Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma presenting as retroperitoneal fibrosis

Retroperitoneal fibrosis is a rare fibroinflammatory condition involving the abdominal aorta, iliac vessels, and ureters that carries an association with several other autoimmune conditions. Most cases of retroperitoneal fibrosis are thought to be idiopathic. The disorder can affect all age groups but is most common in persons between the ages of 50 and 70 years. A subset of cases is associated with an underlying immunohematologic abnormality including lymphoma. We describe in this case report a highly unusual presentation of a young woman who died with a diagnosis of "idiopathic retroperitoneal fibrosis" based on multiple biopsy procedures. Postmortem examination, however, revealed disseminated anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. The clinical and histopathologic importance of this very unusual presentation of anaplastic lymphoma kinase-positive anaplastic large cell lymphoma with retroperitoneal fibrosis is discussed.     

软组织及骨的小细胞型间变性大细胞淋巴瘤1例报道

目的 :阐述罕见的小细胞型间变性大细胞淋巴瘤 (ALCL)的病理形态学特点。方法 :对 1例发生于双侧肩胛区、累及骨和周围软组织的小细胞型ALCL进行了光镜、免疫组织化学观察和PCR基因分析。结果 :病变以小到中体积的恶性淋巴细胞为主 ,局部可见大的间变性细胞 ,部分肿瘤细胞围绕小血管呈花环状排列 ,肿瘤间有较多的中性粒细胞和组织细胞。肿瘤细胞表达CD30和EMA ,并具有T细胞表型和TCR β基因重排。 结论 :此型ALCL具有特殊的组织学表现和侵袭性的生物学行为 ,应注意与炎症和嗜酸性肉芽肿等疾病进行鉴别。     

Breast implant-associated ALK-negative anaplastic large cell lymphoma: a case report and discussion of possible pathogenesis

Breast implant associated anaplastic large cell lymphoma (BIA-ALCL) is a recently recognized clinical entity, with only 39 well-documented cases reported worldwide, including 3 fatalities. Because of its rarity, the clinical and pathologic features of this malignancy have yet to be fully defined. Moreover, the pathogenesis of ALCL in association with textured silicone gel breast implants is poorly understood. Here we report a case of BIA-ALCL arising in a 67-year-old woman with a mastectomy due to breast cancer followed by implantation of textured silicone gel breast prosthesis. The patient presented with breast enlargement and tenderness 8 years following reconstructive surgery. MRI revealed a fluid collection surrounding the affected breast implant. Pathologic examination confirmed the presence of malignant ALCL T cells that were CD30+, CD8+, CD15+, HLA-DR+, CD25+ ALK- and p53. A diagnosis of indolent BIA-ALCL was made since tumor cells were not found outside of the capsule. Interestingly, an extensive mixed lymphocytic infiltrate and ectopic lymphoid tissue (lymphoid neogenesis) adjacent to the fibrous implant capsule were present. The patient was treated with capsulectomy and implantation of new breast prostheses. Six months later, the patient was found to have BIA-ALCL involvement of an axillary lymph node with cytogenetic evolutionof the tumor. To our knowledge, this is the sixth reported case of aggressive BIA-ALCL. Unique features of this case include the association with lymphoid neogenesis and the in vivo cytogenetic progression of the tumor. This case provides insight into the potential role of chronic inflammation and genetic instability in the pathogenesis of BIA-ALCL.     

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.     

Intrinsic apoptotic pathway in anaplastic large cell lymphoma

Anaplastic large cell lymphoma (ALCL) includes a subset of tumors that has abnormalities of chromosome 2p23, resulting in overexpression of anaplastic lymphoma kinase (ALK). Previous studies have reported differences in apoptotic rate and expression levels of apoptosis regulatory proteins between ALK+ and ALK- ALCL. In this study, we assessed for expression of the intrinsic apoptotic pathway proteins cytochrome c, apoptosis protease-activating factor 1, and procaspase 9 in 2 ALK+ ALCL cell lines and 42 ALCL tumors (17 ALK+, 25 ALK-). We used the Karpas 299 and SU-DHL-1 cell lines, and the inhibitors Z-LEHD-FMK (specific for caspase 9) and Boc-D-FMK (general caspase inhibitor) to investigate the role of caspase 9 activation in chemotherapy-induced apoptotic cell death. Caspase 9 activity was significantly increased in Karpas-299 and SU-DHL-1 cells after chemotherapy treatment, but remained as low as control levels with addition of either caspase inhibitor. Both caspase inhibitors rescued a substantial fraction of Karpas 299 and SU-DHL-1 cells from drug-induced cell death. In ALCL tumors, expression of cytochrome c, apoptosis protease-activating factor 1, and procaspase 9 was also assessed and correlated with apoptotic rate and activated caspase 3 levels. Cytochrome c was expressed in all 13 (100%) ALK+ and 18 (95%) of 19 ALK- ALCL tumors. Apoptosis protease-activating factor 1 was detected in 14 (88%) of 16 ALK+ and 19 (79%) of 24 ALK- ALCL tumors. Procaspase 9 was expressed in 5 (30%) of 17 ALK+ and 2 (8%) of 25 ALK- ALCL tumors (P = .09). In the entire study group (ALK+ and ALK- ALCL), procaspase 9 expression levels significantly correlated with apoptotic rate (P = .02) and activated caspase 3 levels (P = .05). This correlation could not be shown in the ALK+ or ALK- ALCL subgroups, presumably because of the small sample size. In conclusion, chemotherapy-induced cell death in ALK+ ALCL cells involves the intrinsic apoptotic pathway, and apoptosome function may be an important determinant of apoptosis in ALCL tumors.     

