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Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journals–No manuscripts–No authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."
Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011
Dr. Shankar P.R.
"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."
Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011 Anuradha
Dear team JCDR, I would like to thank you for the very professional and polite service provided by everyone at JCDR. While i have been in the field of writing and editing for sometime, this has been my first attempt in publishing a scientific paper.Thank you for hand-holding me through the process.
Dr. Anuradha
E-mail: anuradha2nittur@gmail.com
On Jan 2020
Original article / research
Full Version
ALK-positive Large B-cell Lymphoma: A Clinicopathologic Retrospective Descriptive Study from a Tertiary Care Cancer Centre in India
Correspondence Address :
Dr. Jayasudha Arundhathi Vasudevan,
Associate Professor, Department of Pathology, Regional Cancer Centre, Thiruvananthapuram-695011, Kerala, India.
E-mail: drjayasiv@gmail.com
Introduction: Anaplastic Lymphoma Kinase (ALK) positive Large B-Cell Lymphoma (ALK+ LBCL) is a very rare aggressive B-cell lymphoma presenting significant diagnostic challenges due to their rarity and unique immunophenotypic features. ALK is a tyrosine kinase receptor and is expressed by ALK+ LBCL due to ALK rearrangement.
Aim: To analyse the histopathological features including morphology and immunophenotype, clinical details, pattern of care, Progression Free Survival (PFS) and overall survival of cases diagnosed as ALK+ LBCL.
Materials and Methods: This clinicopathological retrospective descriptive study was conducted in the Department of Pathology at a Tertiary Care Cancer Centre, Thiruvananthapuram, Kerala, India. The duration of the study was six months, from January 2022 to June 2022. All the cases of ALK+ LBCL were diagnosed over a period of 10 years, from January 1st 2010 to December 31st 2020. The cases of LBCL diagnosed during the 10 year period were reviewed. Clinical details were obtained from the case sheets of the cases diagnosed as ALK+ LBCL and summarised. Data collection variables included age, sex, stage, nodal and extranodal status, bone marrow, Central Nervous System (CNS) involvement, haemoglobin, Total Leukocyte Count (TLC) and platelet count, Lactate Dehydrogenase (LDH) value, performance status, date of diagnosis, date of treatment started, date of progression, date of last follow-up, date of death (if dead). Review of Haematoxylin and Eosin (H&E) sections and immunohistochemical slides were done and observations were recorded. Descriptive statistics was used to summarise the basic features of the dataset and Kaplan-Meier method was used for calculation of survival.
Results: The age of study participants ranged from 16-56 years. During the 10 year period, LBCL accounted for 2415 cases. Among these, ALK+ LBCL constituted 6 (0.25%) cases. There was a male predilection (n=5). Blood counts were normal except for anaemia in three patients. LDH was raised in all the patients. Advanced stage disease was present in two patients. Histopathologically, tumour cells in all the cases showed plasmablastic morphology. Immunohistochemistry (IHC) revealed plasma cell immunophenotype and positivity for ALK in all the cases. Cytokeratin (CK) and Epithelial Membrane Antigen (EMA) were positive in three cases simulating carcinomas. Six year overall survival and PFS in the present study was 50% and 33.3%, respectively.
Conclusion: Careful interpretation of the morphology and immunophenotype is essential for diagnosis of ALK+ LBCL, as it can be easily misdiagnosed as a non haematological malignancy thus, affecting the treatment and prognosis in these patients.
