Anaplastic lymphoma kinase-positive diffuse large B-cell lymphoma with a complex karyotype and cryptic 3' ALK gene insertion to chromosome 4 q22-24

Anaplastic lymphoma kinase (ALK)-positive diffuse large B-cell lymphoma (DLBCL) is a rare tumor that is frequently associated with t(2;17)(p23;q23), a translocation fusing the ALK gene at 2p23 to the clathrin heavy chain gene (CLTC) at 17q23. Here, we report a unique case of ALK-positive DLBCL with plasmablastic morphology and focal cytoplasmic granular ALK stain in an HIV-negative 33-year-old man. By conventional karyotyping, the lymphoma cells were near-tetraploid and included 4 structurally normal copies each of chromosomes 2 and 17. Fluorescence in situ hybridization revealed an apparently normal, intact ALK gene on each of the 4 chromosome 2 homologs plus a cytogenetically cryptic ALK gene insertion into 2 of the 4 chromosome 4 homologs at band 4q22-24. The lymphoma cells expressed CD138, lambda light chain, focal and weak CD30, and exhibited aberrant T-cell antigens, including perforin. This case indicates that ALK-positive DLBCL is more heterogeneous at the cytogenetic/molecular level than previously recognized.     

ALK阳性大B细胞淋巴瘤3例临床病理及分子遗传学分析

目的探讨间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)阳性的弥漫性大B细胞淋巴瘤(diffuse large B-cell lym-phoma,DLBCL)的临床病理及分子遗传学特点。方法对3例ALK(+)DLBCL进行光镜观察、免疫组化及荧光原位杂交检测,并复习相关文献。结果镜下观察淋巴结结构破坏,可见淋巴窦侵犯,肿瘤细胞大,呈免疫母细胞样,免疫组化示肿瘤细胞ALK、Bob-1、CD4、CD10、CD45、CD56、CD138、EMA、MUM1、Oct-2均(+),CD20、CD79a、PAX-5、CD3和CD30均(-),3例荧光原位杂交均检测到ALK基因易位。结论 ALK(+)DLBCL是一种DLBCL的少见独立亚型,具有特征性免疫表型、形态学及分子遗传学特点。     

Anaplastic lymphoma kinase-positive diffuse large B-cell lymphoma presenting as an isolated nasopharyngeal mass: a case report and review of literature

Anaplastic lymphoma kinase (ALK)-positive diffuse large B-cell lymphoma is a rare and distinct variant of diffuse large B-cell lymphoma with characteristic morphologic, immunophenotypic, and cytogenetic features. We report a case of ALK-positive diffuse large B-cell lymphoma in a 44-year-old male with progressively worsening unilateral nasal congestion and obstruction secondary to a nasopharyngeal mass. Radiologically, the mass was showed to extend to orophanrynx from nasopharynx. Histologically, the tumor cells exhibited plasmablastic morphology with expression of Bob-1, CD4, CD10, CD45, CD56, CD138, EMA, MUM1, Oct-2, and kappa immunoglobulin light chain, but negative for CD20, CD30, CD79a, PAX-5, and lambda. More importantly, the neoplastic cells showed positive immunoreactivity for ALK with exclusive cytoplasmic granular staining pattern. This case represented the second reported ALK-positive diffuse large B-cell lymphoma in the nasopharyngeal region.     

A small cell variant of ALK-positive, CD8-positive anaplastic large cell lymphoma with primary subcutaneous presentation mimicking subcutaneous panniculitis-like T-cell lymphoma

ALK-positive anaplastic large cell lymphoma (ALK+ ALCL) is an uncommon non-Hodgkin's lymphoma of T-cell origin, the majority of which express CD4 and show frequent pan-T-cell antigen loss. While most cases of ALK+ ALCL have the common pattern characterized by anaplastic morphology with hallmark cells, a less common but well-recognized variant with a small cell pattern may pose a diagnostic challenge. We report a case of ALK+ ALCL with small cell morphology and CD8 subset restriction in a 53-year-old male patient who presented primarily with multiple recurrent subcutaneous nodules with histopathologic features simulating a subcutaneous panniculitis-like T-cell lymphoma (SPTCL). The case was initially diagnosed as SPTCL but was reconsidered as ALK+ ALCL when the incidental finding of CD30 positivity on a subsequent biopsy prompted an ALK immunostain, which turned out to be positive in the neoplastic T-cells. The diagnosis of ALK+ ALCL, small cell variant, was then confirmed by detection of an ALK gene rearrangement by FISH analysis. This report highlights a case of ALK+ ALCL with a deceiving clinical and histopathologic presentation, and emphasizes the value of immunohistochemical panel studies and genetic tests in such cases to avoid diagnostic errors.     

