenvironment, which sustains cell survival and proliferation. Although the use of rituximab has improved the outlook of most FL patients, further genomic studies are needed to identify those of high risk who can benefit from innovative therapies. This review provides an updated synopsis of FL, including the molecular and cellular pathogenesis, key events of transformation, and targeted treatments.
... The aberrant genetic hallmark characterized by the t(14;18) (q32;q21) is identified in as many as 90% of grades 1-2 nodal FLs and involves translocation between the IGH and BCL2 genes resulting in the antiapoptotic protein BCL2 overexpression [57]. Nevertheless, BCL2 translocation is generally absent in testicular, diffuse, and in pediatric variants [1,59,60]. Additional genetic alterations in nodal FL include loss of 1p, 6q, 10q, and 17p and gains of chromosomes 1, 6p, 7, 8, 12q, X, and 18q [1]. ...
Background
Mature B-cell non-Hodgkin lymphomas are one of the most common hematological malignancies with a divergent clinical presentation, phenotype, and course of disease regulated by underlying genetic mechanism.
Main body
Genetic and molecular alterations are not only critical for lymphomagenesis but also largely responsible for differing therapeutic response in these neoplasms. In recent years, advanced molecular tools have provided a deeper understanding regarding these oncogenic drives for predicting progression as well as refractory behavior in these diseases. The prognostic models based on gene expression profiling have also been proved effective in various clinical scenarios. However, considerable overlap does exist between the genotypes of individual lymphomas and at the same time where additional molecular lesions may be associated with each entity apart from the key genetic event. Therefore, genomics is one of the cornerstones in the multimodality approach essential for classification and risk stratification of B-cell non-Hodgkin lymphomas.
Conclusion
We hereby in this review discuss the wide range of genetic aberrancies associated with tumorigenesis, immune escape, and chemoresistance in major B-cell non-Hodgkin lymphomas.
... Compared to WHO-HAEM4, there are two changes in the ICC but not in the WHO-HAEM5 concerning FL: (1) testicular FL is recognized as a distinct form of FL in young boys; and (2) BCL2-Rnegative, CD23-positive follicle center lymphoma [3] is recognized as provisional entity (Table 1). Testicular FL shares clinicopathological features with pediatric-type FL [68,69]. In particular, it occurs in children, is limited to testis and usually shows a grade 3 [69]. ...
Several editions of the World Health Organization (WHO) classifications of lympho-hemopoietic neoplasms in 2001, 2008 and 2017 served as the international standard for diagnosis. Since the 4th WHO edition, here referred as WHO-HAEM4, significant clinico-pathological, immunophenotypic and molecular advances have been made in the field of lymphomas, contributing to refining diagnostic criteria of several diseases, to upgrade entities previously defined as provisional and to identify new entities. This process has resulted in two recent classifying proposals of lymphoid neoplasms, the International Consensus Classification (ICC) and the 5th edition of the WHO classification (WHO-HAEM5). In this paper, we review and compare the two classifications in terms of diagnostic criteria and entity definition, with focus on mature B-cell neoplasms. The main aim is to provide a tool to facilitate the work of pathologists, hematologists and researchers involved in the diagnosis and treatment of lymphomas.
... 84 Testicular FL, recognized as a new distinct entity of FL in young boys, shares pathological and clinical features with pediatrictype FL, because most patients can be managed conservatively, without systemic chemotherapy. 85,86 Large B-cell lymphoma with IRF4 rearrangement, upgraded now to a definite entity, is most common in children and young adults and usually has at least a partially follicular growth pattern. 69 However, the same disease is not commonly seen in adults. ...
Since the publication of the Revised European-American Classification of mature lymphoid neoplasms in 1994, subsequent updates of the classification of mature lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress in the characterization of malignancies of the immune system in the last years, with many new insights provided by genomic studies, have led to the current proposal. We have followed the same process that was successfully used for the 3rd and 4th editions of the WHO classification of hematological neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional are now upgraded to definite entities. Terminology of some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification (ICC) of mature lymphoid, histiocytic, and dendritic cell tumors.
... 4 and 5; PBX1 and HOX family). Moreover, enhancers overlapping with the mutation blocks in the upstream 5 0 distance region of CDCA4 were targeting IgH genes which are a molecular hallmark of FL [77,78]. There are few IgH genes like IGHG and IGHD also present in the same TAD as seen in Fig. 7. ...
A major challenge in human genetics is of the analysis of the interplay between genetic and epigenetic factors in a multifactorial disease like cancer. Here, a novel methodology is proposed to investigate genome-wide regulatory mechanisms in cancer, as studied with the example of follicular Lymphoma (FL). In a first phase, a new machine-learning method is designed to identify Differentially Methylated Regions (DMRs) by computing six attributes. In a second phase, an integrative data analysis method is developed to study regulatory mutations in FL, by considering differential methylation information together with DNA sequence variation, differential gene expression, 3D organization of genome (e.g., topologically associated domains), and enriched biological pathways. Resulting mutation block-gene pairs are further ranked to find out the significant ones. By this approach, BCL2 and BCL6 were identified as top-ranking FL-related genes with several mutation blocks and DMRs acting on their regulatory regions. Two additional genes, CDCA4 and CTSO, were also found in top rank with significant DNA sequence variation and differential methylation in neighboring areas, pointing towards their potential use as biomarkers for FL. This work combines both genomic and epigenomic information to investigate genome-wide gene regulatory mechanisms in cancer and contribute to devising novel treatment strategies.
... The testicular variant of FL is rare. This neoplasm was initially identified in children but has also rarely been reported in adults [38]. These neoplasms have several features similar to pediatric type FL. ...
Follicular lymphoma (FL) is the most common indolent B-cell lymphoma and originates from germinal center B-cells (centrocytes and centroblasts) of the lymphoid follicle. Tumorigenesis is believed to initiate early in precursor B-cells in the bone marrow (BM) that acquire the t(14;18)(q32;q21). These cells later migrate to lymph nodes to continue their maturation through the germinal center reaction, at which time they acquire additional genetic and epigeneticabnormalities that promote lymphomagenesis. FLs are heterogeneous in terms of their clinicopathologic features. Most FLs are indolent and clinically characterized by peripheral lymphadenopathy with involvement of the spleen, BM, and peripheral blood in a substantial subset of patients, sometimes accompanied by constitutional symptoms and laboratory abnormalities. Diagnosis is established by the histopathologic identification of a B-cell proliferation usually distributed in an at least partially follicular pattern, typically, but not always, in a lymph node biopsy. The B-cell proliferation is biologically of germinal center cell origin, thus shows an expression of germinal center-associated antigens as detected by immunophenotyping. Although many cases of FLs are typical and histopathologic features are straightforward, the biologic and histopathologic variability of FL is wide, and an accurate diagnosis of FL over this disease spectrum requires knowledge of morphologic variants that can mimic other lymphomas, and rarely non-hematologic malignancies, clinically unique variants, and pitfalls in the interpretation of ancillary studies. The overall survival for most patients is prolonged, but relapses are frequent. The treatment landscape in FL now includes the application of immunotherapy and targeted therapy in addition to chemotherapy.
... Testicular metastasis in patients with ALL is a poor prognostic factor. Follicular lymphoma may appear as a primary testicular tumor (53). Radiotherapy and systemic chemotherapy are standard treatment options used (23). ...
... A vast majority of primary testicular lymphoid neoplasms (80%-95%) are DLBCLs [2]. Previously reports of other rare histological types of malignant lymphoma included mantle cell lymphoma [9], testicular follicular lymphoma [10], extranodal marginal zone lymphoma [11], natural killer/T-cell lymphoma, nasal type [12], peripheral T-cell lymphoma (PTCL) [13], and activin receptor-like kinase-1-negative anaplastic large cell lymphoma [14]. On the other hand, testicular involvement of lymphoid leukemia has been described in some previous reports [7,8]. ...
A 59-year-old man presented with a painless testicular mass and underwent a radical orchiectomy. The resected specimen showed a 5-cm-sized, white-yellow and homogenous solid mass in the testicular parenchyma. Histologically, the central part of the tumor exhibited typical features of seminoma. The peripheral part of the tumor exhibited diffuse infiltration of small, monotonous lymphoid cells involving the tunica albuginea. The monotonous lymphoid cells were immunoreactive for CD20, CD79a, CD5, and CD23, and negative for CD3, CD10, and cyclin D1. Kappa light chain restriction was detected on flow cytometry using the resected specimen. Considering the circulating lymphoid cell count of > 5.0 × 10 3 /µL, we diagnosed the peripheral component of the tumor as an infiltration of chronic lymphocytic leukemia. This extremely rare combination of seminoma and lymphoid neoplasm should be considered in the differential diagnosis of classic seminoma with extensive lymphoid reaction in tumors arising in elderly patients.
... De PAS et al. [15] showed that the recurrence rate of 83 patients with FDCS after surgical resection was 46.3%, and the overall recurrence rate of patients receiving adjuvant therapy such as chemotherapy or radiotherapy was 35%. Therefore, some scholars believe that for the patients with Ki-67 > 20%, tumor diameter > 6cm or located in the abdominal cavity, in addition to complete tumor resection, adjuvant chemotherapy and / or radiotherapy may be bene cial to the residual or locally recurrent tumor [16]. Five cases of pancreatic FDCS reported in the literature were treated with surgery without adjuvant therapy. ...
Background: Follicular Dendritic Cell Sarcoma (FDCS) is a rare malignant tumor originated from follicular dendritic cells. Presently radical resection is the standard treatment; however there is no clear optimal chemotherapy for unresectable lesions. We presented the clinical data, pathological features, imaging features, diagnosis and treatment of a very rare patient with recurrence and metastasis after radical resection of pancreatic FDCS.
Case presentation: A 64-year-old male patient was delivered to hospital due to intermittent chest tightness and pain. A pancreatic mass was found after thorough physical examination. Enhanced MRI showed a round solid mass in the head and neck of pancreas. The patient underwent radical resection. The pathological diagnosis was FDCS. CHP regimen was used for consolidation chemotherapy for 6 cycles. Two years later, due to a large amount of effusion, the patient was confirmed to have relapse and extensive abdominal metastasis. Both CHOP regimen and bendamustine were ineffective.
Conclusions: FDCS of pancreas is very rare, and its imaging findings are not specific. If the disease relapses or metastases, though applies a variety of chemotherapy regimens, it is difficult to obtain satisfactory curative effect, and long-term prognosis is pessimistic. This is the first reported case that bendamustine was ineffective in the treatment of FDCS.