Anaplastic lymphoma kinase, Carcinoma, Frequency, Immunophenotype
The ALK is a receptor tyrosine kinase playing important role in the development of brain and regulation of nerve cell proliferation (1). ALK expression was initially found in Anaplastic Large Cell Lymphoma (ALCL) (2). The ALK gene is also found to be mutated in other tumours also, like ALK+ LBCL, epithelioid fibrous histiocytoma, inflammatory myofibroblastic tumour, adenocarcinoma of lung etc., (3),(4),(5),(6). The first description of ALK+ LBCL was in 1997 (3). It is an aggressive neoplasm of large B-cells and usually has a plasma cell phenotype. These tumours can also be mistaken for carcinomas as occasional cases show positivity for CK and EMA in combination with negative staining for LCA (7). The most frequent genetic abnormality is t (2;17) resulting in Clathrin Heavy Chain (CLTC)-ALK fusion protein (7). Disease has aggressive clinical course. Significantly longer survival is reported in those with localised disease (8). The present study emphasises the importance of correlation of morphology with an optimal immunohistochemical panel for the accurate diagnosis of ALK+ LBCL and to avoid misdiagnosing it as non haematopoietic neoplasms. Data on ALK+ LBCL is mainly available as case reports, case series, few review and research articles and have highlighted the rarity and the high possibility of pathological misdiagnosis because of its morphologic and immunophenotypic overlap with other haematopoietic and non haematopoietic neoplasms (8),(9),(10),(11),(12),(13),(14),(15),(16),(17),(18),(19),(20),(21),(22),(23),(24),(25),(26),(27),(28).
The present study adds to the existing number of cases to help in further understanding of clinicopathologic features, diagnosis and outcome of this rare entity. Aim of the present study was to study the morphology and immunophenotypic profile, clinical details, pattern of care, PFS and overall survival of patients diagnosed as ALK+ LBCL.
This was a clinicopathological retrospective descriptive study and was conducted in the Department of Pathology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India. The duration of the study was six months, from January 2022 to June 2022. Period of study was for a duration of 10 years from January 2010 December 2020. The study was approved by Human Ethics Committee, letter number (HEC No. 29/22 dated 24th May 2022). The study was in accordance with the ethical standards of the responsible committee on human experimentation (Institutional) and with the Helsinki Declaration of 1964 as revised in 2013. Waiver of informed consent was approved by HEC, as it was a retrospective study of six cases, involving only data collection and did not involve revealing the patient identity at any point of time.
Inclusion criteria: Cases of ALK+ LBCL, diagnosed in the centre during the study period were included in the study.
Exclusion criteria: Cases of ALK+ LBCL, whose slides and blocks could not be retrieved from the archives and the non registered cases were excluded from the study.
Study Procedure
The slides and blocks of selected cases were retrieved and reviewed. Case sheets of all the six cases were retrieved. The details of the cases were collected and entered into the proforma for analysis. Data collection variables included age, sex, stage, lymph node status, extranodal involvement, bone marrow, CNS involvement (neurological examination/radiological examination/pathological study by stereotactic biopsy/lumbar puncture) (29), haemoglobin (reference range-females: 12.1-15.1 gm/dL, males: 13.8-17.2 gm/dL), TLC (reference range-4500-11,000 White Blood Cells (WBC)/mL), platelet count (reference range-1,50,000-4,50,000/mL), LDH value (reference range-120-246 u/L), performance status {measured by Eastern Cooperative Oncology Group (ECOG) scale} (30), date of diagnosis, date of treatment started, date of progression, date of last follow-up, date of death (if dead). Primary outcome was the spectrum of morphologic and immunohistochemical profile of cases diagnosed as ALK+ LBCL. Secondary outcome was the clinical scenario, progression- free and overall survival of the cases (31). In order to reduce the lost to follow-up cases, the authors attempted to contact the patients through phone, and data were collected.
The IHC is a diagnostic laboratory technique used to detect specific antigens in tissues based on antigen-antibody recognition. It is important in diagnostic pathology for the diagnosis and classification of tumours. IHC is also important for identification of prognostic and predictive markers (32). Immunophenotyping by IHC was done by automation in Ventana BenchMark XT. Panel of antibodies used for IHC include Cluster of Differentiation (CD) markers CD45 (clone 2B11-PD7/26, Dallas Area Kitefliers Organisation (DAKO), 1:500 dilution), CD20 {clone L26, DAKO, 1:50 dilution), CD79a (clone JCB117, DAKO, Ready-to-Use (RTU)}, CD5 (clone4C7, Biocare, 1:50 dilution), CD30 (clone Beryllium hydride2 (BeH2), DAKO, 1:50 dilution), CD138 (clone M115, DAKO, 1:50 dilution), CD38 (clone Epithelial (EP)135, PathnSitu, RTU), CK (clone AE1/AE3, DAKO, 1:100 dilution), EMA (clone E29, DAKO, 1:50 dilution), PAX5 (Paired box 5) (clone DAK-nuclear protein in the paired-box (PAX5), DAKO, RTU), Multiple Myeloma1 (MUM1) (clone MUM1p, DAKO, RTU), Ki-67 (Kiel-67) (clone MIB1, DAKO, 1:50 dilution), ALK (clone ALK-1, DAKO, 1:50 dilution), Kappa (clone L1C1, Biocare, 1:50 dilution), Lambda (clone N10/2, Biocare, 1:50 dilution), CyclinD1 (clone SP4, Biocare, 1:50 dilution) and CD56 (123C3, DAKO, RTU).