Chronic myeloid leukemia as a secondary malignancy after ALK-positive anaplastic large cell lymphoma

The development of Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in the adolescent population is very rare. CML occurring as a secondary malignancy in individuals treated for anaplastic large cell lymphoma (ALCL) is also rare. We present the case of a 16-year-old adolescent boy who developed a right orbital mass that was diagnosed as ALCL with the t(2;5)(p23;q25) chromosomal aberration. Four years after receiving treatment for ALCL, he presented with a swollen leg and a white cell count of 431,000. Peripheral blood and bone marrow evaluation revealed a myeloproliferative disorder. Cytogenetic and molecular studies demonstrated the presence of t(9;22). We present the histopathologic, molecular, and cytogenetic findings of this patient's initial presentation with systemic ALCL as well as his secondary presentation with CML 4 years later. Therapy-related CML and non-therapy-related secondary CML are discussed as potential explanations of this highly unusual clinical presentation.     

Expression of p63 in anaplastic large cell lymphoma but not in classical Hodgkin's lymphoma

Immunohistochemical determination of p63 protein is frequently used in the pathologic diagnosis of nonhematological solid tumors. In malignant hematological disease, p63 expression has been reported in 22% of follicular lymphoma, about 35% of diffuse large B-cell lymphoma, 23% of chronic lymphocytic leukemia, and in some cases of blast crisis of chronic myelogenous leukemia. Anaplastic large cell lymphoma is a rare disease that accounts for less than 5% of all cases of non-Hodgkin's lymphoma. There is little information concerning p63 expression in this specific type of lymphoma. In some cases, the morphological and phenotypic features between anaplastic large cell lymphoma and classical Hodgkin's lymphoma are similar, making this differential diagnosis challenging. We studied p63 expression using a tissue microarray approach in 154 cases of anaplastic large cell lymphoma, including 38% anaplastic large cell kinase positive and 62% anaplastic large cell kinase negative, and 58 Hodgkin's lymphoma cases. Sixty-eight cases of anaplastic large cell lymphoma (44%) showed p63 nuclear positivity (41% of anaplastic large cell kinase positive and 47% of anaplastic large cell kinase negative). Of 130 cases of systemic-anaplastic large cell lymphoma, 42% showed p63 positivity. The neoplastic cells expressed p63 in 38% of the cases of CD45-negative/anaplastic large cell kinase-negative null cell-type anaplastic large cell lymphoma, a subgroup that offers the most difficulties in the differential diagnosis with classical Hodgkin's lymphoma. In contrast, none of the cases of classical Hodgkin's lymphoma demonstrated any p63 expression. These results demonstrate that p63 protein expression is frequently expressed in a subset of anaplastic large cell lymphoma cases and may be used as a potential tool in the differential diagnosis between anaplastic large cell lymphoma and classical Hodgkin's lymphoma.     

儿童及青少年间变性大细胞淋巴瘤预后因素的Meta分析

目的:应用Meta分析方法,对儿童及青少年间变性大细胞淋巴瘤(ALCL)一些有争议的临床预后因素进行定量分析,以客观评价这些因素对患者生存率的影响.方法:计算机检索中英文数据库,搜索从建库起至2020年12月31日间,儿童及青少年ALCL回顾性队列分析的文献.筛选文献并提取其中的生存数据,应用Review Manage...     