Follicular lymphoma (FL) is a lymphoid neoplasm composed of follicle center (germinal center) B cells, with varying proportions of centrocytes and centroblasts, that usually has a predominantly follicular architectural pattern. Over the past decade, our understanding of FL has evolved significantly, with new recognition of several recently defined FL variants characterized by distinct clinical presentations, behaviors, genetic alterations, and biology. This manuscript aims to review the heterogeneity of FL and its variants, to provide an updated guide on their diagnosis and classification, and to describe how approaches to the histologic subclassification of classic FL have evolved in current classification schemes.
Although pediatric hematopathology overlaps with that of adults, certain forms of leukemia and lymphoma, and many types of reactive conditions affecting the bone marrow and lymph nodes, are unique to children. As part of this series focused on lymphomas, this article (1) details the novel subtypes of lymphoblastic leukemia seen primarily in children and described since the 2017 World Health Organization classification and (2) discusses unique concepts in pediatric hematopathology, including nomenclature changes and evaluation of surgical margins in selected lymphomas.
Mature B-cell lymphomas, (B- or T-cell) lymphoblastic lymphomas (LBL), and anaplastic large cell lymphoma (ALCL) correspond to about 90% of all non-Hodgkin lymphoma (NHL) cases occurring in children and adolescents. The remaining 10% encompass a complex group of entities characterized by low/very low incidences, paucity of knowledge in terms of underlying biology in comparison to their adult counterparts, and consequent lack of standardization of care, information on clinical therapeutic efficacy and long-term survival. At the Seventh International Symposium on Childhood, Adolescent and Young Adult NHL, organized on October 20-23, 2022, in New York City, New York, US, we had the opportunity to discuss clinical, pathogenetic, diagnostic, and treatment aspects of certain subtypes of rare B- or T-cell NHL and they will be the topic of this review.
Diagnostic Pediatric Hematopathology is unique in providing an accurate and up-to-date guide to the diagnosis of benign and malignant hematologic disorders of childhood. The text discusses the development of the hematopoietic and lymphoid systems - and how this affects normal and abnormal findings in children at various ages. Also examined are the morphologic, immunophenotypic, cytogenetic, and molecular genetic characteristics of most pediatric-specific hematologic diseases. This is an excellent reference that ensures accurate diagnoses when evaluating peripheral blood, bone marrow, and lymph nodes of children. The text is written by a team of experienced pediatric hematopathologists and clinical scientists drawn from major academic children's hospitals in the United States, Europe, and Canada. It will be a valuable tool in the every day practice of pathologists, pediatric pathologists, and hematopathologists, and a ready educational resource for fellows, pathology residents, medical students, clinical scientists in the field, and pediatric hematologists/oncologists.
Diagnostic Pediatric Hematopathology is unique in providing an accurate and up-to-date guide to the diagnosis of benign and malignant hematologic disorders of childhood. The text discusses the development of the hematopoietic and lymphoid systems - and how this affects normal and abnormal findings in children at various ages. Also examined are the morphologic, immunophenotypic, cytogenetic, and molecular genetic characteristics of most pediatric-specific hematologic diseases. This is an excellent reference that ensures accurate diagnoses when evaluating peripheral blood, bone marrow, and lymph nodes of children. The text is written by a team of experienced pediatric hematopathologists and clinical scientists drawn from major academic children's hospitals in the United States, Europe, and Canada. It will be a valuable tool in the every day practice of pathologists, pediatric pathologists, and hematopathologists, and a ready educational resource for fellows, pathology residents, medical students, clinical scientists in the field, and pediatric hematologists/oncologists.
Diagnostic Pediatric Hematopathology is unique in providing an accurate and up-to-date guide to the diagnosis of benign and malignant hematologic disorders of childhood. The text discusses the development of the hematopoietic and lymphoid systems - and how this affects normal and abnormal findings in children at various ages. Also examined are the morphologic, immunophenotypic, cytogenetic, and molecular genetic characteristics of most pediatric-specific hematologic diseases. This is an excellent reference that ensures accurate diagnoses when evaluating peripheral blood, bone marrow, and lymph nodes of children. The text is written by a team of experienced pediatric hematopathologists and clinical scientists drawn from major academic children's hospitals in the United States, Europe, and Canada. It will be a valuable tool in the every day practice of pathologists, pediatric pathologists, and hematopathologists, and a ready educational resource for fellows, pathology residents, medical students, clinical scientists in the field, and pediatric hematologists/oncologists.
Diagnostic Pediatric Hematopathology is unique in providing an accurate and up-to-date guide to the diagnosis of benign and malignant hematologic disorders of childhood. The text discusses the development of the hematopoietic and lymphoid systems - and how this affects normal and abnormal findings in children at various ages. Also examined are the morphologic, immunophenotypic, cytogenetic, and molecular genetic characteristics of most pediatric-specific hematologic diseases. This is an excellent reference that ensures accurate diagnoses when evaluating peripheral blood, bone marrow, and lymph nodes of children. The text is written by a team of experienced pediatric hematopathologists and clinical scientists drawn from major academic children's hospitals in the United States, Europe, and Canada. It will be a valuable tool in the every day practice of pathologists, pediatric pathologists, and hematopathologists, and a ready educational resource for fellows, pathology residents, medical students, clinical scientists in the field, and pediatric hematologists/oncologists.
Diagnostic Pediatric Hematopathology is unique in providing an accurate and up-to-date guide to the diagnosis of benign and malignant hematologic disorders of childhood. The text discusses the development of the hematopoietic and lymphoid systems - and how this affects normal and abnormal findings in children at various ages. Also examined are the morphologic, immunophenotypic, cytogenetic, and molecular genetic characteristics of most pediatric-specific hematologic diseases. This is an excellent reference that ensures accurate diagnoses when evaluating peripheral blood, bone marrow, and lymph nodes of children. The text is written by a team of experienced pediatric hematopathologists and clinical scientists drawn from major academic children's hospitals in the United States, Europe, and Canada. It will be a valuable tool in the every day practice of pathologists, pediatric pathologists, and hematopathologists, and a ready educational resource for fellows, pathology residents, medical students, clinical scientists in the field, and pediatric hematologists/oncologists.
Diagnostic Pediatric Hematopathology is unique in providing an accurate and up-to-date guide to the diagnosis of benign and malignant hematologic disorders of childhood. The text discusses the development of the hematopoietic and lymphoid systems - and how this affects normal and abnormal findings in children at various ages. Also examined are the morphologic, immunophenotypic, cytogenetic, and molecular genetic characteristics of most pediatric-specific hematologic diseases. This is an excellent reference that ensures accurate diagnoses when evaluating peripheral blood, bone marrow, and lymph nodes of children. The text is written by a team of experienced pediatric hematopathologists and clinical scientists drawn from major academic children's hospitals in the United States, Europe, and Canada. It will be a valuable tool in the every day practice of pathologists, pediatric pathologists, and hematopathologists, and a ready educational resource for fellows, pathology residents, medical students, clinical scientists in the field, and pediatric hematologists/oncologists.
Diagnostic Pediatric Hematopathology is unique in providing an accurate and up-to-date guide to the diagnosis of benign and malignant hematologic disorders of childhood. The text discusses the development of the hematopoietic and lymphoid systems - and how this affects normal and abnormal findings in children at various ages. Also examined are the morphologic, immunophenotypic, cytogenetic, and molecular genetic characteristics of most pediatric-specific hematologic diseases. This is an excellent reference that ensures accurate diagnoses when evaluating peripheral blood, bone marrow, and lymph nodes of children. The text is written by a team of experienced pediatric hematopathologists and clinical scientists drawn from major academic children's hospitals in the United States, Europe, and Canada. It will be a valuable tool in the every day practice of pathologists, pediatric pathologists, and hematopathologists, and a ready educational resource for fellows, pathology residents, medical students, clinical scientists in the field, and pediatric hematologists/oncologists.
Diagnostic Pediatric Hematopathology is unique in providing an accurate and up-to-date guide to the diagnosis of benign and malignant hematologic disorders of childhood. The text discusses the development of the hematopoietic and lymphoid systems - and how this affects normal and abnormal findings in children at various ages. Also examined are the morphologic, immunophenotypic, cytogenetic, and molecular genetic characteristics of most pediatric-specific hematologic diseases. This is an excellent reference that ensures accurate diagnoses when evaluating peripheral blood, bone marrow, and lymph nodes of children. The text is written by a team of experienced pediatric hematopathologists and clinical scientists drawn from major academic children's hospitals in the United States, Europe, and Canada. It will be a valuable tool in the every day practice of pathologists, pediatric pathologists, and hematopathologists, and a ready educational resource for fellows, pathology residents, medical students, clinical scientists in the field, and pediatric hematologists/oncologists.
Diagnostic Pediatric Hematopathology is unique in providing an accurate and up-to-date guide to the diagnosis of benign and malignant hematologic disorders of childhood. The text discusses the development of the hematopoietic and lymphoid systems - and how this affects normal and abnormal findings in children at various ages. Also examined are the morphologic, immunophenotypic, cytogenetic, and molecular genetic characteristics of most pediatric-specific hematologic diseases. This is an excellent reference that ensures accurate diagnoses when evaluating peripheral blood, bone marrow, and lymph nodes of children. The text is written by a team of experienced pediatric hematopathologists and clinical scientists drawn from major academic children's hospitals in the United States, Europe, and Canada. It will be a valuable tool in the every day practice of pathologists, pediatric pathologists, and hematopathologists, and a ready educational resource for fellows, pathology residents, medical students, clinical scientists in the field, and pediatric hematologists/oncologists.
Diagnostic Pediatric Hematopathology is unique in providing an accurate and up-to-date guide to the diagnosis of benign and malignant hematologic disorders of childhood. The text discusses the development of the hematopoietic and lymphoid systems - and how this affects normal and abnormal findings in children at various ages. Also examined are the morphologic, immunophenotypic, cytogenetic, and molecular genetic characteristics of most pediatric-specific hematologic diseases. This is an excellent reference that ensures accurate diagnoses when evaluating peripheral blood, bone marrow, and lymph nodes of children. The text is written by a team of experienced pediatric hematopathologists and clinical scientists drawn from major academic children's hospitals in the United States, Europe, and Canada. It will be a valuable tool in the every day practice of pathologists, pediatric pathologists, and hematopathologists, and a ready educational resource for fellows, pathology residents, medical students, clinical scientists in the field, and pediatric hematologists/oncologists.
