High frequency of t(14;18) in Hodgkin's lymphoma associated with follicular lymphoma

t(14;18) is a common cytogenetic abnormality in B-cell lymphoma, especially in follicular lymphoma (FL), but is rarely seen in Hodgkin's lymphoma (HL). However, due to the small number of cases, the incidence of t(14;18) in HL associated with FL remains unclear. In this study, we applied chromogenic in situ hybridization and fluorescence in situ hybridization for t(14;18) on paraffin-embedded tissue from four HL associated with FL cases and 11 HL cases without a history of FL for comparison. t(14;18) was present in all of the three successfully-tested HL associated with FL cases and one case without a history of FL. The frequency of t(14;18) was significantly high in HL associated with FL (p = 0.013). All Hodgkin's and Reed-Sternberg (HRS) cells having t(14;18) showed immunoreactivity for BCL2 and were negatively stained for nuclear factor-κB (NF-κB), even in Epstein-Barr virus (EBV)-infected cases. However, HRS cells without t(14;18) showed BCL2 and NF-κB immunoreactivity in 33% and 57% of cases, respectively. There was an inverse correlation between t(14;18) and NF-κB. In conclusion, we assume the incidence of t(14;18) in HL associated with FL is higher than previously believed and BCL2 expression derived from t(14;18) may play a role in the pathogenesis of HL associated with FL.     

Germinal center B-cell-like diffuse large B-cell lymphoma of the duodenum is associated with t(14;18) translocation

Diffuse large B-cell lymphoma (DLBCL) rarely involves the duodenum, and its clinicopathological characteristics have not been well elucidated. We performed clinicopathological examinations and identified 15 patients with duodenal DLBCL using 18 gastric or colonic DLBCL as a control. Eleven of the 15 patients (73%) were subclassified by immunohistochemical analysis according to the Choi algorithm as germinal center B-cell-like (GCB) type, whereas the 18 control gastric and colonic DLBCL were predominantly subclassified as activated B-cell-like (ABC) type. The classifications according to organ involvement were statistically significant (P= 0.011 and P= 0.035). Macroscopically, the GCB lesions were varied, while all ABC lesions were ulcerative. Fluorescence in situ hybridization analysis revealed a higher frequency of t(14;18) translocation in patients with duodenal DLBCL (3 of 13) as compared with non-duodenal gastrointestinal tract DLBCL (0 of 18), however, the difference was not significant (P = 0.064). Furthermore, the three patients with t(14;18) translocations were classified as GCB. In addition, overall survival of patients was statistically different between those with and without t(14;18) translocation (P= 0.040). In conclusion, duodenal DLBCL predominantly exhibits GCB-type tumors and the frequency of t(14;18) translocation appears to be higher in duodenal GCB-type DLBCL compared to non-duodenal tumors.     

Lack of Bcl-2 expression in follicular lymphoma may be caused by mutations in the BCL2 gene or by absence of the t(14;18) translocation

Follicular lymphoma (FL), except grade 3B, is characterized by the chromosomal translocation t(14;18)(q32;q21), which results in over-expression of the Bcl-2 protein. Ten per-cent of all FLs, however, do not show Bcl-2 protein expression with standard immunohistochemistry using a monoclonal Bcl-2 antibody against residues 41-54 of the Bcl-2 protein. In this study, the biological background of 18 Bcl-2-negative FL cases grade I, II, or IIIa was investigated by immunohistochemical staining and western blot analysis with alternative antibodies. Bcl-2 protein was demonstrated in five of the 18 cases and all of these carried the t(14;18) translocation. Of the 13 cases that were Bcl-2 negative with alternative antibodies, 12 lacked the t(14;18) translocation. PCR and subsequent sequence analysis of cDNA demonstrated that three cases with a t(14;18) contained somatic mutations in the translocated BCL2 gene, resulting in amino acid replacements in the region of the epitope recognized by the antibody. In conclusion, the majority of Bcl-2-negative FL lack a t(14;18) but a significant subset of these tumours are false negative due to mutations in the BCL2 gene. These findings may have consequences for the use of Bcl-2 immunohistochemistry for diagnostic purposes.     

