ISSN: 1948-5956
Journal of Cancer Science & Therapy
Make the best use of Scientific Research and information from our 700+ peer reviewed, Open Access Journals that operates with the help of 50,000+ Editorial Board Members and esteemed reviewers and 1000+ Scientific associations in Medical, Clinical, Pharmaceutical, Engineering, Technology and Management Fields.
Meet Inspiring Speakers and Experts at our 3000+ Global Conferenceseries Events with over 600+ Conferences, 1200+ Symposiums and 1200+ Workshops on
Medical, Pharma, Engineering, Science, Technology and Business

ALK-postive Large B-cell Lymphoma: Report of Two Cases and Review of the Literature

Hong Yu1, Xiao-jian Liu2, Hui Li3, Da-ren Shi4 and Chao-Fu Wang4*
1Department of Pathology,Taizhou People’s Hospital, Jiangsu Province, 210 Yingchun Road, Taizhou 225000, China
2Department of Oncology, Cancer Hospital of Fudan University , Shanghai, 270 Dongan Road, Shanghai 200032, China
3Department of Pathology, Shanghai Medical College, Fudan University,130 Dongan Road, Shanghai 200032, China
4Department of Pathology, Cancer Hospital of Fudan University,270 Dong An Road, Shanghai 200032, China
Corresponding Author : Dr. Chao-Fu Wang, MD, PhD
Department of Pathology
Cancer Hospital of Fudan University
270 Dong An Road, Shanghai, 200032, China
Tel: +86-21-64175590-8320
Fax: +86-21-64170067
Received April 07, 2011; Accepted November 18, 2011; Published November 20, 2011
Citation: Yu H, Liu XJ, Li H, Shi DR, Wang CF (2011) ALK-postive Large B-cell Lymphoma: Report of Two Cases and Review of the Literature. J Cancer Sci Ther 3: 228-232. doi: 10.4172/1948-5956.1000094
Copyright: © 2011 Yu H, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Related article at
DownloadPubmed DownloadScholar Google