Diagnostic Pediatric Hematopathology is unique in providing an accurate and up-to-date guide to the diagnosis of benign and malignant hematologic disorders of childhood. The text discusses the development of the hematopoietic and lymphoid systems - and how this affects normal and abnormal findings in children at various ages. Also examined are the morphologic, immunophenotypic, cytogenetic, and molecular genetic characteristics of most pediatric-specific hematologic diseases. This is an excellent reference that ensures accurate diagnoses when evaluating peripheral blood, bone marrow, and lymph nodes of children. The text is written by a team of experienced pediatric hematopathologists and clinical scientists drawn from major academic children's hospitals in the United States, Europe, and Canada. It will be a valuable tool in the every day practice of pathologists, pediatric pathologists, and hematopathologists, and a ready educational resource for fellows, pathology residents, medical students, clinical scientists in the field, and pediatric hematologists/oncologists.
Diagnostic Pediatric Hematopathology is unique in providing an accurate and up-to-date guide to the diagnosis of benign and malignant hematologic disorders of childhood. The text discusses the development of the hematopoietic and lymphoid systems - and how this affects normal and abnormal findings in children at various ages. Also examined are the morphologic, immunophenotypic, cytogenetic, and molecular genetic characteristics of most pediatric-specific hematologic diseases. This is an excellent reference that ensures accurate diagnoses when evaluating peripheral blood, bone marrow, and lymph nodes of children. The text is written by a team of experienced pediatric hematopathologists and clinical scientists drawn from major academic children's hospitals in the United States, Europe, and Canada. It will be a valuable tool in the every day practice of pathologists, pediatric pathologists, and hematopathologists, and a ready educational resource for fellows, pathology residents, medical students, clinical scientists in the field, and pediatric hematologists/oncologists.
Diagnostic Pediatric Hematopathology is unique in providing an accurate and up-to-date guide to the diagnosis of benign and malignant hematologic disorders of childhood. The text discusses the development of the hematopoietic and lymphoid systems - and how this affects normal and abnormal findings in children at various ages. Also examined are the morphologic, immunophenotypic, cytogenetic, and molecular genetic characteristics of most pediatric-specific hematologic diseases. This is an excellent reference that ensures accurate diagnoses when evaluating peripheral blood, bone marrow, and lymph nodes of children. The text is written by a team of experienced pediatric hematopathologists and clinical scientists drawn from major academic children's hospitals in the United States, Europe, and Canada. It will be a valuable tool in the every day practice of pathologists, pediatric pathologists, and hematopathologists, and a ready educational resource for fellows, pathology residents, medical students, clinical scientists in the field, and pediatric hematologists/oncologists.
Diagnostic Pediatric Hematopathology is unique in providing an accurate and up-to-date guide to the diagnosis of benign and malignant hematologic disorders of childhood. The text discusses the development of the hematopoietic and lymphoid systems - and how this affects normal and abnormal findings in children at various ages. Also examined are the morphologic, immunophenotypic, cytogenetic, and molecular genetic characteristics of most pediatric-specific hematologic diseases. This is an excellent reference that ensures accurate diagnoses when evaluating peripheral blood, bone marrow, and lymph nodes of children. The text is written by a team of experienced pediatric hematopathologists and clinical scientists drawn from major academic children's hospitals in the United States, Europe, and Canada. It will be a valuable tool in the every day practice of pathologists, pediatric pathologists, and hematopathologists, and a ready educational resource for fellows, pathology residents, medical students, clinical scientists in the field, and pediatric hematologists/oncologists.
Diagnostic Pediatric Hematopathology is unique in providing an accurate and up-to-date guide to the diagnosis of benign and malignant hematologic disorders of childhood. The text discusses the development of the hematopoietic and lymphoid systems - and how this affects normal and abnormal findings in children at various ages. Also examined are the morphologic, immunophenotypic, cytogenetic, and molecular genetic characteristics of most pediatric-specific hematologic diseases. This is an excellent reference that ensures accurate diagnoses when evaluating peripheral blood, bone marrow, and lymph nodes of children. The text is written by a team of experienced pediatric hematopathologists and clinical scientists drawn from major academic children's hospitals in the United States, Europe, and Canada. It will be a valuable tool in the every day practice of pathologists, pediatric pathologists, and hematopathologists, and a ready educational resource for fellows, pathology residents, medical students, clinical scientists in the field, and pediatric hematologists/oncologists.
Diagnostic Pediatric Hematopathology is unique in providing an accurate and up-to-date guide to the diagnosis of benign and malignant hematologic disorders of childhood. The text discusses the development of the hematopoietic and lymphoid systems - and how this affects normal and abnormal findings in children at various ages. Also examined are the morphologic, immunophenotypic, cytogenetic, and molecular genetic characteristics of most pediatric-specific hematologic diseases. This is an excellent reference that ensures accurate diagnoses when evaluating peripheral blood, bone marrow, and lymph nodes of children. The text is written by a team of experienced pediatric hematopathologists and clinical scientists drawn from major academic children's hospitals in the United States, Europe, and Canada. It will be a valuable tool in the every day practice of pathologists, pediatric pathologists, and hematopathologists, and a ready educational resource for fellows, pathology residents, medical students, clinical scientists in the field, and pediatric hematologists/oncologists.
Diagnostic Pediatric Hematopathology is unique in providing an accurate and up-to-date guide to the diagnosis of benign and malignant hematologic disorders of childhood. The text discusses the development of the hematopoietic and lymphoid systems - and how this affects normal and abnormal findings in children at various ages. Also examined are the morphologic, immunophenotypic, cytogenetic, and molecular genetic characteristics of most pediatric-specific hematologic diseases. This is an excellent reference that ensures accurate diagnoses when evaluating peripheral blood, bone marrow, and lymph nodes of children. The text is written by a team of experienced pediatric hematopathologists and clinical scientists drawn from major academic children's hospitals in the United States, Europe, and Canada. It will be a valuable tool in the every day practice of pathologists, pediatric pathologists, and hematopathologists, and a ready educational resource for fellows, pathology residents, medical students, clinical scientists in the field, and pediatric hematologists/oncologists.
Diagnostic Pediatric Hematopathology is unique in providing an accurate and up-to-date guide to the diagnosis of benign and malignant hematologic disorders of childhood. The text discusses the development of the hematopoietic and lymphoid systems - and how this affects normal and abnormal findings in children at various ages. Also examined are the morphologic, immunophenotypic, cytogenetic, and molecular genetic characteristics of most pediatric-specific hematologic diseases. This is an excellent reference that ensures accurate diagnoses when evaluating peripheral blood, bone marrow, and lymph nodes of children. The text is written by a team of experienced pediatric hematopathologists and clinical scientists drawn from major academic children's hospitals in the United States, Europe, and Canada. It will be a valuable tool in the every day practice of pathologists, pediatric pathologists, and hematopathologists, and a ready educational resource for fellows, pathology residents, medical students, clinical scientists in the field, and pediatric hematologists/oncologists.
Diagnostic Pediatric Hematopathology is unique in providing an accurate and up-to-date guide to the diagnosis of benign and malignant hematologic disorders of childhood. The text discusses the development of the hematopoietic and lymphoid systems - and how this affects normal and abnormal findings in children at various ages. Also examined are the morphologic, immunophenotypic, cytogenetic, and molecular genetic characteristics of most pediatric-specific hematologic diseases. This is an excellent reference that ensures accurate diagnoses when evaluating peripheral blood, bone marrow, and lymph nodes of children. The text is written by a team of experienced pediatric hematopathologists and clinical scientists drawn from major academic children's hospitals in the United States, Europe, and Canada. It will be a valuable tool in the every day practice of pathologists, pediatric pathologists, and hematopathologists, and a ready educational resource for fellows, pathology residents, medical students, clinical scientists in the field, and pediatric hematologists/oncologists.
Diagnostic Pediatric Hematopathology is unique in providing an accurate and up-to-date guide to the diagnosis of benign and malignant hematologic disorders of childhood. The text discusses the development of the hematopoietic and lymphoid systems - and how this affects normal and abnormal findings in children at various ages. Also examined are the morphologic, immunophenotypic, cytogenetic, and molecular genetic characteristics of most pediatric-specific hematologic diseases. This is an excellent reference that ensures accurate diagnoses when evaluating peripheral blood, bone marrow, and lymph nodes of children. The text is written by a team of experienced pediatric hematopathologists and clinical scientists drawn from major academic children's hospitals in the United States, Europe, and Canada. It will be a valuable tool in the every day practice of pathologists, pediatric pathologists, and hematopathologists, and a ready educational resource for fellows, pathology residents, medical students, clinical scientists in the field, and pediatric hematologists/oncologists.
Diagnostic Pediatric Hematopathology is unique in providing an accurate and up-to-date guide to the diagnosis of benign and malignant hematologic disorders of childhood. The text discusses the development of the hematopoietic and lymphoid systems - and how this affects normal and abnormal findings in children at various ages. Also examined are the morphologic, immunophenotypic, cytogenetic, and molecular genetic characteristics of most pediatric-specific hematologic diseases. This is an excellent reference that ensures accurate diagnoses when evaluating peripheral blood, bone marrow, and lymph nodes of children. The text is written by a team of experienced pediatric hematopathologists and clinical scientists drawn from major academic children's hospitals in the United States, Europe, and Canada. It will be a valuable tool in the every day practice of pathologists, pediatric pathologists, and hematopathologists, and a ready educational resource for fellows, pathology residents, medical students, clinical scientists in the field, and pediatric hematologists/oncologists.
The hematopoietic system is not fully developed at birth, and the normal hematologic values of newborns and infants differ as compared to older children and adults. The differences are a manifestation of the unique characteristics of the embryonal and fetal development of the hematopoietic system that continues to evolve after birth. Furthermore, preanalytical and analytical factors unique for neonates and young children also contribute to these differences. This chapter will explore these factors and discuss how they define the normal hematologic values for different age groups.
Developmental hematopoiesis: a general view
The hematopoietic development, unlike any other organ system, occurs in successive anatomic sites where the hematopoietic stem cells (HSCs) are generated, maintained, and differentiate into various cell types [1]. The hematopoiesis begins in the yolk sac with the generation of angioblastic foci or “blood islands” that contain primitive erythroblasts. It then progresses further in several waves involving multiple anatomic sites: the aorta–gonadal–mesonephros (AGM) region, fetal liver, and bone marrow (BM) [2, 3]. Depending on the site of major hematopoietic activity, the hematopoiesis has been divided into three stages: the mesenchymal, hepatic, and myeloid stages with the yolk sac, liver, and bone marrow as major hematopoietic sites where hematopoietic cells with characteristic features are generated [4] (Fig. 1.1). There is a considerable temporal overlap between different stages. At birth and thereafter, the hematopoiesis is restricted to the bone marrow and continues to evolve in order to adapt to the new oxygen-rich environment and the needs of the growing organism.