Pathobiology and diagnosis of follicular lymphoma

Follicular lymphoma is one of the most frequent lymphomas in the western hemisphere. The diagnosis of this lymphoma is based primarily on morphology and immunohistochemistry. Although the basic diagnostic principles have been unchanged for decades, the concept of lymphoma pathogenesis and subtyping is still being developed. Most importantly, the grading of follicular lymphoma and the definition of transformation continue to be controversial. Early lesions of follicular lymphoma can be identified using immunohistochemistry, which presents a challenge to diagnostic histopathologists, but can by contrast help us to understand the pathogenesis of the disease. Histopathologists should be aware of variants of this lymphoma that present with specific histologic and clinical features, such as pediatric follicular lymphoma.     

14;18 translocation in primary intestinal lymphoma: detection by polymerase chain reaction in routinely processed tissue

Chromosomal translocations involving the heavy chain immunoglobulin locus on chromosome 14 and a region on chromosome 18 encoding the bcl-2 gene [t(14;18)] are a characteristic and prevalent chromosomal abnormality in nodal malignant lymphoma, particularly follicular lymphoma. Using the polymerase chain reaction on routinely processed tissue, t(14;18) has been demonstrated in 22% of primary intestinal lymphomas, i.e. in two of nine cases of malignant lymphomatous polyposis, in four of 19 cases of polymorphic B-cell lymphoma and in one of four high-grade unclassified tumours. The findings in this study contradict those of other studies which have shown no such translocation in primary gastric and small intestinal lymphoma. The presence of t(14;18) indicates heterogeneity of molecular abnormalities within histopathologically homogeneous tumours and suggests that caution should be employed in using molecular cytogenetic data to support theories of tumour histogenesis. The low prevalence of this translocation in intestinal lymphoma makes the use of such a methodology as a primary diagnostic aid doubtful, although the technique may help to distinguish primary and secondary lymphoma and could also be used to demonstrate secondary spread.     

CD5‐positive follicular lymphoma characterized by CD25, MUM1, low frequency of t(14;18) and poor prognosis

CD5‐positive follicular lymphoma (FL), although rare, has been described in a number of case reports. However, a statistically valid, clinicopathological comparison between CD5‐positive FL and CD5‐negative FL has never been performed because of its rarity. We statistically compared clinicopathological characteristics of 22 cases of CD5‐positive FL, diagnosed by immunohistochemistry, flow cytometry and morphological findings, with those of 62 cases of FL without CD5 expression (control cases). CD5‐positive FL patients showed a higher tendency of peripheral blood involvement (P = 0.076) and a higher frequency of CD25 expression (P = 0.0004) and MUM1 protein expression (P = 0.0008), and a lower frequency of t(14;18)(q32;q21) (P = 0.017). The overall survival (OS) curve of CD5‐positive FL was significantly worse than that of control cases (P = 0.0266), although progression‐free survival curves did not show a significant difference (P = 0.7899). Moreover, CD5 expression was shown to be an independent poor prognostic factor for OS in both univariate analysis [Hazard Ratio (HR), 3.63; P = 0.0464] and multivariate analysis (HR, 57.16; P = 0.0001). CD5‐positive FL showed different clinicopathological characteristics from FL lacking CD5 expression. These results suggest that CD5‐positive FL should be considered a different type of FL, and its clinicopathological management should be conducted differently.     

In situ follicular lymphoma with progressive transformation of the germinal centers confirmed by laser capture microdissection, IGH gene rearrangement analysis, and fluorescence in situ hybridization for t(14;18)

The authors report an unusual case of in situ follicular lymphoma associated with progressive transformation of the germinal centers. The patient was a 74-year-old Chinese woman with sequential lymphadenopathy in the right and left cervical regions over a period of 2 months. The first biopsy revealed in situ follicular lymphoma with progressive transformation of germinal centers, and the biopsy of the second lymph node led to a diagnosis of in situ follicular lymphoma. The immunophenotype, polymerase chain reaction amplification of the immunoglobulin heavy chain gene, and fluorescence in situ hybridization for t(14;18) were analyzed in each biopsy specimen, which showed both specimens to have t(14;18)(q32;q21) and revealed progression from polyclonality to monoclonality. These findings suggest a case of multicentric in situ follicular lymphoma and provide new insights into the pathogenesis of this disease.     