Visit for more related articles at Journal of Cancer Science & Therapy

Case Descriptions
Case 1
A 25-year old man presented a mass on the right neck that had been noticed for about one month. Physical examination showed the mass of right neck was 1.5×1.2×1.0cm in size with a tender. No fever was reported. Hematologic studies, lactate dehydrogenase and serum protein electrophoresis were all within normal limits. An excisional biopsy of the mass was done, and the diagnosis of ALK+ LBCL was finally made (see below). Bone marrow biopsy, computed tomography (CT), and magnetic resonance imaging (MRI) of the thorax and abdomen were performed. The results showed bone marrow was negative for involvement by lymphoma, and no additional mass lesion or lymphadenopathy was detected anywhere else in the body. The disease was in stage I. The patient underwent six cycles of CHOP chemotherapy followed by right neck irradiation. Follow-up imaging studies showed no evidence of recurrence. At 16 months, he was free of disease.
Case 2
A previously healthy 32-year old man complained of a rapidly enlarging tender lump on his left neck with a low fever for about 2 months. Physical examination showed he had superficial lymphadenopathies in his axillary and inguinal areas besides the mass of left neck. CT imaging showed no other mass or lymphadenopathy in anywhere else in the body. The range of the lymphadenopathies in size is from 1.5cm to 3.0cm in the maximum diameter. An excisional biopsy of the neck mass was done, and the diagnosis of ALK+ LBCL was finally made (see below). A bone marrow biopsy was followed, and no involvement by lymphoma was found. Other laboratory tests showed no distinct abnormalities. The disease was in stage III. The patient underwent six cycles of CHOP chemotherapy therapy, and died at 8 months after diagnosis.
The clinical features of the two patients are summarized in Table 1.
Materials and Methods
Preparation of specimen
The two cases were sent to our department for consultation from other hospitals with the samples of hematoxylin and eosin(HE) slides and corresponding paraffin blocks. The submitted paraffinembedded tissue blocks were respectively cut into 3μm, 4μm, and 6μm sections for HE staining, Immunohistochemical staining, and DNA extraction,respectively. Additionally, the tumor tissue of case 1 from the submitted paraffin-embedded tissue blocks was cut 6 sections in 10μm thickness for RNA extraction. Clinical and laboratory data for each of the two patients were obtained through physician interview and medical chart review.
Immunohistiochemical analysis
Immunohistochemical analysis was performed for the two cases on 4μm formalin-fixed, paraffin-embedded tissue sections using EnVision (Dako, Denmark) two-step method. Briefly, the sections were deparaffinized with xylene and rehydrated using graded ethanol concentrations. After heat-induced antigen retrieval in 0.01 mol/L citrate buffer (pH6.0), the slides were incubated with primary antibodies (Dako) LCA, ALK1, EMA, CD57, IgA, CD138, VS38C, CD3, CD45RO, CD20, CD79a, CD68, and CD30 (Table 2) at 4°C overnight. The next day, the sections were washed with phosphate buffered saline three times, incubated with the EnVision reagent (Dako) at room temperature for 30 minutes, visualized with 3,3′-diaminobenzidinechromagen solution and finally counterstained with hematoxylin (Sigma). Appropriate positive and negative tissue control samples were used with each run.
Clone rearrangement of IgH gene by DNA PCR
Five 6μm paraffin-embedded sections of tumor tissues of the two cases were deparaffinized. The 6μm sections were lightly stained with hematoxylin for microdissection The microdissections were performed under a dissection microscope with a scalpel. Tumor cells should account for at least 80% of the total cells isolated. The microdissected tissues were transferred directly into an Eppendorf tube with 200μl cell lysis buffer (0.5 mol/L Tris-HCl, 20 mmol/L EDTA, 10 mmol/L NaCl, 10 g/L SDS, 0.5 g/L Proteinase K). The subsequent DNA extraction was performed according to the protocol of the DNA extraction kit (Qiagen). PCR amplification was performed with the condition described by Tan et al. [2] employing commercially available PCRbased kits (InVivoScribe Technologies, San Diego, CA). No template DNA was used as negative control. PCR products were analyzed by electrophoresis using 1.0% agarose gels, stained with ethiudium bromide.
RNA extraction and RT-PCR sequencing