Diagnostic Pediatric Hematopathology is unique in providing an accurate and up-to-date guide to the diagnosis of benign and malignant hematologic disorders of childhood. The text discusses the development of the hematopoietic and lymphoid systems - and how this affects normal and abnormal findings in children at various ages. Also examined are the morphologic, immunophenotypic, cytogenetic, and molecular genetic characteristics of most pediatric-specific hematologic diseases. This is an excellent reference that ensures accurate diagnoses when evaluating peripheral blood, bone marrow, and lymph nodes of children. The text is written by a team of experienced pediatric hematopathologists and clinical scientists drawn from major academic children's hospitals in the United States, Europe, and Canada. It will be a valuable tool in the every day practice of pathologists, pediatric pathologists, and hematopathologists, and a ready educational resource for fellows, pathology residents, medical students, clinical scientists in the field, and pediatric hematologists/oncologists.
Hematopoietic disorders, benign or malignant, involving the liver and/or spleen are heterogenous in clinical, biological, genetic, and molecular aspects. It is widely accepted that these hematopoietic diseases are mostly driven by genetic alterations including gene deletion, amplification, translocation, karyotypic rearrangements, mutations, or epigenetic changes. Understanding the gene profiles of a hematopoietic disorder helps us to have better insights into the disease pathogenesis, make accurate diagnosis and subclassification, perform risk stratification, predict clinical outcome and treatment response, and moreover develop novel targeted therapy for the patients with the disorder. In addition to traditional cytogenetic analyses [karyotype analysis, fluorescence in situ hybridization (FISH)], emerging novel molecular technologies have introduced a number of laboratory methods, e.g., next-generation sequencing (NGS), ultra-deep polymerase chain reaction (PCR), whole genome sequencing, and exome sequencing, which have given us unprecedented view into the genomics of hematopoietic malignancies.
Although weighing only about 19 grams, the testis is responsible for a complex array of neoplasms. The rapidly proliferating spermatogenic cells give rise to the majority of testicular tumors, 95% of which are of germ cell derivation. Most are malignant and usually occur in young men, but they can be cured by current therapies; therefore accurate diagnosis is essential. The supporting cells and interstitial cells of the testis are responsible for the less common sex cord–stromal tumors that compose a disproportionate number of diagnostic problems. Some of these are associated with clinical syndromes that may be suspected based on the testicular pathology. A number of tumors of soft tissue origin may be identified in the paratestis, and secondary tumors are relatively frequent in both the testis and paratestis. The spectrum of lesions and the capacity of many tumors to mimic others make testicular neoplasia a continuing challenge to surgical pathologists, and this topic has been the subject of several recent reviews.
The non-Hodgkin lymphomas (NHL) of childhood occur relatively frequently with between 500-750 new cases diagnosed in the United States each year. The most common subtypes encountered include Burkitt lymphoma, diffuse large B cell lymphoma, T-lymphoblastic lymphoma and anaplastic large cell lymphoma. The relative frequency of these subtypes varies with geographical location. Children with congenital or acquired immunodeficiency syndromes are at increased risk to develop NHL. There have been significant advances in our understanding of the biology of pediatric NHL, which have in some cases led to novel approaches to therapy. The prognosis is generally excellent for all subtypes and has been accomplished through the refinement of sequential multiagent chemotherapy-based approaches. Involved field radiation therapy has largely been eliminated from the initial management of NHL in children. In the future, novel targeting agents will be explored based on existing and future biological study of these tumors. The continued study of both acute and late effects of therapy are also crucial, particularly as novel agents are explored.
Follicular lymphoma is the most common, indolent lymphoma in the western world; this chapter discusses the pathobiology that will touch upon the evolutionary history and the role of germinal centers that provide a landscape for B cells to acquire oncogenic mutations leading to malignant transformation. The molecular alterations leading to disease progression, divergent evolutionary pathway, and the role of microenvironment are discussed. The morphological variants and clinical-histologic variants, immunophenotype, prognostic factors, and differential diagnosis are discussed. In summary, the chapter will trace the diagnostic evolution of this entity in the past five decades.
All patients with chronic myelogenous leukemia (CML) undergo clinical transition from chronic to acute phase. This transition is often associated with deletion of the short arm of chromosome 17 in the form of the i(17q) aberration. Since the p53 gene is a suppressor gene and is located on 17p13, we examined the possibility that it is inactivated during progression of CML. Therefore, we studied the structure and expression of p53 in the leukemic cells of a large number of CML patients in acute phase. We found that although the gene is rarely rearranged, one p53 allele is completely deleted in patients with the i(17q) aberration as well as in some patients who do not show karyotypic changes. In all of these patients the remaining allele is inactivated through loss of expression, rearrangement, or point mutation. Detailed analysis of some patients who carry both p53 alleles indicated neither loss of expression nor structural alterations. It appears that p53 loss of function is associated with progression of around 25% of CML patients.
The LAZ3 gene encodes a novel zinc-finger protein that shares homology with several Drosophila transcription factors. This gene was identified by its disruption in translocations involving chromosome 3q27 in diffuse large-cell lymphomas. To assess the frequency and role of this gene's involvement in lymphomagenesis and tumor progression, we examined a series of 170 cases of non-Hodgkin's lymphomas of B-cell lineage for LAZ3 gene rearrangement, expression, and mutation. The cases included 35 de novo diffuse aggressive lymphomas (DAL; 19 large-cell, 4 mixed-cell, and 12 large-cell immunoblastic), 52 transformed aggressive lymphomas derived from follicular lymphomas (TFL), 42 indolent follicular lymphomas (FL), 14 mantle cell lymphomas (MCL), and 27 small noncleaved cell lymphomas (SNCL). LAZ3 rearrangements were found in 10 DAL (28.6%), 9 TFL (17.3%), and 6 FL (14.3%), but not in any of the SNCL or MCL. LAZ3 rearrangement was not exclusive of bcl-2 rearrangement. Most rearrangement breakpoints mapped to a 10-kb BamHI-Xba I fragment located 5' to the LAZ3 coding sequence, consistent with previously reported breakpoint locations. Northern analysis of both rearranged and nonrearranged B-cell lymphoma cases showed similar levels of a transcript of approximately 3.8 kb, indicating that LAZ3 is broadly expressed in B-cell tumors and is not confined to rearranged cases. To investigate whether mutation of the LAZ3 gene might contribute to a potential role for this gene in lymphomagenesis, we screened the coding sequences of 13 rearranged cases, 6 nonrearranged cases, and 13 hematopoietic tumor cell lines. Although three probable polymorphisms were identified, mutations were detected in only 2 rearranged cases. Only 1 of these resulted in an amino acid substitution. Two cell lines (SU-DHL4 and Molt-4) also contained mutations; only one resulted in an amino acid substitution. We conclude (1) that LAZ3 rearrangements occur in a significant fraction of de novo DAL as well as in a smaller subset of indolent and transformed follicular lymphomas; (2) that LAZ3 message is expressed in both rearranged and nonrearranged B-cell lymphomas; and (3) that mutation of the LAZ3 gene does not contribute to its putative oncogenic role in most 3q27 translocated B-cell lymphomas.
Structural alterations of the 5' noncoding region of the BCL-6 gene have been found in 40% of diffuse large cell lymphoma (DLCL) and 5% to 10% of follicular lymphomas (FL), suggesting that deregulated BCL-6 expression may play a role in lymphomagenesis. Nucleotide sequencing of BCL-6 cDNA predicted a protein containing six zinc-finger domains, suggesting that it may function as a transcription factor. Using antisera raised against N- and C-terminal BCL-6 synthetic oligopeptides in immunoprecipitation, immunoblot, and immunocytochemical assays, this study identifies the BCL-6 gene product as a 95-kD nuclear protein. Western blot analysis of human tumor cell lines representative of various hematopoietic lineages/stages of differentiation showed that the BCL-6 protein is predominantly expressed in the B-cell lineage where it was found in mature B cells. Immunohistochemical analysis of normal human lymphoid tissues indicated that BCL-6 expression is topographically restricted to germinal centers including all centroblasts and centrocytes. The BCL-6 protein was also detectable in inter- and intra-follicular CD4+ T cells, but not in other follicular components including mantle-zone B cells, plasma cells, dendritic cells, and macrophages. Immunohistochemical analysis of DLCL and FL biopsy samples showed that the BCL-6 protein is detectable in these tumors independent of the presence of BCL-6 gene rearrangements. These results indicate that the expression of the BCL-6 gene is specifically regulated during B-cell differentiation and suggest a role for BCL-6 in germinal center development or function. Because DLCL derive from germinal-center B cells, deregulated BCL-6 expression may contribute to lymphomagenesis by preventing postgerminal center differentiation.
The pathogenesis of non-Hodgkin's lymphoma (NHL) with a large cell component (DLLC, including diffuse large cell, DLCL; diffuse mixed cell, MX-D; and immunoblastic, IMB) is unknown. A novel candidate proto-oncogene, BCL6, that is involved in chromosome band 3q27 aberrations in NHL has been recently identified. We have investigated the incidence and disease-specificity of BCL6 rearrangements in a large panel of lymphoid tumors, including acute and chronic lymphoid leukemias (96 cases), various NHL types (125 cases), and multiple myelomas (23 cases). BCL6 rearrangements were found in 16/45 (35.5%) DLLC, more frequently in DLCL (15/33, 45%) than in MX-D (1/10, 10%), in 2/31 (6.4%) follicular NHL, and in no other tumor types. BCL6 rearrangements represent the first genetic lesion specifically and recurrently associated with DLLC and should prove useful for understanding the pathogenesis as well as for the clinical monitoring of these tumors.
We have recently shown that an evolutionary conserved gene LAZ3, encoding a zinc finger protein, is disrupted and overexpressed in some B-cell lymphomas (mainly with a large cell component) that show chromosomal rearrangements involving 3q27. Because the breakpoints involved in these rearrangements are focused in a narrow major translocation cluster (MTC) on chromosome 3, we used genomic probes from this region to study the molecular rearrangements of LAZ3 in a large series of patients (217) with non-Hodgkin's lymphoma (NHL). Southern blot analysis showed LAZ3 rearrangement in 43 patients (19.8%). Rearrangement was found in 11 of the 84 patients (13%) with follicular lymphoma but was most frequent in aggressive lymphoma (diffuse mixed, diffuse large cell, and large cell immunoblastic subtypes), in which 31 of the 114 patients (27%) were affected. The highest proportion of LAZ3 alteration was observed in B-cell aggressive lymphoma (26 of 71 cases, 37%). Eleven of the 32 patients with 3q27 chromosomal abnormality had no LAZ3 rearrangement, suggesting the possibility of LAZ3 involvement outside the MTC. On the other hand, 18 of the 39 patients with LAZ3 rearrangement and available cytogenetic results did not have visible chromosomal break at 3q27, suggesting that almost a half of the rearrangements are not detectable by cytogenetic methods. No statistical association could be found between LAZ3 status and initial features of the disease or clinical outcome in either follicular or aggressive lymphomas. We conclude that LAZ3 alteration is a relatively frequent event in B-cell lymphoma, especially in those of aggressive histology. It could be used as a genomic marker of the disease, and further studies are needed to clarify clinical implications of these alterations.