Statistical Analysis
Descriptive statistics such as mean, standard deviation, frequency and percentage were calculated. Kaplan-Meier method was used for calculating survival.
During the 10 years of period, around 2415 cases of LBCL were diagnosed in the cancer centre. Among these, ALK+ LBCL constituted 6 (0.25%) cases. Clinical details are summarised in (Table/Fig 1). Age ranged from 16-56 years. There was a male predominance 5 (83.33%) cases. Anaemia was present in four patients. TLC and platelet counts were within the normal range in all patients. LDH was raised in all patients and ranged from 546 u/L-1686 u/L. Advanced stage disease was seen in 2 (33.33%) patients. Among the two patients, one patient is alive with evidence of disease and the other patient died of disease. Bone marrow was uninvolved in all the cases.
Histopathology of all the cases showed, large tumour cells with plasmablastic appearance and diffuse infiltrative growth patterns.
Analysis of IHC findings revealed that, tumour cells in all the cases were positive for ALK in a cytoplasmic granular pattern (Table/Fig 2),(Table/Fig 3),(Table/Fig 4),(Table/Fig 5),(Table/Fig 6). The LCA was positive with varying intensity in five cases. CK was positive with varying intensity in three cases. CD20 was negative in all the cases. MUM1 and CD138 were positive in all the cases. Immunophenotype is summarised in (Table/Fig 7). Cases three and four were challenging as tumour cells were focally weak positive to negative for LCA coupled with weak positivity for CK. Case 4 presented with epigastric mass and was positive for CK, EMA, c-Kit and negative for LCA by IHC. Kappa lambda light chain staining was done in four cases and showed light chain restriction in three cases.
Patients were primarily treated by Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisolone (CHOP) regimen. Relapsed and refractory cases were managed by Dexamethasone, High Dose Cytarabine, Cisplatin (DHAP), Ifosfamide, Carboplatin, Etoposide (ICE) regimens according to the age and performance status of individuals. Follow-up at four years was 100% and at five years was 83.3%. Median follow-up period was 75 months. Six-year overall survival was 50% (SE=0.20) and PFS was 33.3% (SE=0.19) (Table/Fig 8)a,b.
The ALK+ LBCL is rare and accounts for less than 1% of LBCL (7). The frequency of ALK+ LBCL is similar to that mentioned in literature (7). Median age reported in literature, is 43 years with age range of 9-85 years (7). Age range mentioned in the present study, is similar to that in other studies (9),(10),(11),(12),(13),(14). One third of cases of ALK+ LBCL are reported in paediatric age group (7). ALK+ LBCL shows a male predilection, which was also seen in the present study (7). ALK+ LBCL are primarily a nodal disease (7). All patients had primary involvement of nodes. Among the extranodal sites, upper airway is the most affected site (10). Other sites includes bone, gastrointestinal tract, spleen, liver and skin (7),(10). Case 4 and 5 showed contiguous involvement of liver and small intestine, respectively. Bone marrow was uninvolved in all the six cases. Bone marrow is reported to be involved in 25% of cases of ALK+ LBCL but none of the cases in the present study had bone marrow involvement (7). Another study showed bone marrow infiltration in 33% of patients (10). Although, patients are more likely to present with advanced stage disease (stage 3/4), advanced disease was present in 2 (33.33%) cases.