ALK-negative anaplastic large cell lymphoma primarily involving the bronchus: a case report and literature review

Anaplastic large cell lymphoma (ALCL) is a mature T cell lymphoma with characteristic morphologic, immunophenotypic and cytogenetic features. Current WHO classification includes anaplastic lymphoma kinase (ALK)-positive and ALK-negative variants. ALCL rarely presents with obstructive symptoms of the main airway. In addition to reporting a HIV-associated bronchial ALK-negative ALCL in a 44 year-old female, our literature review identified eight cases of bronchial ALCL with several interesting clinicopathological features, including: 1) a female predominance (67%); 2) two thirds of patients younger than 18 years old; 3) uniformly presented with respiratory symptoms and progressed to respiratory failure; 4) the tumor involving the main airways; 5) often with localized disease at the initial presentation. This unusual presentation of ALCL may pose as a diagnostic pitfall and delay the treatment.     

Small cell variant of anaplastic large cell lymphoma diagnosed by a novel chromosomal abnormality t(2;5;3)(p23;q35;p21) of bone marrow cells

Because of the rarity and the morphological variations, small cell variant of anaplastic large cell lymphoma (ALCL) represents a diagnostic challenge. Herein is reported a case of leukemic type of small cell variant of ALCL, in which the diagnosis was established by a cytogenetic analysis. The patient was a 23-year-old woman who presented with fever and leukocytosis with circulatory atypical lymphoid cells. The initial differential diagnosis on bone marrow trephine biopsy sections included viral infection and peripheral T-cell lymphoma unspecified. But a cytogenetic study on bone marrow cells indicated a novel complex translocation, t(2;5;3)(p23;q35;p21), which led to confirmation of anaplastic lymphoma kinase (ALK)-positive pleomorphic small to medium-sized cells scattered in bone marrow cells, on immunohistochemistry. ALK was distributed in both nuclear and cytoplasmic regions of neoplastic cells. The patient achieved complete remission after four courses of combination chemotherapy, and received autologous peripheral stem cell transplantation (auto-PBSCT) after two additional courses of combination chemotherapy, but relapsed 2 months after auto-PBSCT in the bilateral lung. Allogeneic stem cell transplantation led to a second remission. This case demonstrates the diagnostic importance of cytogenetic study for malignant lymphoma involving bone marrow.     

Primary cerebral anaplastic large cell lymphoma containing abundant reactive histiocytes and eosinophils. A case report and literature review

Primary cerebral anaplastic large cell lymphoma (ALCL) is very rare. We report on our experience with such a case and review the literature. A 46-year-old Taiwanese woman presented with headache, weakness of her right extremity, and limited eye movement. A solid mass (5 cm x 4 cm) at the left occipital lobe was almost completely removed. The neoplastic cells, some of which had reniform or embryo-like nuclei, were large and were admixed with abundant eosinophils, histiocytes, and some small lymphocytes. These neoplastic cells expressed CD30, CD43, granzyme B and T-cell intracellular antigen-1, but not ALK1, CD3, CD20, CD45, CD79a, cytokeratin, and EMA. They were positive for Epstein-Barr virus-encoded mRNA by in situ hybridization. Polymerase chain reaction study of formalin-fixed tissue showed a clonal gene arrangement of the T-cell receptor-gamma chain. ALCL of T-cell lineage with cytotoxic phenotype was diagnosed. The patient received cranial irradiation and has remained with no evidence of disease for 25 months of follow-up.     

Cytomorphologic features of primary anaplastic large cell lymphoma of the psoas muscle: A case report and literature review

Ki‐1 (CD30) positive anaplastic large cell lymphoma (ALCL) is an uncommon malignancy, which may present with nodal as well as extra‐nodal disease. Primary skeletal muscle Ki‐1 (CD30) positive ALCL is an even rarer event with few cases reported in the literature and only some with published cytomorphologic features. An 83‐year‐old woman underwent a fine needle aspiration (FNA) of a psoas muscle mass. Smears demonstrated a predominantly discohesive population of large pleomorphic cells. The nuclei were hypechromatic and lobulated, with often multinucleation. Nucleoli were prominent in a subset of cells. Cytoplasmic vacuolization was also present. No lymphoglandular bodies were identified. A cytodiagnosis of malignant cells favoring metastatic melanoma vs. poorly differentiated carcinoma was rendered. Morphologic and immunohistochemical features later revealed a primary psoas muscle Ki‐1 (CD30) positive ALCL with negative staining for anaplastic large cell lymphoma kinase (ALK). Cytologic features of ALCL mimic epithelial neoplasms, sarcomas, melanoma and other lymphomas. Although rare, ALCL should be a diagnostic consideration when discohesive pleomorphic malignant cells are encountered on FNA of a muscle neoplasm. Diagn. Cytopathol. 2010. © 2009 Wiley‐Liss, Inc.     