The molecular pathogenesis of diffuse large-cell lymphoma (DLCL), the most frequent and clinically relevant type of lymphoma,
is unknown. A gene was cloned from chromosomal translocations affecting band 3q27, which are common in DLCL. This gene, BCL-6,
codes for a 79-kilodalton protein that is homologous with zinc finger-transcription factors. In 33 percent (13 of 39) of DLCL
samples, but not in other types of lymphoid malignancies, the BCL-6 gene is truncated within its 5' noncoding sequences, suggesting
that its expression is deregulated. Thus, BCL-6 may be a proto-oncogene specifically involved in the pathogenesis of DLCL.
The majority of low-grade non-Hodgkin's lymphomas (NHL) undergo clinical progression toward intermediate- and high-grade lymphomas. This progression is often associated with histologic transformation from follicular to diffuse-type NHL. The pathogenetic mechanisms underlying this evolution are presently unknown. In this study, we have analyzed the role in NHL progression of relevant genetic lesions affecting proto-oncogenes and tumor suppressor genes. Sequential biopsies from 21 patients with clinical progression with (5 cases) or without (16 cases) evidence of histologic transformation were analyzed for karyotypic changes, c-myc rearrangements and deletions affecting 6q27 by Southern blot analysis, and p53 mutations by single-strand conformation polymorphism (SSCP) analysis coupled with direct sequencing of polymerase chain reaction-amplified products. No novel cytogenetic aberration was detected in association with progression, and all samples analyzed displayed a normal c-myc gene. Mutations of the p53 gene were detected in 4 of 5 cases displaying histologic transformation from follicular to diffuse-type NHL and in none of the 16 cases displaying clinical progression in the absence of histologic transformation. In 1 of these positive cases, the same mutation was also present in the pretransformation biopsy, correlating with the presence of diffuse-type areas within a predominant follicular pattern. In 1 of these cases, a deletion of 6q27 was also detected in the posttransformation biopsy along with a p53 mutation. These findings indicate that p53 mutations are associated with and may be responsible for histologic transformation of follicular lymphoma.
We have recently shown that an evolutionary conserved gene LAZ3, encoding a zinc finger protein, is disrupted and overexpressed in some B-cell lymphomas (mainly with a large cell component) that show chromosomal rearrangements involving 3q27. Because the breakpoints involved in these rearrangements are focused in a narrow major translocation cluster (MTC) on chromosome 3, we used genomic probes from this region to study the molecular rearrangements of LAZ3 in a large series of patients (217) with non-Hodgkin's lymphoma (NHL). Southern blot analysis showed LAZ3 rearrangement in 43 patients (19.8%). Rearrangement was found in 11 of the 84 patients (13%) with follicular lymphoma but was most frequent in aggressive lymphoma (diffuse mixed, diffuse large cell, and large cell immunoblastic subtypes), in which 31 of the 114 patients (27%) were affected. The highest proportion of LAZ3 alteration was observed in B-cell aggressive lymphoma (26 of 71 cases, 37%). Eleven of the 32 patients with 3q27 chromosomal abnormality had no LAZ3 rearrangement, suggesting the possibility of LAZ3 involvement outside the MTC. On the other hand, 18 of the 39 patients with LAZ3 rearrangement and available cytogenetic results did not have visible chromosomal break at 3q27, suggesting that almost a half of the rearrangements are not detectable by cytogenetic methods. No statistical association could be found between LAZ3 status and initial features of the disease or clinical outcome in either follicular or aggressive lymphomas. We conclude that LAZ3 alteration is a relatively frequent event in B-cell lymphoma, especially in those of aggressive histology. It could be used as a genomic marker of the disease, and further studies are needed to clarify clinical implications of these alterations.
The BCL-6 gene is known to be located on chromosome 3q27, at the breakpoint of the 3q27-associated translocations that occur frequently in human non-Hodgkin's lymphomas (NHLs). To identify the BCL-6 protein, two antibodies that recognized distinct domains of this protein were raised in rabbits. Immunoprecipitation and immunoblotting of lysates of BCL-6-expressing cells using both antibodies showed a broad 92- to 98- kD band. Dephosphorylation of BCL-6 protein reduced the size of this band to 87 kD, suggesting that BCL-6 may be expressed in a phosphorylated form. Immunostaining with both antibodies showed that BCL-6 protein was localized in the nuclei of most of the germinal center B cells and a small number of marginal zone B cells. Furthermore, BCL-6 protein was expressed in follicular, Burkitt's, and diffuse large B-cell lymphomas. These results suggest that the BCL-6 protein, expressed in B cells of the germinal centers which are important in the maturation of immune responses, may play some physiological role(s) in the germinal center B cells.
An international multi-institutional clinicopathologic study of 1175 cases of non-Hodgkin's lymphoma sponsored by the National Cancer Institute has been completed. Histologic slides and clinical records were examined from previously untreated patients seen during the period between July 1971 and December 1975 at four institutions, three in the United States and one in Italy. The reproducibility and clinical relevance of the six major classifications of the non-Hodgkin's lymphomas was tested by six “expert” pathologists, each a proponent of a major classification, and six very experienced pathologists not identified with one of the major classifications. Immunologic methods were not employed in the study design. A summary of the methods employed and the conclusions of the study is described. The major conclusion was that all six classifications were valuable and comparable in reproducibility and clinical correlations. The clinical significance of a follicular architecture, independent of cell type was confirmed. A working formulation of non-Hodgkin's lymphomas is described which separates the disease into ten major types utilizing morphologic criteria only. Subtypes are also described which allow translation of all of the major classifications into comparable groups. Histologic criteria are presented for each major type and equivalent terms are given for each type in the six major classifications. The formulation is not proposed as a new classification but a means of translation among the various systems and to facilitate clinical comparisons of case reports and therapeutic trials. The report contains commentaries by five of the “expert” pathologists on the value and conclusions of this unique study.
We studied 69 cases of malignant lymphoma of the testis, epididymis, and spermatic cord, including 64 cases in which the tumor involved these sites at presentation and five cases in which lymphoma relapsed in the testis. The patients without prior lymphoma were 16 to 91 (mean, 56) years old. Fifty-two patients had diffuse large-cell lymphomas [seven large cleaved cell (two with follicular areas), 27 large noncleaved, two multilobated, six not otherwise specified (NOS), 10 immunoblastic]; six, small noncleaved cell; two, diffuse mixed small and large cell; one, diffuse small cleaved; one, follicular mixed small cleaved and large cell; and two, high grade, unclassified in the Working Formulation. Twenty-nine cases (55%) were stage I; five (9%), stage II; one (2%), stage III, and 18 (34%), stage IV. Forty patients (73%) achieved a complete remission; 23 had a relapse of tumor at 4 to 274 months (median, 13) and five were salvaged. At last follow-up, 20 (36%) patients were free of disease, six (11%) were alive with disease, and 29 (53%) had died of lymphoma. Features associated with longer disease-free actuarial survival (DFS) included stage I disease (p = 0.0001) and sclerosis (p = 0.0001). Among patients with stage I lymphoma, those with right-sided tumors (p = 0.005) or tumors with sclerosis (p = 0.0017) had longer DFS. Lymphomas with extensive sclerosis were all stage I (p = 0.0057). Four of five patients with secondary testicular lymphoma had extranodal primary sites. They ranged from 13 to 66 years (median, 35). Testicular relapses occurred 13-37 months after initial diagnosis. Three had diffuse large, noncleaved cell type; one, lymphoblastic and one, diffuse mixed small and large cell. Immunophenotyping showed B lineage in 33 cases and T lineage in one case. Most testicular lymphomas are B-lin-eage large-cell lymphomas, which frequently involve other extranodal sites at presentation and at relapse, and which often have an aggressive clinical course.
PurposeThe initial management of stage I nonHodgkin's lymphoma of the testis is by orchiectomy but the role and efficacy of adjuvant strategies are uncertain. We reviewed cases of lymphoma at our institution to determine whether adjuvant treatment was beneficial.Materials and MethodsA retrospective review of outcome was conducted on 26 patients who presented to our institution. Median followup for the group was 54 months. Kaplan-Meier actuarial analyses were performed on the entire group and subsets.ResultsActuarial 5 and 10-year overall survival rates were 79 percent and 63 percent, and relapse-free survival rates were 61 percent and 46 percent, respectively. In patients who received adjuvant combination chemotherapy the 5-year relapse-free survival rate improved (75 percent versus 50 percent) but effect did not achieve statistical significance and was lost by 10 years. No relapse-free survival advantage was noted for patients receiving adjuvant irradiation to the pelvic and para-aortic nodes. Patients who did not receive irradiation remained free of isolated relapses in the pelvic or para-aortic regions.Conclusions
These data lend support to the use of adjuvant chemotherapy but do not support a role for adjuvant nodal irradiation.