Advanced stage disease is reported in around 60% of patients (7),(10). Morphology of tumour cells in all the cases showed a plasmablastic appearance. IHC also showed plasma cell phenotype in all the cases. Cases 2, 3 and 4 mimicked non haematopoietic tumours as tumour cells were weakly positive for CK and were focally positive to negative for LCA. Case 4 presented with epigastric mass and was positive for CK, EMA, c-Kit and negative for LCA by IHC, thus, initially suggesting the diagnosis of epithelioid gastrointestinal stromal tumour. These cases can be easily misdiagnosed morphologically and immunophenotypically as non haematopoietic neoplasms or other haematopoietic neoplasms with a limited panel of IHC markers (7),(10),(11),(12),(13),(14). Comparison of IHC of the present study and similar other published studies is given in (Table/Fig 9) (9),(12),(13),(17),(18),(26).
Differential diagnosis of these tumours includes metastatic carcinomas, LBCL {Diffuse large B cell lymphoma (DLBCL)- anaplastic variant, Primary Effusion Lymphoma (PEL), plasmablastic lymphoma} plasmacytoma, Anaplastic Large Cell Lymphoma (ALCL) of T-cell origin (7). Occasional cases of ALK+ LBCL are positive for CK, EMA and negative for LCA thus, simulating carcinomas (7). MUM1 positivity in ALK+ LBCL will help in differentiating from carcinomas in these instances. Carcinomas are MUM1 negative (13). Napsin A which is a marker of lung and ovarian adenocarcinomas can also be positive in ALK+ LBCL. A small subset of ALK positive lung adenocarcinomas, further add to the diagnostic difficulty. All the documented cases of napsin positive ALK+ LBCL are LCA positive (15),(16). DLBCL anaplastic variant express pan B-cell lineage antigens and is negative for ALK (7). PEL usually present clinically as serous effusions and is universally associated with HHV-8 and usually occurs in immunodeficiency settings (7),(13). They express LCA, but lack pan B cell lineage antigens. Plasma cell markers are often positive by IHC. Tumour cells are positive for HHV-8 and negative for ALK (7),(13). Tumour cells are also positive for Epstein-Barr Encoding Region (EBER) by in-situ hybridisation. ALK+ LBCL usually occur in immunocompetent individuals and is negative for EBER and HHV-8 (7). Plasmablastic Lymphoma (PBL) mostly occurs in association with Human Immunodeficiency Virus (HIV) infection. It is a high grade lymphoma with plasmablastic features morphologically and immunophenotypically, negative for ALK and express EBER by in-situ hybridisation (7),(33),(34). Plasmacytoma with plasmablastic morphology can simulate ALK+ LBCL but, ALK is negative in plasmacytoma. Plasmacytoma is also characterised by distinctive clinical, biochemical and radiology findings. Demonstration of molecular alteration t (11;14) in a tumour with plasmablastic features is diagnostic of plasmacytoma (35). ALK positive ALCL of T-cell origin is CD30 strongly positive. ALK+ LBCL are negative for T-cell lineage markers and is negative for CD30 although, focal weak staining of CD30 is reported (7).
Six-year overall survival was 50% and PFS was 33.3%. The median overall survival of patients with advanced stage disease is reported to be 11 months (17). Morgan EA and Nascimento AF, reported five-year survival rate of 25% with a median survival of 12 months herpesvirus(11). Pan Z et al., reported five year overall survival of 34% and median survival of 1.83 years (9). Castillo JJ et al., reported five year overall survival of 28% (10). Another study showed a median overall survival of nine months (14). Improved overall survival and PFS were noted in the present study but, statistical significance cannot be assessed due to limited number of cases.
Limitation(s)
Limitation of the study was that, molecular studies were not done and no statistical significance can be carried out due to the small sample size of the study.
The ALK+ LBCL are a very rare clinically aggressive B cell lymphoma, which usually displays plasmablastic morphology and plasma cell immunophenotype. Awareness of this rare entity is extremely important, as it can be easily misdiagnosed as a non haematopoietic neoplasm due to its unique immunophenotypic profile.
DOI: 10.7860/JCDR/2023/62619.18104
Date of Submission: Jan 03, 2023
Date of Peer Review: Feb 17, 2023
Date of Acceptance: Apr 21, 2023
Date of Publishing: Jun 01, 2023
AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? Yes
• Was informed consent obtained from the subjects involved in the study? Yes
• For any images presented appropriate consent has been obtained from the subjects. NA
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