Total RNA of case 1 was extracted from tumor tissue using Trizol reagent (Invitrogen Life Technologies) as described previously [3-5]. RNAs extracted from the t(2;5)-positive SU-DHL-1 and Karpas299 cell line were used as positive controls, while DEPC water and RNA from proper negative tissue (normal lymph node) were used as negative controls. Reverse transcription of RNA into cDNA was performed by incubating one μg RNA (purified by DNase digestion using TURBO DNase from Ambion), one μL of random primer (Promega, USA), and 200 U of reverse transcriptase (Promega, USA) in a 25 μL reaction volume at 37°C for one hour. One μL cDNA was then submitted to PCR amplification. To assess the quality of cDNA, the transcript of a housekeeping gene PGK was simultaneously detected as an internal control. PCR reaction was performed using specific primers (CLTC F-GAAGGAGTACTTGACAAAGGTGGAT; ALK R-CGGAGCTTGCTCAGCTTGTA). Information regarding the primers, their sequences and annealing temperatures were previously described. The optimized thermal cycling condition for ALK mRNA and ALK-associated fusion gene amplification consisted of an initial denaturation step at 95°C for 10 minutes and then 42 cycles of 94°C for 30 seconds, 57°C/60°C for 30 seconds, and 72°C for 1 minute, followed by a final extension at 72°C for 10 minutes. The presence of PCR products was tested using 2% agarose gels, compared with a 100 bp DNA marker. After the bands were clearly observed and the sized was determined, the products were purified. Sequencing was performed on the ABI Prism 3730 Sequence Detector System. ALK and CLT structures were obtained from Ensembl (
The histologic findings in the two cases were similar. They showed a diffusely infiltrating growth pattern, but focally arranged in nested and gland-like construction in case 1. Neoplasm cells exhibited distinct immunoblast-like morphologic features with regular uniform big round nuclei containing large central nucleoli and moderate lightly basiphilic cytoplasm. Both of the cases presented similar immunophenotypic profiles, the tumor cells were positive for LCA, ALK1, IgA, CD138, CD38, VS38c, CD57, EMA, whereas negative for CD20, CD79a, CD3, CD45RO, CD30 and CD68. With regard to ALK protein, its expression in the two cases was restricted to the cytoplasm that showed a fine granular cytoplasmic-staining pattern ALK expression (Figure 1). The rearrangement of the clone IgH gene was found in the two cases, and ALK-CLTC fusion was identified by direct sequencing in case 1 (Figure 2). (Test of ALK-CLTC fusion was not performed in case 2).
ALK+ LBCL was originally described by Delsol et al. [3] in 1997. This lymphoma was identified due to its characteristic lack of CD30 expression in an otherwise large series of classical T-/null cell ALKpositive anaplastic large cell lymphomas (ALCL) [4]. It showed very aggressive behavior, high relapse rate and little response to standard regimens [5]. For the time being, this rare tumor had been recognized as “Diffuse large B-cell lymphoma with expression of full-length ALK” by WHO classification of lymphomas (3th edition) [6]. The disease was defined as an entity, and termed “ALK positive large B-cell lymphoma” in the latest WHO classification of lymphomas (4th edition) [7]. This lymphoma often exhibited a sinusoidal growth pattern and was composed of monomorphic large immunoblast-like cells with round pale nuclei containing large central nucleoli and abundant cytoplasm, or showed plasmablastic differentiation. Atypical multinucleated neoplastic giant cells might be seen [8,9]. It was revealed to derive from B cells based on expression of monotypic light chain [8], but exhibited a unique immunophenotypic profile characterized by cytoplasmic, granular ALK reactivity consistently [10] with expression of EMA, plasmacytic markers (e.g CD38, CD138), and variable expression of CD4 and CD57, while often lacking expression of B-lineage (e.g CD20, CD79a), T-lineage (e.g CD2, CD3) markers and CD30. Genetic studies showed that the majority of ALK+ LBCL cases were characterized by the CLTC-ALK fusion, and a small minority had the NPM-ALK rearrangement [11]. Although ALK+ LBCL is one of B cell lymphomas, it expresses EMA and plasma cell markers (CD38, CD138, VS38c) instead of expressing CD20 and CD79a, which may be mistaken as metastatic poorly differentiated carcinoma or plasma cell neoplasm. It is a potential challenge for pathologists to make the diagnosis due to the abnormal immunophenotypes as well as infrequence of the entity.