The LAZ3 gene encodes a novel zinc-finger protein that shares homology with several Drosophila transcription factors. This gene was identified by its disruption in translocations involving chromosome 3q27 in diffuse large-cell lymphomas. To assess the frequency and role of this gene's involvement in lymphomagenesis and tumor progression, we examined a series of 170 cases of non-Hodgkin's lymphomas of B-cell lineage for LAZ3 gene rearrangement, expression, and mutation. The cases included 35 de novo diffuse aggressive lymphomas (DAL; 19 large-cell, 4 mixed-cell, and 12 large-cell immunoblastic), 52 transformed aggressive lymphomas derived from follicular lymphomas (TFL), 42 indolent follicular lymphomas (FL), 14 mantle cell lymphomas (MCL), and 27 small noncleaved cell lymphomas (SNCL). LAZ3 rearrangements were found in 10 DAL (28.6%), 9 TFL (17.3%), and 6 FL (14.3%), but not in any of the SNCL or MCL. LAZ3 rearrangement was not exclusive of bcl-2 rearrangement. Most rearrangement breakpoints mapped to a 10-kb BamHI-Xba I fragment located 5′ to the LAZ3 coding sequence, consistent with previously reported breakpoint locations. Northern analysis of both rearranged and nonrearranged B-cell lymphoma cases showed similar levels of a transcript of approximately 3.8 kb, indicating that LAZ3 is broadly expressed in B-cell tumors and is not confined to rearranged cases. To investigate whether mutation of the LAZ3 gene might contribute to a potential role for this gene in lymphomagenesis, we screened the coding sequences of 13 rearranged cases, 6 nonrearranged cases, and 13 hematopoietic tumor cell lines. Although three probable polymorphisms were identified, mutations were detected in only 2 rearranged cases. Only 1 of these resulted in an amino acid substitution. Two cell lines (SU-DHL4 and Molt-4) also contained mutations; only one resulted in an amino acid substitution. We conclude (1) that LAZ3 rearrangements occur in a significant fraction of de novo DAL as well as in a smaller subset of indolent and transformed follicular lymphomas; (2) that LAZ3 message is expressed in both rearranged and nonrearranged B-cell lymphomas; and (3) that mutation of the LAZ3 gene does not contribute to its putative oncogenic role in most 3q27 translocated B-cell lymphomas.
The clinical and histopathological findings in 26 children with non-Hodgkin's lymphoma without initial marrow involvement are reviewed. A marked male predominance similar to that observed in previous series was noted. Biopsy material was classified according to the recommendations of Rappaport in 22 cases. All have diffuse lymphomas, and 16 of 22 patients had diffuse, poorly-differentiated, lymphocytic lymphoma. Twelve of 26 patients had involvement of the mediastinum as part of their initial presentation. Of these 12, 5 developed lymphomatous involvement of the central nervous system prior to the development of leukemic transformation of the bone marrow. This observation suggests that prophylactic therapy against CNS relapse be considered for children with mediastinal non-Hodgkin's lymphoma, even in the absence of initial marrow involvement.
A series of 1,467 Caucasian patients with non-disseminated lymphomas of extranodal origin was taken from data collected by the End Results Group of cancer registries in the years 1950-1964. Excluding Hodgkin's disease, about one fourth of the lymphomas reported arose in sites other than lymph nodes. Survival rates and distributions are listed for site of origin, major histologic types, sex, age, and extent of disease. For the more frequently reported sites, survival rates are given according to the type of initial treatment used. The prognosis of patients with extranodal lymphomas is compared with that for “all cancers” of the same site, and the lymphoma patients appear to fare appreciably better when the site of origin is stomach, lung, or tonsil.
The pathologic and clinical features of 31 cases of childhood non-Hodgkin's lymphoma (NHL) were reviewed retrospectively using Rappaport's classification and a modification of the Ann Arbor staging system. Twenty-nine (93.5%) of the patients had diffuse and 2 (6.5%) had nodular lymphoma. Diffuse histiocytic lymphoma accounted for 10 cases (32.3%), diffuse undifferentiated for 9 (29%), and diffuse lymphocytic, poorly differentiated for 5 (16.1%). Five cases (16.1%) were unclassifiable. No cases of well-differentiated lymphocytic or mixed cell lymphoma were found. A modified classification was attempted, which included also large basophilic cell (LBC), convoluted T-lymphocytic (CTL), and Burkitt's lymphomas. These pathologic subgroups accounted for 35.4%, 16.1%, and 6.5% of the cases, respectively. The patients were almost equally divided between clinically localized and generalized stages, and their survival was stage-dependent. The overall survival was 32.3%; the 3-year survival was 50% for Stages I and II, compared to 7.7% for Stages III and IV. The gastrointestinal tract was the most common site of origin. In 22% of the cases, the disease originated in extra-lymphatic tissues. Central nervous system involvement occurred in 10 of 31 children (32%), and a leukemic picture developed in 6 of 31 (19%). The CTL lymphomas were confined to the mediastinum, whereas the LBC lymphomas arose mostly in Waldeyer's ring and Peyer's patches. We conclude that the extent of the disease as determined by clinical staging has prognostic significance in childhood NHL. The prognostic value of the histological classification could not be clearly established from our data.
Thesis (M. S. in Urology) - Univ. of Minnesota. Xerox copy.
Thirty patients under 20 years of age with non-Hodgkin's lymphoma, with nodal and extranodal involvement, were reviewed retrospectively according to Rappaport's classification. All cases had a diffuse histologic pattern. There were 10 patients with lymphoblastic lymphoma (nine with convoluted nuclei and one with non-convoluted nuclei), 10 with Burkitt's lymphoma, six with undifferentiated lymphoma, and four with histiocytic lymphoma. Histochemistry was done in 28 cases, and electron microscopy in three. Twenty-four patients were male and six were female; ages at presentation ranged from 3 to 19 years. Nine patients with lymphoblastic lymphoma (with convoluted nuclei) and two with Burkitt's lymphoma had a mediastinal mass at diagnosis. Three patients with Burkitt's lymphoma and one with undifferentiated lymphoma had bone marrow involvement initially. Leukemic transformation occurred in four patients with lymphoblastic lymphoma within a year of diagnosis. Initial treatment included radiotherapy alone in three patients, chemotherapy alone in three patients, and combined radiotherapy and chemotherapy in 24 patients. Thirteen patients have died at 2 to 52 months from diagnosis: five of 10 with lymphoblastic lymphoma, three of 10 with Burkitt's lymphoma, four of six with undifferentiated lymphoma, and one of four with histiocytic lymphoma. Our findings suggest that in this patient population, non-Hodgkin's lymphoma can be classified using Rappaport's criteria and that malignant lymphomas of the lymphoblastic type and undifferentiated lymphoma seem to have the worst prognosis.
A clinical analysis was made of 556 prepubertal children with testis tumors. Germinal tumors comprised 76 per cent of this group, and the most common of these tumors was the yolk sac carcinoma. Although many appellations have been used to describe this tumor, experimental and clinical evidence support the use of this term. The over-all two-year survival was 72 per cent and was better in children less than two years of age. The tumor is distinctly different from the embryonal carcinoma of the adult. The role of lymphadenectomy needs to be reassessed in view of the low incidence of lymph node metastases and the propensity for pulmonary metastases. Chemotherapy appears to be of benefit. Tumor markers, particularly alpha-fetoprotein, may be of assistance in planning therapy.The other germinal tumor is the teratoma. This is a benign, nonmetastasizing disease in children and requires only orchiectomy.Nongerminal tumors comprised 24 per cent of tumors and require only orchiectomy. Sertoli cell tumors are rare, and there has been only one report of metastatic disease. Leydig cell tumors present with endocrine manifestations and are benign in children. They may be difficult to distinguish from tumors associated with congenital adrenal hyperplasia.Rhabdomyosarcomas should be treated with a combination of surgery, chemotherapy, and radiation. The over-all survival of 74 per cent for these patients indicates the benefits of aggressive therapy.
Eight cases of follicular lymphoma (FL) were found amount 318 children with non-Hodgkin's lymphoma seen in two decades in four large institutions (overall incidence: 2.5%). The children's ages ranged from 3 to 13 years (median 8). Four patients presented with localized peripheral lymphadenopathy, two with tumors of the digestive tract, two with disseminated disease. Five were tentatively classified as stage I or II and 3 as stage IV. The existence of other diseases responsible for lymphadenopathy could satisfactorily be exclued. All patients are alive after follow-up periods of 1 to 14 years from diagnosis (median 4). Morphologically, 5 lymphomas were mixed and 3 histiocytic. The growth pattern was "expansile" in the younger patients (3 to 9 years), and "infiltrative," as in the adult disease, in the three older children (11 to 13 years). The histiocytic cytology correlated with stage IV disease. FL in children appears to be different from both its adult counterpart and the diffuse childhood lymphomas. Differences with the former include the absence of tumors of poorly differentiated lymphocytic type, the higher frequency of stage I-II disease and the better prognosis. This last feature, as well as the higher frequency of peripheral node involvement and the absence of leukemic conversion or CNS disease, differentiates the follicular from the diffuse childhood lymphomas.
One hundred twenty two children with non-Hodgkin's lymphoma were studied from January 1966 to December 1975. The first group (1966-1972) did not receive an uniform treatment. The second group (1973-1975) entered in a G.A.T.L.A. protocol consisting of: vincristine-prednisone plus surgery and/or radiotherapy as induction treatment, craniocervical radiotherapy and intrathecal methotrexate as CNS preventive treatment and anti-leukemia (6-mercaptopurine, methotrexate and vincristine-prednisone pulses) or anti-lymphoma (COPP) treatment as maintenance, in a randomized trial. Comparison of survival of the two groups are as follows: series 1966-1972, 22% and 20% at 12 and 24 months of evolution, respectively, and series 1973-1975, 33% and 26% at 12 and 24 months, respectively. After 2 years of complete remission we have not seen any relapse. We conclude that 1) this disease is highly malignant and must be treated with more intensive chemotherapeutic treatment, and 2) there is no difference between antileukemia or anti-lymphoma maintenance treatment, as yet.
A 12-year-old boy with primary reticulum cell sarcoma of the testis who is alive and free of tumor 32 months after orchiectomy, radiation therapy to inguinal, iliac and retroperitoneal lymph nodes and chemotherapy is reported. Seven previously documented cases of childhood primary testicular lymphoma are reviewed. The patient with reticulum cell and one with lymphosarcoma were alive and tumor-free 4 and 18 months respectively. The other 5 with primary testicular lymphosarcoma died. Four survived for periods up to 1 year, 3 developing generalized lymphosarcoma and 1 leukemia. The fifth was tumor-free for 4 years and developed leukemia 2 weeks before death. The small number of cases precludes evaluation of survival in relation to various modes of therapy. Primary lymphoma of testis, no evidence of lymphoma elsewhere at time of orchiectomy, does exist. Its relatively benign biologic behavior in some remains an enigma.