Anaplastic lymphoma kinase-positive large B-cell lymphoma: a case report with emphasis on the cytological features of the pleural effusion

Anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma (ALK-positive LBCL) is an extremely rare distinct clinicopathological subtype of LBCL, characterized by the presence of ALK-positive monomorphic large immunoblast-like neoplastic B cells. Herein, we describe the first cytological report on ALK-positive LBCL in the pleural effusion. A 69-year-old Japanese male with a past history of malignant lymphoma of the cecum presented with progressive dyspnea and pleural effusion. Removal of the pleural effusion and aspiration of bone marrow were performed. May-Grünwald-Giemsa stain of the pleural fluid revealed abundant single or small aggregates of large-sized round cells. These cells had centrally-located large round to oval nuclei. The peculiar finding was the presence of pseudopodial cytoplasmic projections, and some neoplastic cells had eosinophilic pseudopodial cytoplasmic projections, which resembled “flaming plasma cells”. Histopathological and immunohistochemical studies of the bone marrow demonstrated CD138⁺, ALK1⁺, CD20^-, CD79a^-, CD30^-, and IgA⁺ large-sized neoplastic cells. Therefore, a diagnosis of ALK-positive LBCL was made. The peculiar finding of the present case was that most of the neoplastic cells had pseudopodial cytoplasmic projections, and some of them had eosinophilic pseudopodial cytoplasmic projections that resembled “flaming plasma cells”, which has been recognized as the characteristic finding of IgA myeloma. Therefore, tumor cells that resembled “flaming plasma cells” in the pleural effusion may have had IgA in the cytoplasm. Albeit extremely rare, ALK-positive LBCL shows aggressive clinical course, thus, recognition of the cytomorphological features of this type of malignant lymphoma is important for early and correct diagnosis.     

表达间变性淋巴瘤激酶蛋白的弥漫性大B细胞淋巴瘤的临床病理和免疫表型观察

目的探讨表达间变性淋巴瘤激酶（ALK）蛋白的弥漫性大B细胞淋巴瘤（DLBCL）的临床病理特点。方法根据2001年版WHO淋巴造血组织肿瘤分类收集945例DLBCL,以LSAB法作ALK-11染色。对阳性病例再用EnVision法作ALK-11染色,仅EnVision法阳性病例为最终纳入病例。对纳入病例标本用LSAB法加做CD20、CD3、CD30、上皮细胞膜抗原（EMA）、粒酶B、T细胞胞质内抗原（TIA）-1和浆细胞（PC）抗体等免疫表型检测,进行IgH基因重排检测并收集随访资料。结果945例弥漫性大B细胞淋巴瘤中仅5例表达ALK蛋白。4例男性,1例女性,年龄34—72岁,全部原发于淋巴结。临床分期Ⅰ期1例、Ⅱ期2例、Ⅲ期2例。5例随访最长32个月,最短4个月。随访截止时死亡4例,死亡病例最长存活时间32个月。表达ALK蛋白的DLBCL包括中心母细胞性2例、免疫母细胞性1例、间变性1例、浆母细胞性1例;2例中心母细胞性、1例免疫母细胞性和1例间变性均表达CD20。浆母细胞性表达K轻链而不表达CD20。5例均检测到IgH基因重排。ALK蛋白表达：在CD20阳性4例中,1例免疫母细胞性为胞膜和胞质阳性,2例中心母细胞性和1例间变性为胞质颗粒状阳性;1例浆母细胞性为胞核和胞质弥漫阳性。结论ALK蛋白阳性表达DLBLC是一种罕见的,临床过程具侵袭性且预后较差的淋巴瘤,可见于浆母细胞性、中心母细胞性、免疫母细胞性和间变性的大B细胞淋巴瘤。发现1例ALK蛋白表达于胞膜和胞质。     

Composite diffuse large B-cell lymphoma and CD20-positive peripheral T-cell lymphoma