Extranodal follicular lymphoma: a clinicopathological and genetic analysis of 15 cases arising at non-cutaneous extranodal sites

AIMS: Recent studies of primary cutaneous follicular lymphoma suggest that it represents a clinicopathological entity distinct from nodal follicular lymphoma (FL). The purpose of this study was to determine if FL arising at other extranodal sites is more closely related to FL occurring in the skin or in lymph nodes. METHODS AND RESULTS: Fifteen cases of non-cutaneous extranodal follicular lymphoma (ENFL) were identified from the Scotland and Newcastle Lymphoma Group (SNLG) database. All were stage 1E at presentation and involved the tonsil (n = 3), palate (n = 3), skeletal muscle (n = 2), ileum (n = 2), duodenum (n = 1), stomach (n = 1), thyroid gland (n = 1), submandibular gland (n = 1) and fallopian tube (n = 1). Polymerase chain reaction for t(14;18) using primers to the major breakpoint cluster region was performed on 14 cases of ENFL and the incidence of the translocation compared with that found in 16 cases of stage 1 nodal FL. Clinical and follow-up data were obtained from the SNLG database for the 15 cases of ENFL and 87 cases of stage 1 nodal FL, and a comparison of outcomes made. Only 2/14 cases of ENFL had detectable t(14;18) compared with 9/16 stage 1 nodal FL (P < 0.01). Freedom from progression and disease-specific survival was similar for the 15 cases of ENFL and 87 cases of stage 1 nodal FL. However, 13/15 patients with ENFL were disease free at the end of follow-up compared with 49/87 stage 1 nodal FL (P < 0.02). CONCLUSIONS: The low incidence of t(14;18) and favourable outcome encountered in ENFL in this study is similar to that previously found for primary cutaneous FL. These results support the concept of a subtype of FL lacking t(14;18) involving the major breakpoint cluster region, and with a propensity to arise at extranodal sites. Despite a high relapse rate, patients with ENFL are more likely to achieve complete remission and may ultimately have a more favourable long-term prognosis than those with equivalent nodal disease.     

In situ follicular lymphoma with a 14;18 translocation diagnosed by a multimodal approach

The main differential diagnosis for follicular lymphoma (FL, or in situ localization of follicular lymphoma) is follicular hyperplasia. However, this differentiation is quite challenging when the initial presentation of FL is in one lymph node and such a lymph node is only partially involved. In other words, only a few lymphomatous follicles are present in an otherwise nodal reactive follicular hyperplasia. The use of FISH on formalin-fixed, paraffin-embedded tissue as an adjunct to routine histomorphological and immunohistochemical evaluation is valuable for reaching an initial diagnosis of in situ follicular lymphoma in a lymph node which shows predominantly reactive follicular hyperplasia. In this report, we describe our experience in rendering such an initial diagnosis of in situ FL in an apparently healthy individual who has a single persistently enlarged lymph node. The recognition of in situ FL is of utmost importance because it is associated with localized early stage disease (stage I), which according to standard regimens is amenable to local radiation therapy with a good chance for inducing remission. To the best of our knowledge, this is the first such case reported in the English literature using innovative FISH technology on formalin-fixed, paraffin-embedded tissue in conjunction with other routine histological modalities to produce an initial diagnosis of in situ follicular lymphoma.     

Translocation t(13;14) in nine generations with a case of translocation homozygosity

The Robertsonian translocation 5(13;14)(p11;q11) was studied in three families with probable common ancestry in Eastern Finland. In the largest family the translocation has segregated through at least nine generations. The same family also included a female who was homozygous for t(13;14). No clear-cut effect of the translocation on fertility could be demonstrated and only one case of trisomy 13 was recorded in the offspring of t(13;14) carriers. The results are discussed, with implication for human chromosomal evolution.     

Follicular lymphoma with marginal zone differentiation: cytogenetic findings in support of a high-risk variant of follicular lymphoma