The pathologic and clinical features of 31 cases of childhood non-Hodgkin's lymphoma (NHL) were reviewed retrospectively using Rappaport's classification and a modification of the Ann Arbor staging system. Twenty-nine (93.5%) of the patients had diffuse and 2 (6.5%) had nodular lymphoma. Diffuse histiocytic lymphoma accounted for 10 cases (32.3%), diffuse undifferentiated for 9 (29%), and diffuse lymphocytic, poorly differentiated for 5 (16.1%). Five cases (16.1%) were unclassifiable. No cases of well-differenitated lymphocytic or mixed cell lymphoma were found. A modified classification was attempted, which included also large basophilic cell (LBC), convoluted T-lymphocytic (CTL), and Burkitt's lymphomas. These pathologic subgroups accounted for 35.4%, 16.1%, and 6.5% of the cases, respectively. The patients were almost equally divided between clinically localized and generalized stages, and their survival was stage-dependent. The overall survival was 32.3%; the 3-year survival was 50% for Stages I and II, compared to 7.7% for Stages III and IV. The gastrointestinal tract was the most common site of origin. In 22% of the cases, the disease originated in extra-lymphatic tissues. Central nervous syste, involvement occurred in 10 of 31 children (32%), and a leukemic picture developed in 6 of 31 (19%). The Ctl lymphomas were confined to the mediastinum, whereas the LBC lymphomas arose mostly in Waldeyer's ring and Peyer's patches. We conclude that the extent of the disease as determined by clinical staging had prognostic significance in childhood NHL. The prognostic value of the histological classification could not be clearly established from our data.
The clinical and histopathological findings in 26 children with non-Hodgkin's lymphoma without initial marrow involvement are reviewed. A marked male predominance similar to that observed in previous series was noted. Biopsy material was classified according to the recommendations of Rappaport in 22 cases. All have diffuse lymphomas, and 16 of 22 patients had involvement of the mediastinum as part of their initial presentation. Of these 12, 5 developed lymphomatous involvement of the central nervous system prior to the development of leukemic transformation of the bone marrow. This observation suggests that prophylactic therapy against CNS relapse be considered for children with mediastinal non-Hodgkin's lymphoma, even in the absence of initial marrow involvement.
The Bcl-2 proto-oncogene was discovered at the t(14;18) breakpoint found in most follicular B-cell lymphomas and some diffuse large-cell lymphomas. Bcl-2 is unique among proto-oncogenes, being localized to mitochondria and extending cell survival by blocking programmed cell death. We examined Bcl-2 protein expression in 82 hematologic malignancies and reactive lymphoid processes. All lymphomas with Bcl-2 rearrangement demonstrated high levels of Bcl-2 protein. However, most follicular and diffuse lymphomas without Bcl-2 rearrangement also displayed intense Bcl-2 staining. In these cases, mechanisms other than classic translocation may be deregulation Bcl-2. The pattern of Bcl-2 staining in follicular lymphoma is the inverse of the pattern in reactive hyperplasia, confirming a role for Bcl-2 immunolocalization in routine diagnosis. Small lymphocytic malignancies, including small lymphocytic lymphoma, mantle zone lymphoma, and chronic lymphocytic leukemia, expressed intermediate levels of Bcl-2. Bcl-2 protein varied in plasma cell dyscrasias. Bcl-2 protein levels in T-cell lymphomas reflected their corresponding stage of development. No substantial Bcl-2 was present in the Reed-Sternberg cells of nodular sclerosing Hodgkin's disease. Chronic myelogenous leukemia was strongly positive for Bcl-2, consistent with the presence of Bcl-2 in normal myeloid progenitors. Immunohistochemistry identified an expanded spectrum of hematopoietic neoplasms in which Bcl-2 may provide a cell survival advantage.
Testicular tumours are rare in childhood. The clinical, pathological and follow-up details of 48 children are presented. The combined approach of surgery, chemotherapy and radiotherapy is confirmed as being extremely effective. Transcrotal orchiectomy is not an appropriate surgical procedure. Testicular biopsy is detrimental to prognosis.
The clinicopathologic features of twenty cases of follicular lymphoma (FL) in pediatric patients are described. Fifteen boys and five girls were 2 to 20 yr (mean 10 yr) of age at diagnosis. In ten cases (50%) the lymphoma was localized in lymph nodes and in ten cases (50%) in extranodal sites. Fifteen patients had stage I, two stage II and three stage III disease at the time of presentation. The faucial tonsils were the primary site in seven cases, other head and neck sites in five, inguinal lymph nodes in four and possibly another, and the abdomen in two. Six cases (30%) were classified as follicular small cleaved cell type (FSCC), five (25%) as follicular mixed small cleaved and large cell (FMC), and nine (45%) as follicular large cell (FLC). The architectural pattern was purely follicular (F) in five cases (20%), predominantly follicular (F greater than D) in six (30%), follicular and diffuse (F = D) in six (30%) and predominantly diffuse (F less than D) in three (15%). In one case a progression from F greater than D LC to F less than D LC was documented. All patients attained complete remission (CR). One died of acute lymphoblastic leukemia 7 yr after the original diagnosis of FSCC non-Hodgkin's lymphoma (NHL), but the others are all alive and free of disease with a follow-up ranging from 6 mo to 16 yr (median 4 yr). In three patients therapy was initially deferred with no known adverse influence on outcome.(ABSTRACT TRUNCATED AT 250 WORDS)
Among 131 boys with advanced (stage III or IV) non-Hodgkin's lymphoma (NHL) consecutively treated at St. Jude Children's Research Hospital, testicular involvement was present at the time of diagnosis in six and as an isolated site of relapse in three. Testicular involvement was not seen in any patient with localized (stage I or II) disease. Four of the six patients with involvement at presentation are free of disease 2.9+ to 8.3+ years after diagnosis, following chemotherapy alone (three patients) or chemotherapy plus orchiectomy. Overt testicular relapse while on therapy resulted in death from progressive disease in two patients; the third relapsed after completing therapy for Burkitt's lymphoma and is in second remission after chemotherapy, orchiectomy, and scrotal irradiation. The prolonged remissions seen in children with testicular involvement at diagnosis suggest that scrotal irradiation may not be necessary in chemosensitive disease. By contrast, testicular relapse on therapy appears to indicate drug-resistant disease and a poor prognosis, despite testicular irradiation and chemotherapy.
Between 1962 and 1986, a total of 338 consecutive newly diagnosed children and adolescents with non-Hodgkin's lymphomas (NHLs) were evaluated and treated at St Jude Children's Research Hospital (SJCRH). Median follow-up is 6.6 years (range, 1.8 to 23 years). The patients ranged in age from 7 months to 21 years (median, 10 years), and 71% were males. All cases were staged (I to IV) by a clinical staging system. Eighteen percent were stage I, 21% stage II, 43% stage III, and 18% stage IV. Cases frankly leukemic at diagnosis (ie, greater than 25% marrow blasts) were excluded from the analysis. Pathologic material from all cases was reviewed and classified according to the Working Formulation. The histologic distribution of cases was as follows: 38.8% diffuse small non-cleaved cell (undifferentiated, Burkitt's and non-Burkitt's); 26.3% diffuse large-cell, mainly immunoblastic; 28.1% lymphoblastic; and 6.8% other. Treatment policy evolved over time to a stage- and histology-specific strategy for treatment assignment, and overall results significantly improved by era from 37% (+/- 5%) 2-year event-free survival (EFS) for patients treated before 1975 to 77% (+/- 4%) since 1978. By univariate and multivariate Cox regression analyses, the era of treatment (hence, the protocol-specific treatment itself), the stage, and the log of the initial serum lactic dehydrogenase (LDH) emerged as the most powerful prognostic indicators, while histology per se was not significantly related to outcome. For the 154 patients treated since 1978, the 2-year EFS by stage was 97% (+/- 3%) for stage I, 86% (+/- 6%) for stage II, 73% (+/- 6%) for stage III, and 47% (+/- 11%) for stage IV (P less than .0001). Compared with our previous experience, we conclude that the cure rate of childhood NHL has doubled in the last decade with modern management.
For many non-Hodgkin's lymphomas, the bcl-2 gene has been implicated as a likely proto-oncogene, since it is consistently located at or near the breakpoint sites of t(14;18) chromosomal translocations. To define the role of the protein product of the bcl-2 gene in lymphoid cancers, we used anti-bcl-2 antibodies to perform immunohistochemical studies of frozen sections of 136 tissue specimens affected by lymphoma or non-neoplastic lymphoid disorders. Immunoreactive bcl-2 protein was observed in the neoplastic cells in almost all the follicular lymphomas, whereas no bcl-2 protein was detected in follicles affected by non-neoplastic processes or in normal lymphoid tissue. Every tumor with molecular-genetic evidence of t(14;18) translocation expressed detectable levels of bcl-2 protein, regardless of whether the breakpoint was located in or at a distance from the bcl-2 gene. These data show consistent expression of a proto-oncogenic protein in a large proportion of non-Hodgkin's lymphomas and provide further support of a role for bcl-2 in the pathogenesis of all lymphomas with the t(14;18) karyotypic abnormality. Increased expression of bcl-2 after t(14;18) translocations may be a specific marker for B-cell cancers, and demonstration of the protein with use of anti-bcl-2 antibodies could be useful in the diagnosis of many non-Hodgkin's lymphomas.
Malignant lymphomas of the testis account for approximately 5 percent of testicular neoplasms, and they are the most common testicular malignancy between the ages of 60 and 80. Testicular lymphoma has a propensity to be associated with involvement of the skin, the central nervous system, Waldeyer's ring and adjacent structures, and the contralateral testicle. In general, essentially all patients with testicular lymphoma have been categorized as having "poor-risk" non-Hodgkin's lymphoma, with diffuse histiocytic lymphoma being the most common histologic subtype. All patients with testicular lymphoma should be treated with aggressive combination chemotherapy, with or without radiotherapy.
Several steps in the clinical evolution of human neoplasia are associated with a variety of recurrent chromosomal defects that could prove essential to the understanding of cancer. We found 15 types of nonrandom chromosomal abnormalities in a study of 71 patients with follicular lymphoma; 10 of the types appeared to influence the histopathological findings, clinical course, or response to treatment. A translocation, t(14;18), observed in 85 percent of all patients appeared to be the main determinant of a follicular pattern. Ten patients with a t(14;18) as a single defect had the histologic features of follicular small cleaved-cell lymphoma. Most did not require treatment for one to four years, because their tumors had an initial indolent course. In contrast, patients with follicular small cleaved-cell lymphoma with t(14;18) and deletion 13q32 acquired the hematologic features of leukemia and had an acceleration of the disease. A deletion 6q together with a complete or partial trisomy 7 or trisomy 12 (or both) was associated with the clinically more aggressive follicular mixed small- and large-cell or large-cell histologic type, which often evolves from follicular small-cell lymphoma. A complete or partial trisomy 3, 18, or 21 correlated almost exclusively with follicular large-cell lymphoma. In all follicular stages, a trisomy 2 or duplication 2p often accompanied an accelerated clinical course and a poor response to treatment. This study suggests that several discrete genomic defects may govern the evolution of a patient's malignant disease.