Composite lymphoma is defined as two or more distinct types of lymphoma in a single anatomical site. Among various combinations, composite B-cell and T-cell non-Hodgkin's lymphomas (CBTL) are very infrequent. Herein we describe a 66-year-old female with CBTL presenting with lymphadenopathy, multiple bone lesions and an epidural tumor. Light microscopic examination of a biopsied cervical node revealed a dual population of lymphoid cells: sheets of large cells admixed with medium-sized cells. The large cells expressed B-cell markers and showed immunoglobulin light chain restriction, consistent with diffuse large B-cell lymphoma (DLBCL). The medium-sized cells were positive for CD20 as well as T-cell markers. Because polymerase chain reaction amplification showed monoclonal rearrangement of the T-cell receptor β chain gene, this population was compatible with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS). We therefore made a diagnosis of composite DLBCL and CD20-positive PTCL-NOS. Complete remission was achieved after six cycles of R-CHOP regimen (rituximab, doxorubicin, vincristine, cyclophosphamide and prednisolone). This is the first report of CD20-positive PTCL-NOS associated with composite lymphoma. Moreover, a literature review of composite DLBCL and PTCL-NOS indicates that this rare clinical entity may be featured by efficacy of systemic chemotherapy in spite of prevalent extranodal lesions.     

Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma presenting as a bladder neoplasm

Malignant lymphoma presenting in the bladder has been classified in primary cases, as the first sign of disseminated disease and as a secondary infiltration. Most of the examples in the literature have been reported as single cases. Reported herein is the case of a 45-year-old man with an anaplastic large cell lymphoma (anaplastic lymphoma kinase (ALK) and granzyme B positive) that presented as a bladder neoplasm. The morphological differential diagnosis was complex because the EMA-positive immunophenotype, CD45 and CD3 negativity and the clinical manifestation simulated a transitional cell carcinoma. It is important to be aware of its existence because a poorly differentiated bladder carcinoma cannot be ruled out if CD30 and ALK immunostaining are not performed. T-cell receptor-γ clonal rearrangement could be also helpful in these cases. Although bladder involvement by recurrent lymphoma is a sign of widely disseminated disease and it is associated with a very poor prognosis, it seems that chemotherapeutic regimens in this kind of ALK-positive lymphoma could be effective, given that the present patient had an impressive response to chemotherapy treatment.     

A fulminant case of classical Hodgkin lymphoma: A diagnostic dilemma of Epstein‐Barr virus‐positive large B‐cell neoplasms

We report a fulminant case of classical Hodgkin lymphoma (CHL). The patient died only approximately 2 months after the onset of subjective symptoms. Autopsy specimens revealed atypical cells resembling Hodgkin and Reed‐Sternberg (HRS) cells in a rich inflammatory background in various organs. There were marked, characteristic angiodestructive lesions from infiltrating HRS‐like cells and numerous macrophages. The HRS‐like cells were infected with Epstein‐Barr virus (EBV), immunohistochemically positive for PAX5 and CD30, and negative for CD3, CD20, and ALK. Most B‐cell markers other than PAX5 were negative, and the HRS‐like cells also expressed cytotoxic molecules. Monoclonal rearrangement of immunoglobulin heavy chain was detected by PCR analysis. According to the 2016 WHO classification, we diagnosed mixed cellularity CHL. However, EBV‐positive diffuse large B‐cell lymphoma (DLBCL), not otherwise specified and EBV‐positive B‐cell lymphoma, unclassifiable with features intermediate between DLBCL and CHL were considered as differential diagnoses because both tumors are aggressive EBV‐positive large B‐cell neoplasms with reactive inflammatory cells and sometimes contains HRS‐like cells. The clinical condition of the current case was closer to these two entities than to CHL. A diagnosis of EBV‐positive large B‐cell neoplasms was difficult because of overlapping morphological and immunohistochemical characteristics, but should be considered for prognosis.     

间变性大细胞淋巴瘤形态学及免疫表型观察

目的：探讨间变性大细胞淋巴瘤（ALCL）的形态学和免疫表型特征。方法：对6例ALCL和2例弥温性大B细胞淋巴瘤（DLBCL）进行形态学和免疫组织化学染色（ABC法）观察。结果：6例ALCL中，普通型2例、淋巴组织细胞型2例、ALK－变型2例，均可见单型性或多形性的标志性大细胞。普通型和ALK－变型大细胞沿淋巴窦内生长，而淋巴组织细胞型大细胞则呈散在分布；2例DLBCL形态上颇似ALCL；6例ALCL均为T细胞，CD30＋，儿童患者共同表达ALK＋和EMA＋，年长者则ALK－和EMA－。2例DLBCL均为B细胞，ALK＋、CD30－和EMA－。结论：不论何型ALCL，均可见CD30＋的标志性大细胞，淋巴窦内生长多见于普通型和ALK－变型。ALCK均为T细胞，儿童常有ALK和EMA共同表达，年长者则ALK和EMA－。DLBCL的免疫表型不同于ALCL。     

Occurrence of anaplastic large cell lymphoma following IgG4-related autoimmune pancreatitis and cholecystitis and diffuse large B-cell lymphoma