Clinically, the average age of the reported ALK+ LBCL in the literature was 37.9 years, ranging from 9 to 72 years of age with a bimodal age distribution, with an average age of 12.5 years in the nonadult and an average age of 43.5 years in the adult. The male to female ratio was about 3:1. Data on primary sites of presentation were available in 51 cases. Twenty-seven (52.9%) were exclusively nodal in origin. The lymph node was the commonest primary site of involvement, particularly cervical and mediastinal areas. The remaining cases (47.1%) had some extranodal component, including bone (n=9), liver and spleen (n=4), head and neck (n=4), gastrointestinal tract (n=3), and others (n=8) including bone marrow, CNS, gonads and muscle. Both of our patients were male. One was 25 years and the other was 32 years. The sites of involvement were both located in the lymph nodes.
Microscopically, ALK+ LBCL is characteristic of immunoblastic/ plasmablastic microscopical appearance with round nuclei, prominent single central nucleoli, and abundant cytoplasm. Sometimes, the neoplastic cells demonstrate ample eosinophilic cytoplasm, somewhat resembling epithelioid appearance. This lymphoma often shows a sinusoidal growth pattern. In this report, both of the presented cases mainly showed a diffusely infiltrating pattern instead of sinusoidal growth.However, the neoplastic cells in case 1 showed focally nested and gland-like arrangement. In terms of morphology, differential diagnosis of ALK+ LBCL should include anaplastic variant of DLBCL, plasmablastic lymphoma, plasmblastic myeloma, and metastatic pooly differentiated carcinomas.
Immunohistochemically, this lymphoma does rarely express the usual B-lineage (e.g. CD 19, CD20, CD79a) or T-lineage markers (e.g. CD2, CD3, CD7), demonstrating the “null” phenotype with ALK expression and EMA, which strongly suggests an anaplastic large cell lymphoma (ALCL). ALK+ LBCL, however, expresses plasmacytic differentiation markers, such as CD138, CD38, and VS38c besides ALK and EMA.
ALK+ LBCL presents 100% positivity for plasmacytic differentiation markers like CD138, VS38c and MUM. EMA was expressed in 97% of the cases. B-cell related antigens such as CD20 and CD79a were expressed in ALK+ LBCL in 11% and 18%, respectively. These observations support the inference that ALK+ LBCL is derived from post-germinal B-cell lymphocytes that have undergone class switching and plasmacytic differentiation. Additionally, expression of monotypic cytoplasmic light chain occurred in 85% of all cases. Based on these findings, ALK+ LBCL falls into the category of non-GC DLBCL [5,12]. In our study, both cases exhibited immunophenotypic profiles similar to those in the published literature. Table 3 shows immunohistochemical features of 55 cases of ALK+ LBCL reported in the literature.
Genetically, the most frequent ALK gene rearrangement was clathrin-ALK in 75% cases; however 17% corresponded to NPMALK fusion [11,13,14]. The ALK gene is located on chromosome 2p23 and it can be translocated to either the clathrin gene locus located on chromosome 17q23 or to the NPM1 gene located on chromosome 5q35, constituting the clathrin-ALK or NPM-ALK fusion products, respectively [11,12,15]. In the literature, the clone rearrangement of immunoglobulin heavy chain (IgH) gene was investigated by PCR in 20 studied cases of ALK+ LBCL, and the rearrangement was found in 17 of the 20 cases (85%), which confirmed the B-cell lineage of this disorder. In this report, the fusion in case 1 was studied employing analysis of direct sequencing, and CLTC-ALK fusion was found, which was identical to those reported previously [10,12,15-17]. Additionally, the rearrangement of the IgH gene was detected in both cases. Table 4 shows genetic features of investigated cases of ALK+ LBCL reported in the literature.
Prognostically, the clinical course of ALK+ LBCL was aggressive with primary refractory disease and high relapse rates. Its prognosis depended largely on clinical stage [10]. The classical CHOP regimen appeared insufficient to treat this condition, which indicates newer, more intensive therapies will be needed, even though some cases could have prolonged survival times as the authors described in the article [10]. In this report, both patients were treated with six cycles of CHOP chemotherapy. Case 1, in stage I and simultaneously treated with radiation therapy, was alive at 16 months after diagnosis. Another patient, in stage III, treated with CHOP chemotherapy, died at 8 months after diagnosis.
We believe that a combination of chemotherapy and radiotherapy could prolong the survival time, while stage of disease could be the most important prognosis factor. To improve understanding of ALK+ LBCL and develop newer therapeutic techniques for its treatment, more collection of patient cases and prospective studies are needed.