AIMS: The pathogenesis and clinical significance of marginal zone differentiation in follicular lymphoma remains to be determined, although genetic alterations are likely to be important determinants of both. We therefore report the cytogenetic findings in three cases of follicular lymphoma with marginal zone differentiation studied by routine karyotyping and in-situ hybridization. METHODS AND RESULTS: The morphology and immunophenotype of each case was typical of follicular lymphoma displaying marginal zone differentiation. Karyotyping, performed on GTL-banded preparations of cell cultures derived from fresh lymph node tissue, revealed a complex karyotype in all three cases, including t(14;18)(q32;q21) and abnormalities associated with progression and/or transformation of follicular lymphoma. In addition, trisomy 3 was found in one case and translocations between the q27-29 region of chromosome 3 and chromosome 2 in the other two cases; the latter was identified only in subclones derived from less complex stem lines possessing t(14;18). In-situ hybridization, performed on sections cut from routinely processed paraffin-embedded tissue blocks, localized cells possessing these abnormalities of chromosome 3 to both the follicular and marginal zone components of two lymphomas studied in this way. CONCLUSIONS: Trisomy 3 and alterations involving the q27-29 region of chromosome 3 are implicated in the pathogenesis of de novo marginal zone lymphoma. Their presence in the current cases indicates that they may also be responsible for marginal zone differentiation in follicular lymphoma when cells harbouring these genetic alterations are exposed to the appropriate microenvironment. Our findings are consistent with follicular lymphoma with marginal zone differentiation as a high-risk variant of follicular lymphoma.     

Lack of PAX5 rearrangements in lymphoplasmacytic lymphomas: reassessing the reported association with t(9;14)

A t(9;14)(p13;q32) involving the PAX5 and IGH genes has been described in association with lymphoplasmacytic lymphoma. Although often described as common, the incidence of this translocation in nodal lymphoplasmacytic lymphoma has never been investigated. Recent studies of patients with Waldenstr?m's macroglobulinemia (often corresponding to marrow-based lymphoplasmacytic lymphoma) have failed to identify the t(9;14). These studies have suggested that either nodal and marrow-based lymphoplasmacytic lymphomas have distinct pathogenetic mechanisms or that the t(9;14) is less frequent in lymphoplasmacytic lymphoma than was believed previously. We therefore analyzed a series of nodal or other extramedullary lymphoplasmacytic lymphomas for the presence of the t(9;14) with paraffin section interphase fluorescence in situ hybridization. We developed a BAC contig probe spanning all previously described PAX5 breakpoints and validated this assay with the KIS-1 cell line that expresses a t(9;14). Analysis with the PAX5 probe showed a lack of PAX5 rearrangements in all cases that were analyzed successfully. Similarly, analysis by an IGH fluorescence in situ hybridization probe showed no evidence of translocations involving the IGH locus. These findings indicate that the t(9;14) is at least uncommon in lymphoplasmacytic lymphoma and should no longer be considered a characteristic finding in this type of lymphoma as defined by World Health Organization criteria.     

Histiocytic and dendritic cell neoplasms: Reappraisal of a Japanese series based on t(14;18) and neoplastic PD-L1 expression

Histiocytic and dendritic cell (H/DC) neoplasms are heterogeneous, originating from myeloid- or stromal-derived cells. Multiple reports describe the cross-lineage transdifferentiation of neoplastic B cells into H/DC neoplasms. Most such cases are from Western countries, and rarely from Japan or East Asia. Here we report 17 cases of H/DC neoplasms in Japanese patients, with analysis of t(14;18) by fluorescence in situ hybridization, and of neoplastic programmed death-ligand 1 (PD-L1) expression by immunostaining (clones SP142, E1J2J, and 28-8). These 17 cases were diagnosed according to the 2017 World Health Organization (WHO) classification, and included two histiocytic sarcomas (HS), two interdigitating cell (IDC) sarcomas, one Langerhans cell sarcoma, two dendritic cell sarcomas, and 10 follicular dendritic cell (FDC) sarcomas. No case had any past history of follicular lymphoma (FL). Two cases of HS and one IDC sarcoma, all of which were myeloid-driven, were found to exhibit t(14;18). In the latter case, at 30 months after IDC sarcoma diagnosis, FL development was detected. Three (30%) FDC sarcoma cases exhibited neoplastic PD-L1 expression with all the three PD-L1 antibody clones. This is the first report of t(14;18) and neoplastic PD-L1 expression on H/DC neoplasms among Japanese patients, each of which appeared to be associated with HS and FDC sarcoma, respectively.     