IgG4-related sclerosing disease is an established disease entity with characteristic clinicopathological features. Recently, the association between IgG4-related sclerosing disease and the risk of malignancies has been suggested. IgG4-related autoimmune pancreatitis with pancreatic cancer has been reported. Further, a few cases of extraocular malignant lymphoma in patients with IgG4-related sclerosing disease have also been documented. Herein, we describe the first documented case of anaplastic large cell lymphoma (ALCL) following IgG4-related autoimmune pancreatitis and cholecystitis and diffuse large B-cell lymphoma (DLBCL). A 61-year-old Japanese male, with a past history of DLBCL, was detected with swelling of the pancreas and tumorous lesions in the gallbladder. Histopathological study of the resected gallbladder specimen revealed diffuse lymphoplasmacytic infiltration with fibrosclerosis in the entire gallbladder wall. Eosinophilic infiltration and obliterative phlebitis were also noted. Immunohistochemically, many IgG4-positive plasma cells had infiltrated into the lesion, and the ratio of IgG4/IgG-positive plasma cells was 71.6%. Accordingly, a diagnosis of IgG4-related cholecystitis was made. Seven months later, he presented with a painful tumor in his left parotid gland. Histopathological study demonstrated diffuse or cohesive sheet-like proliferation of large-sized lymphoid cells with rich slightly eosinophilic cytoplasm and irregular-shaped large nuclei. These lymphoid cells were positive for CD30, CD4, and cytotoxic markers, but negative for CD3 and ALK. Therefore, a diagnosis of ALK-negative ALCL was made. It has been suggested that the incidence of malignant lymphoma may be high in patients with IgG4-related sclerosing disease, therefore, intense medical follow-up is important in patients with this disorder.     

Anaplastic lymphoma kinase positive large B‐cell lymphoma: Literature review and report of an endoscopic fine needle aspiration case with tigroid backgrounds mimicking seminoma

Anaplastic lymphoma kinase‐positive large B‐cell lymphoma (ALK+ LBCL) is a rare distinct type of non‐Hodgkin's lymphoma that arises in association with alterations of the ALK gene. This distinct disease entity is typically associated with an aggressive clinical course and appears in light microscopic preparations as a monomorphic population of large, immunoblast‐like cells. In this report, we describe a case of ALK+ LBCL diagnosed by transgastric endoscopic ultrasound‐guided fine needle aspiration (EUS FNA) of splenic hilar lymph nodes. Modified Giemsa stained direct smears from the FNA sample demonstrated large lesional cells with foamy cytoplasm and macronucleoli admixed with small lymphocytes in tigroid backgrounds, mimicking the cytologic appearance of seminoma. Ancillary immunohistochemical studies subsequently confirmed the diagnosis of ALK+ LBCL with the lesional cells being immunoreactive for CD138, VS38c, MUM1, ALK1, and lambda light chain. The cohesiveness of the cells, the cellular morphology, and the tigroid backgrounds were all pitfalls for accurate diagnosis of this rare specific type of lymphoid malignancy by cytology. To our knowledge this is the first case report detailing the diagnosis of ALK+ LBCL by EUS FNA and the first report describing a glycogen‐rich tigroid background in direct FNA smears. Establishing a refined diagnosis in cases of this rare form of LBCL is necessary, as therapies targeting ALK may be of value in clinical management. Diagn. Cytopathol. 2017;45:148–155. © 2016 Wiley Periodicals, Inc.     

Primary hepatic lymphoma with spindle cell components: a case report

Diffuse large B-cell lymphoma (DLBCL) with spindle cell components is extremely rare and often misdiagnosed as carcinoma or sarcoma. Here, we present a case of primary DLBCL with spindle cell components arising in the liver, for which a preoperative diagnosis by needle biopsies was unsuccessful. The patient was a 70-year-old man with a continuous cough. Thoracic computed tomography incidentally detected a mass of 5 cm in diameter in his liver. The initial and second needle biopsies from the liver mass were pathologically diagnosed as suspicious for sarcomatoid hepatocellular carcinoma. He underwent an extended left hepatectomy. Histological examination revealed a diffuse or epithelioid arrangement of round and polygonal cells, mixed with the fascicles of spindle-shaped cells. Immunohistochemically, all the morphological types of tumor cells showed positive reactions for a lymphocytic marker (CD45RB) and B-cell markers (CD20 and CD79a). Double-immunostaining revealed that the spindle-shaped tumor cells expressed CD20, but never expressed alpha-smooth muscle actin. Malignant lymphoma with a spindle cell morphology is quite uncommon, and this variant can be a diagnostic pitfall, especially in tiny biopsy specimens. We emphasize that pathologists should be reminded of lymphoma as a differential diagnosis of spindle cell tumors.     