Select your language of interest to view the total content in your interested language
Share This Article
Relevant Topics
Disc Abnormal Pap Test
Disc Acute Lymphoblastic Leukemia
Disc Acute Megakaryocytic Leukemia
Disc Acute Myelomonocytic Leukemia
Disc Acute Myleoid Leukemia
Disc Adenocarcinoma pancreas
Disc Advances in Alternative Lung Cancer Treatment
Disc Advances in Breast Cancer Treatment
Disc Aleukemic Leukemia
Disc Alternative Treatments for Breast Cancer
Disc Anal Cancer Diagnosis
Disc Anti-Cancer Drug
Disc Apoptosis
Disc Bile Duct Cancer
Disc Biliary Cancer
Disc Bladder Cancer Diagnosis
Disc Blood Cancer Diagnosis
Disc Bone Cancer Stages
Disc Bone Marrow Cancer Survival
Disc Brain Cancer Diagnosis
Disc Brain Tumor Treatment
Disc Breast Cancer Biology
Disc Breast Cancer Cure
Disc Breast Cancer Diagnosis
Disc Breast Cancer Grading
Disc Breast Cancer Prevention
Disc Breast Cancer Radiotherapy
Disc Breast Cancer Research
Disc Breast Cancer Surgery
Disc Breast Cancer Therapeutic & Market Analysis
Disc Breast Screening
Disc Cancer Diagnosis
Disc Cancer Science
Disc Cancer Therapies
Disc Cancer initiation and progression
Disc Cancer therapy
Disc Carcinogenesis
Disc Carcinoid Tumours
Disc Cellular Oncology
Disc Cervical Biopsy
Disc Cervical Cancer Diagnosis
Disc Cervical Cancer Prevention
Disc Cervical Cancer Treatment
Disc Cervical Intra-epithelial Neoplasia (CIN)
Disc Cervical Screening
Disc Cervix-Cancer
Disc Chemo Resistance
Disc Chronic Lymphocytic Leukemia
Disc Chronic Myleloid Leukemia
Disc Clinical Oncology
Disc Colon Cancer Diagnosis
Disc Colon Cancer Surgery
Disc Colorectal Cancer
Disc Colposcopy
Disc Comparative Oncology
Disc Cone Biopsy
Disc DNA damage
Disc Dental Oncology
Disc Dermatologic Surgery
Disc Ductal adenocarcinoma
Disc Duodenal Cancer
Disc Electro Chemotherapy
Disc Esophageal Cancer
Disc Esophageal Cancer Diagnosis
Disc Feline Leukemia Complex
Disc Fibrocystic Breast
Disc Gall Bladder Cancer
Disc Gastro Intestinal Cancer Treatment
Disc Gastro Intestinal Stromal Tumours
Disc Gastroesophageal (GE) Junction Cancer
Disc Gastrointestinal Carcinoid Tumours
Disc Genital Warts
Disc Genitourinary Oncology
Disc Gynecological Cancers
Disc HPV Vaccination
Disc Hairy Cell Leukemia
Disc Hereditary Breast Cancer
Disc Human Immunodeficiency Virus (HIV)
Disc Human Papillomavirus (HPV)
Disc Inflammatory Breast Cancer
Disc Interventional Oncology
Disc Invasive Ductal Carcinoma
Disc Jaundice
Disc Kidney Cancer Diagnosis
Disc Kidney Cancer Prognosis
Disc Kidney Cancer Surgery
Disc Leukemia
Disc Leukemia Diagnosis
Disc Leukemia Drugs
Disc Leukemia Surgery
Disc Liver Cancer Diagnosis
Disc Lung Cancer Diagnosis
Disc Lung Cancer Surgery
Disc Lung Tumor
Disc Lungs Cancer Cure
Disc Lymph Node Cancer
Disc Lymphoma Cancer
Disc Lymphoma Diagnosis
Disc Lymphoma Surgery
Disc Lymphoma Symptoms
Disc Lymphomatous polyposis
Disc Lymphosarcoma
Disc Making Strides in Breast Cancer
Disc Mast Cell Leukemia
Disc Mastectomy
Disc Mesothelioma Diagnosis
Disc Metastatic Breast Cancer
Disc Molecular Oncology
Disc Mouth Cancer Diagnosis
Disc Musculoskeletal Oncology
Disc Mutagenesis
Disc Neurofibromatosis Type 1
Disc Oesophageal Cancer
Disc Oesophageal Cancer Surgery
Disc Oncology Analytics
Disc Oncology Emergency
Disc Oncology Esthetics
Disc Oncology Nutrition
Disc Oseophagus Cancer
Disc Ovarian Cancer Diagnosis
Disc Ovarian Cancer and Prognosis
Disc Pancreatic Cancer
Disc Pancreatic Cancer Diagnosis
Disc Pancreatic Cancer Surgery
Disc Pancreatic Islet Cell Cancer
Disc Papanicolaou Screening
Disc Pediatric Leukemia
Disc Photo carcinogenesis
Disc Plasma Cell Leukemia
Disc Prostate Cancer Diagnosis
Disc Prostate Cancer Surgery
Disc Radiation Therapy
Disc Radio Oncology
Disc Radiotherapy
Disc Radiotherapy for Breast Cancer
Disc Rectal Cancer Diagnosis
Disc Sarcoma Cancer
Disc Sexually Transmitted Disease (STD)
Disc Skin Cancer Diagnosis
Disc Skin Cancer Surgery
Disc Small Bowel Cancer
Disc Small Intestine Cancer
Disc Smoking in Breast Cancer
Disc Spleen Cancer
Disc Squamous Cell Cancer (SCC)
Disc Squamous Cell Carcinoma
Disc Stomach Cancer
Disc Stomach Cancer Surgery
Disc Terminal Breast Cancer
Disc Testicular Cancer Diagnosis
Disc Thoracic Oncology
Disc Throat Cancer Surgery
Disc Thyroid Cancer Diagnosis
Disc Thyroid Cancer Surgery
Disc Tumorigenesis
Disc Uterine Cancer Diagnosis
Disc Vaginal Oncology
Disc Venereal Disease
Disc Veterinary Oncology
Recommended Journals
Disc Gastrointestinal Cancer Journal
Disc Colorectal Cancer Journal
Disc Cervical Cancer Journal
Disc Breast Cancer Journal
Disc Cancer Surgery Journal
Disc Cancer Diagnosis Journal
Disc Leukemia Journal
Disc Integrative Oncology Journal
Disc Carcinogenesis & Mutagenesis Journal
Disc Chemotherapy Journal
  View More»
Recommended Conferences
Disc 10th Oncologists Conference
June 06-08, 2016 Cologne, Germany
Disc 11th Oncologists Meeting
July 11-13, 2016 Kuala Lumpur, Malaysia
Disc 10th Global Nursing & Healthcare Conference
August 18-20, 2016 São Paulo, Brazil
Disc 2nd World Congress on Breast Cancer
September 19-21, 2016 Phoenix, Arizona,USA
Disc Oncology Nursing Congress
September 19-21, 2016 Las Vegas, USA
Disc 12th Cancer Therapy Conference
September 26-28, 2016 London, UK
Disc 3rd World Congress on Women’s Health and Breast Cancer
October 03-05, 2016 London, UK
Disc 15th Euro Nursing & Medicare Summit
October 17-19, 2016 Rome, Italy
Disc 13th Cancer Therapy Summit
October 17-19, 2016 Dubai, UAE
Disc 6th Cancer Therapy Congress
December 01-03, 2016 Baltimore, USA
Disc 10th Nursing and Healthcare
December 05-07, 2016 Dallas, USA
Article Tools
Disc Export citation
Disc Share/Blog this article
Article usage
  Total views: 11183
  [From(publication date):
November-2011 - May 24, 2016]
  Breakdown by view type
  HTML page views : 7456
  PDF downloads :3727