滤泡型淋巴瘤中t(14;18)染色体易位的分析及其临床意义

目的探讨滤泡型淋巴瘤（FL）的分子遗传学特征及其在病理诊断中的意义。方法收集55例FL石蜡标本,对照组小B细胞淋巴瘤28例和反应性滤泡增生（RFH）10例,应用套式PCR技术检测FL中,免疫球蛋白重链基因（IgH）的克隆性重排;应用标准PCR技术检测55例FL中t（14;18）易位,以10例RFH做对照;采用双色荧光原位杂交（FISH）技术检测20例淋巴结FL中t（14;18）易位,以4例RFH作为对照;并与PCR检测结果进行比较。结果（1）55例FL中,结内49例,结外6例。男性33例,女性22例,男女比为1．5：1。发病年龄36—79岁（中位年龄57岁）;FL分级：FL1—3分别为25例、19例和11例。（2）55例中50例（90％）检出β-肌动蛋白（actin）,该50例中FR3A阳性24例（48％）,FR2阳性25例（50％）,其中15例（30％）呈FR3A和FR2双阳性,共34例（68％）IgH基因重排。对照组小B细胞淋巴瘤28例中,25例检出β—actin,其中FR3A阳性18例（64％）,FR2阳性17例（61％）,共24例（86％）可检测出克隆性IgH基因重排。4例RFH均未检出IgH基因重排。（3）在44例结内FL中检出15例（34％）t（14;18）易位,其中14例在MBR,1例在mcr。（4）20例中,有16例（80％）可检出t（14;18）易位。结论（1）IgH克隆性重排在FL中的检测率比其他小B淋巴细胞低。（2）FISH检测石蜡包埋组织中t（14;18）易位有助于FL的诊断。FISH比PCR的敏感性更好,操作简便,可用于检测石蜡包埋组织中的分子遗传学改变。     

t(11;18)染色体易位对于胃黏膜相关淋巴组织淋巴瘤的预后价值

目的 探讨t(11;18)(q21;q21)染色体易位对于胃黏膜相关淋巴组织(mucosal associated lymphoid tissue,MALT)淋巴瘤预后意义.方法 采用回顾性方法对1994年1月至2004年6月间,经术后病理明确诊断的36例MALT淋巴瘤患者进行随访,同时采用间期荧光原位杂交技术检测患者保存的石蜡手术标本有无t(11;18)(q21;q21)染色体易位.结果 36例患者中15例检出t(11;18)(q21;q21)染色体易位,阳性率为41.67％;35例随访至2010年3月,总的中位生存期87个月,伴有t(11;18)(q21;q21)染色体易位者的中位生存期为43个月,无t(11;18)(q21;q21)染色体易位者的中位生存期为130个月,两组之间差异有统计学意义(x2 =29.57,P＜0.01).结论 t(11;18)(q21;q21)染色体易位是MALT淋巴瘤的重要预后因素.     

A marginal zone phenotype in follicular lymphoma with t(14;18) is associated with secondary cytogenetic aberrations typical of marginal zone lymphoma

Marginal zone differentiation of follicular lymphomas (FL), sometimes referred to as monocytoid B-cell differentiation, is a relatively uncommon phenomenon. Recently, this type of differentiation was also linked to secondary cytogenetic aberrations of chromosome 3 in a small number of patients. We have analysed 131 primary nodal FL with t(14;18)(q32;q21) for secondary cytogenetic aberrations previously described as recurrent in marginal zone lymphomas (MZL) to identify their frequency and possible association with morphological evidence of marginal zone differentiation. We searched for trisomy of chromosomes 3, 12, and 18, gains of chromosome arm 3q, deletions of chromosome arm 7p, structural anomalies with break-points in 1q21 and 1p34, as well as the t(1;2)(p22;p12), t(1;14)(p22;q32), t(3;14)(q27;q32), t(6;14)(p21;q32), and t(11;18)(q21;q21) translocations. At least focal morphological evidence of marginal zone differentiation occurred in 35/131 (27%) FL with t(14;18)(q32;q21) as the primary chromosomal abnormality. None of the recurrent balanced translocations characteristic of extranodal MZL were seen secondarily in the nodal FLs with t(14;18)(q32;q21). However, 43/131 (33%) cases had at least one of the above secondary cytogenetic aberrations previously reported as recurrent aberrations in MZL and, when combined, these were significantly more frequent in FL with morphological evidence of marginal zone differentiation (p<0.0001, two-sided Fisher's exact test). Aberrations of chromosome 3 and, in particular, trisomy 3 occurred frequently in FL with marginal zone differentiation (p=0.002 and p<0.0001, respectively, two-sided Fisher's exact test), while chromosome 21, 22, and X chromosome aberrations, which have not been described previously as recurrent in MZL, were also significantly associated with marginal zone differentiation in FL (p=0.002, p=0.037, p=0.039, respectively, two-sided Fisher's exact test).