ALK-positive extramedullary plasmacytoma with expression of the CLTC-ALK fusion transcript

Anaplastic lymphoma kinase (ALK)-positive non-Hodgkin lymphoma (NHL) was long thought to be a disease occurring uniquely in T or null-cell lymphomas. More recently, however, a small number of B-lineage lymphomas have been reported to express ALK fusion genes. These tumors often exhibit a plasmablastic morphology, a finding which prompted our interest in looking for ALK fusions in plasma cell neoplasms. We studied 46 cases of extramedullary plasmacytoma by immunostaining with anti-ALK antibody and fluorescence in situ hybridization (FISH) analysis using an ALK break-apart probe and found one case to be ALK protein-positive and demonstrated the disruption of the ALK gene in this case. Immunohistochemistry showed that the tumor cells were strongly positive for CD138, VS38c, and epithelial membrane antigen, but lacked expression of CD20, CD79a, CD45, and CD30. Both RT-PCR and genomic DNA-PCR confirmed the CLTC-ALK fusion. This finding expands the lists of the ALK-positive tumors, and ALK-positive extramedullary plasmacytoma may benefit from the treatment of ALK inhibitor in the future.     

系统性间变性大细胞淋巴瘤的免疫组织化学特征

目的:探讨系统性间变性大细胞淋巴瘤(anaplastic large cell lymphoma,ALCL)的免疫组织化学特征.方法:回顾性分析48例系统性ALCL的免疫组织化学和10例系统性ALCL原位杂交技术检测EBER(EBV-encoded small RNA)的结果.结果:48例系统性ALCL的肿瘤细胞均表达CD30,而间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)在41.7％(20/48)的病例阳性,其他指标阳性率为CD2为65.0％(26/40),CD3为36.2％(17/47),CD4为72.7％(16/22),CD5为42.9％(15/35),CD7为16.7％(5/30),上皮细胞膜抗原(epithelial membrane antigen,EMA)为65.6％(21/32),T细胞胞质内抗原(T-cell intracellular antigen-1,TIA-1)为79.2％(19/24),颗粒酶B(granzyme B-producing Breg,GrB)为70.0％(14/20).所有病例的B细胞标志(CD20,PAX5,CD79a)均阴性.10例系统性ALCL有2例出现部分肿瘤性大细胞EBER阳性.结论:CD30和ALK是诊断ALCL关键及较为特异的免疫指标;有时出现人类疱疹病毒第四型(Epstein-Barr virus,EBV)感染并不能排除ALCL的诊断.     

Nodular lymphocyte predominant Hodgkin lymphoma and diffuse large B-cell lymphoma: a study of six cases concurrently involving the same site

Cotta C V, Coleman J F, Li S & Hsi E D
(2011) Histopathology  59 , 1194–1203
Nodular lymphocyte predominant Hodgkin lymphoma and diffuse large B‐cell lymphoma: a study of six cases concurrently involving the same site Aims: Nodular lymphocyte‐predominant Hodgkin lymphoma (NLPHL) is a slowly progressing neoplasm with a favourable prognosis. However, in a minority of cases (3–12%) it progresses to a clonally related diffuse large B‐cell lymphoma (DLBCL), diagnosed between 6 months and 24 years after NLPHL. This study investigated six cases of NLPHL and DLBCL at the same location. Methods and results: The patients were five men and one woman. In four cases, the site was an axillary lymph node, and in two it was inguinal. In all cases, NLPHL areas had typical morphological and immunophenotypic features. DLBCL involvement was multifocal, diffuse, and characterized by large centroblastic and anaplastic cells. Immunohistochemical studies showed DLBCL cells to be positive for CD20, CD45, and BCL6. In one case, DLBCL cells were positive for BCL2, and in two cases they were positive for MUM‐1. There were no networks of follicular dendritic cells (FDC) associated with DLBCL. Rosettes of PD‐1‐positive and CD57‐positive cells surrounding malignant cells in NLPHL were absent in DLBCL. All the cases were negative for Epstein–Barr virus. No translocations involving MYC were identified in DLBCL. Treatment and outcome were known in four cases. All of these patients were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP), and this was followed by clinical remission (CR). Conclusions: In adequately sampled tumors, DLBCL can be associated with NLPHL at diagnosis. Diffuse architecture, loss of FDC networks, sometimes immunophenotype shift are characteristics of DLBCL associated with NLPHL. Treatment with R‐CHOP usually leads to CR.