Post your comment

captcha   Reload  Can't read the image? click here to refresh

OMICS International Journals
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals
OMICS International Conferences 2016-17
Meet Inspiring Speakers and Experts at our 3000+ Global Annual Meetings

Contact Us

Agri, Food, Aqua and Veterinary Science Journals

Dr. Krish

1-702-714-7001 Extn: 9040

Clinical and Biochemistry Journals

Datta A

1-702-714-7001Extn: 9037

Business & Management Journals


1-702-714-7001Extn: 9042

Chemical Engineering and Chemistry Journals

Gabriel Shaw

1-702-714-7001 Extn: 9040

Earth & Environmental Sciences

Katie Wilson

1-702-714-7001Extn: 9042

Engineering Journals

James Franklin

1-702-714-7001Extn: 9042

General Science and Health care Journals

Andrea Jason

1-702-714-7001Extn: 9043

Genetics and Molecular Biology Journals

Anna Melissa

1-702-714-7001 Extn: 9006

Immunology & Microbiology Journals

David Gorantl

1-702-714-7001Extn: 9014

Informatics Journals

Stephanie Skinner

1-702-714-7001Extn: 9039

Material Sciences Journals

Rachle Green

1-702-714-7001Extn: 9039

Mathematics and Physics Journals

Jim Willison

1-702-714-7001 Extn: 9042

Medical Journals

Nimmi Anna

1-702-714-7001 Extn: 9038

Neuroscience & Psychology Journals

Nathan T

1-702-714-7001Extn: 9041

Pharmaceutical Sciences Journals

John Behannon

1-702-714-7001Extn: 9007

Social & Political Science Journals

Steve Harry

1-702-714-7001 Extn: 9042

© 2008-2016 OMICS International - Open Access Publisher. Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version