A retrospective study was undertaken reviewing records of all children seen in the Division of Radiation Therapy at Stanford University Hospital between 1961 and 1971 with a diagnosis of non-Hodgkin's lymphoma. Of 41 patients who had been originally diagnosed as having a non-Hodgkin's lymphoma, a diagnosis was confirmed in only 32. Two cases were interpreted as malignant histiocytosis, and 7 other patients were diagnosed as having Hodgkin's disease. Of the 32 patients with a non-Hodgkin's lymphoma, all but 1 had lymphoma of the diffuse type, with diffuse histiocytic lymphoma being the most common histologic diagnosis. Lymphangiography was attempted in all but 1 patient. Fifty-five percent of Stage I patients and 38% of Stage II patients are alive and free of disease more than 2 years after the completion of radiation therapy alone. There were no relapses seen after 12 months. Bone marrow involvement was seen in 5 patients at presentation and developed in an additional 8 patients following the initiation of radiation therapy.
Twelve patients who developed non-Hodgkin's lymphoma with a follicular pattern during the first two decades of life were studied. Eight had the poorly differentiated lymphocytic type; the remaining four had the "histiocytic" type. Eleven of the 12 patients were male. Nine were asymptomatic, and eight had lymphadenopathy in the head and neck region. Comparison of ages revealed the extent of disease tended to be localized (Stages I and II) in the pediatric (less than 16 years old) patients (83%) and generalized in the adolescent-young adult (16-19 years old) patients (83%). Of ten patients treated with chemotherapy and/or radiotherapy, eight achieved complete remissions that lasted 3-58 months (median, 17.5 months). Five are still in remission; three have relapsed. Seven are alive 12-120 months from diagnosis (median, 48 months); six have no clinical evidence of disease. The remaining five patients died two to 164 months after diagnosis (median, 13 months). Three of the four patients who died with lymphoma had diffuse "histiocytic" lymphoma demonstrated at autopsy examination. Poor prognostic factors included 1) failure to achieve a complete remission following initial therapy; 2) extranodal disease (with the exception of the poorly differentiated lymphocytic type involving the spleen and liver); 3) development of diffuse "histiocytic" lymphoma. Follicular lymphoma occurring in the second decade of life has a biologic behavior similar to follicular lymphoma in adults.
Using a new high-resolution technique for chromosomal analysis, we have successfully studied biopsy specimens of lymph nodes from 42 of 44 patients with non-Hodgkin's lymphoma and have categorized them using the new international histologic formulation and immunologic markers. Abnormalities of the clonal chromosomes were detected in all 42 patients. Three recurrent chromosomal aberrations were found to correlate with certain histologic types: a translocation between chromosomes 18 and 14 in 16 of 19 patients with follicular lymphomas (small cleaved cell, mixed cell, and large cell); a translocation between chromosomes 8 and 14 in 5 of 6 patients with small noncleaved-cell (non-Burkitt's) or large-cell immunoblastic lymphoma; and a trisomy 12 in 4 of 11 patients with small-cell lymphocytic lymphoma. Our findings suggest that characteristic chromosomal defects occur in certain lymphoma subtypes and that high-resolution chromosomal analysis promises to become an important tool in improving our basic understanding of lymphoid cancers.
This study was undertaken to compare the ability of cytogenetic analysis (CG), Southern analysis (SA) and the polymerase chain reaction (PCR) to detect the t(14; 18) in follicular lymphoma (FL). All methodologies were performed by standard techniques. The probes used for SA included major breakpoint region (mbr) and minor cluster region (mcr) probes. The primers for PCR were identical or similar to those used by other investigators.
One hundred fifteen cases of FL were ascertained by morphologic criteria, from which sufficient fresh tissue was available for both CG and molecular analysis. Eleven cases failed by both methods (nonrepresentative sampling). One hundred four cases showed evidence of an abnormal clone by CG and/or immunoglobulin gene rearrangement (IgH) studies. Cytogenetic analysis failed in 2 cases, was positive for t(14; 18) in 91 of the remaining 102 cases (89%) and detected a non-t(14;18) close in 11 cases. An IgH clonal rearrangement was confirmed in all 104 cases. Southern analysis detected a mbr or mcr rearrangement in 78 of 104 cases (75%). Polymerase chain reaction detected an mbr or mcr rearrangement in 68 of 104 cases (65%).
The use of PCR as a clinical test to detect t(14;18) -positive lymphomas, with single primer sets for the mbr and mcr, will result in a high false-negative rate. The use of additional primers to detect uncommon breakpoints sites will be required to enhance the sensitivity of PCR for detection of t(14;18) in malignant lymphoma.
The BCL-6 gene is known to be located on chromosome 3q27, at the breakpoint of the 3q27-associated translocations that occur frequently in human non-Hodgkin's lymphomas (NHLs). To identify the BCL-6 protein, two antibodies that recognized distinct domains of this protein were raised in rabbits. Immunoprecipitation and immunoblotting of lysates of BCL-6-expressing cells using both antibodies showed a broad 92- to 98-kD band. Dephosphorylation of BCL-6 protein reduced the size of this band to 87 kD, suggesting that BCL-6 may be expressed in a phosphorylated form. Immunostaining with both antibodies showed that BCL-6 protein was localized in the nuclei of most of the germinal center B cells and a small number of marginal zone B cells. Furthermore, BCL-6 protein was expressed in follicular, Burkitt's, and diffuse large B-cell lymphomas. These results suggest that the BCL-6 protein, expressed in B cells of the germinal centers which are important in the maturation of immune responses, may play some physiological role(s) in the germinal center B cells.
A unique case of primary testicular lymphoma in a child is reported.
Tumor tissue was studied using immunohistochemical techniques and southern blot hybridization to detect immunoglobulin and bcl-2 gene rearrangement and in situ hybridization for the Epstein-Barr virus (EBV) genome.
Light microscopy revealed a lymphocytic infiltrate with a follicular pattern. Immunohistochemical staining revealed lambda light chain restriction and gene rearrangement studies revealed a clonal rearrangement of the immunoglobulin heavy chain, confirming a clonal neoplastic process. Immunostaining failed to detect bcl-2 protein expression, and no evidence of bcl-2 gene rearrangement was noted on southern blot analysis. In situ hybridization for EBV nucleic acid in tumor tissue was negative.
To the authors' knowledge, this is the first report of a case of a primary testicular lymphoma with follicular histology in a child. Despite the follicular histology, no evidence of bcl-2 expression or gene rearrangement was detected.
We studied 69 cases of malignant lymphoma of the testis, epididymis, and spermatic cord, including 64 cases in which the tumor involved these sites at presentation and five cases in which lymphoma relapsed in the testis. The patients without prior lymphoma were 16 to 91 (mean, 56) years old. Fifty-two patients had diffuse large-cell lymphomas [seven large cleaved cell (two with follicular areas), 27 large noncleaved, two multilobated, six not otherwise specified (NOS), 10 immunoblastic]; six, small noncleaved cell; two, diffuse mixed small and large cell; one, diffuse small cleaved; one, follicular mixed small cleaved and large cell; and two, high grade, unclassified in the Working Formulation. Twenty-nine cases (55%) were stage I; five (9%), stage II; one (2%), stage III, and 18 (34%), stage IV. Forty patients (73%) achieved a complete remission; 23 had a relapse of tumor at 4 to 274 months (median, 13) and five were salvaged. At last follow-up, 20 (36%) patients were free of disease, six (11%) were alive with disease, and 29 (53%) had died of lymphoma. Features associated with longer disease-free actuarial survival (DFS) included stage I disease (p = 0.0001) and sclerosis (p = 0.0001). Among patients with stage I lymphoma, those with right-sided tumors (p = 0.005) or tumors with sclerosis (p = 0.0017) had longer DFS. Lymphomas with extensive sclerosis were all stage I (p = 0.0057). Four of five patients with secondary testicular lymphoma had extranodal primary sites. They ranged from 13 to 66 years (median, 35). Testicular relapses occurred 13-37 months after initial diagnosis. Three had diffuse large, noncleaved cell type; one, lymphoblastic and one, diffuse mixed small and large cell. Immunophenotyping showed B lineage in 33 cases and T lineage in one case. Most testicular lymphomas are B-lineage large-cell lymphomas, which frequently involve other extranodal sites at presentation and at relapse, and which often have an aggressive clinical course.
About 40 percent of non-Hodgkin's lymphomas are diffuse lymphomas with a large-cell component (DLLC). Current therapy can induce a long-term remission in half the patients with DLLC, but more intensive treatment has the potential to improve outcome, particularly in patients at high risk for treatment failure. Clinical and cytogenetic markers can identify subgroups at high or low risk. Rearrangement of a novel candidate proto-oncogene, bcl-6, is a possible prognostic indicator in DLLC.
We performed Southern blot hybridization to detect bcl-6 and bcl-2 gene rearrangement in samples of lymphoma from 102 patients with B-cell DLLC. The results were correlated with the patients' histologic features, age, disease stage, tumor sites and bulk of disease, serum lactate dehydrogenase level, and treatment outcome.
Rearranged bcl-6 was found in 23 cases, and rearranged bcl-2 in 21 cases. Nineteen of the patients with rearranged bcl-6 had extranodal DLLC, two had primary splenic lymphomas, and only one had bone marrow involvement. Thirty-six months after diagnosis, the proportion with freedom from progression of disease was projected to be 82 percent (95 percent confidence interval, 66 to 98 percent) among the patients with rearranged bcl-6, as compared with 56 percent (95 percent confidence interval, 43 to 70 percent) for the patients with germ-line bcl-6 and bcl-2 and 31 percent (95 percent confidence interval, 8 to 53 percent) for the patients with rearranged bcl-2. The status of the bcl-6 gene was an independent prognostic marker of survival and freedom from disease progression in a multivariate model and added predictive value to established prognostic signs.
Rearrangement of the bcl-6 gene correlated with a favorable clinical outcome in DLLC and may thus serve as a prognostic marker in patients with this form of malignant lymphoma.
We have shown previously that chromosomal translocations involving chromosome 3q27 and immunoglobulin gene regions are the third most common specific translocations in non-Hodgkin's lymphoma (NHL). We now report the isolation of a gene that is disrupted in two cases by t(3;14) and t(3;4) translocations. The gene (LAZ3) encodes a 79 kDa protein containing six zinc-finger motifs and sharing amino-terminal homology with several transcription factors including the Drosophila tramtrack and Broad-complex genes, both of which are developmental transcription regulators. LAZ3 is transcribed as a 3.8 kb message predominantly in normal adult skeletal muscle and in several NHL carrying 3q27 chromosomal defects. We suggest that it may act as a transcription regulator and play an important role in lymphomagenesis.