Lymphohistiocytic anaplastic large cell lymphoma involving skin: A diagnostic challenge

Systemic anaplastic large cell lymphoma (ALCL) involving the skin should be differentiated from primary cutaneous CD30-positive T-cell lymphoproliferative disorders. The lymphohistiocytic variant of ALCL (LH-ALCL) is rich in reactive histiocytes with relatively few neoplastic cells, which pose a diagnostic challenge. We present a case of LH-ALCL involving skin mimicking granulomatous inflammation.     

间变性大细胞淋巴瘤组织间变性淋巴瘤激酶及survivin蛋白表达及其临床意义

目的研究间变性大细胞淋巴瘤（ALCL）中间变性淋巴瘤激酶（ALK）蛋白及survivin蛋白的表达特点及其临床意义。方法应用免疫组织化学LSAB法检测ALK蛋白及survivin蛋白的表达。结果ALK蛋白在81例ALCL中有51例（63％）阳性,30例（37％）阴性。ALK阳性患者预后优于阴性患者（P〈0．05）。survivin蛋白在77例ALCL中均有不同程度的表达,其中高表达33例（42．9％）,低表达44例（57．1％）。survivin的表达与ALK蛋白表达无关（P〉0．05）。预后：Survivin高表达患者较低表达者差（P〈0．05）。在ALK蛋白阳性病例中,survivin高表达患者较低表达者差（P〈0．05）;ALK阴性病例中,survivin的表达状况与预后无关（P〉0．05）。Cox比例风险回归分析表明ALK的表达、体质性症状及survivin的不同表达状况对存活的影响有统计学意义（P〈0．05）,其中ALK的表达对生存的影响最大,survivin表达的影响最小。结论survivin蛋白在ALCL中的表达与ALK蛋白的表达不相关,是一个独立的指标,可有助于判断ALK阳性ALCL病例的预后。     

Primary anaplastic large cell lymphoma in the dura of the brain: case report and prediction of a favorable prognosis

Anaplastic large cell lymphoma (ALCL) is a rare T-cell lymphoma composed of CD30-positive lymphoid cells. ALCL arising in the dura matter of the brain is even more infrequent, in which only one case has been reported worldwide so far. We report a case of a 30-year-old immunocompetent male with a dura-based mass, radiographically consistent with meningioma. However, the excised mass via a left parieto-occipital craniotomy was composed of large, pleomorphic lymphoid cells to be immunopositive for CD3, CD30, anaplastic lymphoma kinase protein-1 (ALK-1) and epithelial membrane antigen (EMA), and immunonegative for CD20, CD15 and CD68. Multiple ALK gene fusion signals in the ALK locus were detected by fluorescence in situ hybridization (FISH) analysis. The patient was treated with CHOP chemotherapy and intrathecal methotrexate along with brain radiation therapy, which resulted in a complete remission. In an analysis of 25 previously reported primary CNS ALCLs, ALK-1 positivity was shown to be prevalent in younger age, as ALCL occurs outside the brain. Patient less than 23 years, ALK-1 positivity and unifocal tumor may be associated with a better prognosis. However, sex, dural or leptomeningeal involvement, immune status, and tumor necrosis do not appear to have any influence on survival.     

Anti-CD30 antibody conjugated liposomal doxorubicin with significantly improved therapeutic efficacy against anaplastic large cell lymphoma

The use of nano-carriers has been shown to improve the delivery and efficacy of chemotherapeutic agents in cancer patients. Recent studies suggest that decoration of the surface of nano-carriers with various targeting moieties may further improve the overall therapeutic efficacy. In this study, we compared the therapeutic efficacy of Doxil^® (commercial doxorubicin-loaded liposomes) and that of Doxil^® conjugated with anti-CD30 antibodies (CD30-targeted Doxil^®) in treating anaplastic large cell lymphoma (ALCL), a type of T-cell lymphoma characterized by a high CD30 expression. Compared to Doxil^®, the CD30-targeted Doxil^® showed a significantly higher binding affinity to ALCL cells (5.3% versus 27%, p = 0.005) and a lower inhibitory concentration at 50% (IC50) in-vitro (32.6 μg/mL versus 12.6 μg/mL, p = 0.006). In a SCID mouse xenograft model, CD30-targeted Doxil^® inhibited tumor growth more significantly than the unconjugated formulation; specifically, tumors in mice treated with CD30-targeted Doxil^® were significantly smaller than those in mice treated with Doxil^® (average, 117 mm³ versus 270 mm³, p = 0.001) at 18 days after the tumors were inoculated. Our findings have provided the proof-of-principle of using CD30-targeted nano-carriers to treat cancers that are characterized by a high level of CD30 expression, such as ALCL.