Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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Dr Mohan Z Mani

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Professor & Head,
Department of Dermatolgy,
Believers Church Medical College,
Thiruvalla, Kerala
On Sep 2018




Prof. Somashekhar Nimbalkar

"Over the last few years, we have published our research regularly in Journal of Clinical and Diagnostic Research. Having published in more than 20 high impact journals over the last five years including several high impact ones and reviewing articles for even more journals across my fields of interest, we value our published work in JCDR for their high standards in publishing scientific articles. The ease of submission, the rapid reviews in under a month, the high quality of their reviewers and keen attention to the final process of proofs and publication, ensure that there are no mistakes in the final article. We have been asked clarifications on several occasions and have been happy to provide them and it exemplifies the commitment to quality of the team at JCDR."



Prof. Somashekhar Nimbalkar
Head, Department of Pediatrics, Pramukhswami Medical College, Karamsad
Chairman, Research Group, Charutar Arogya Mandal, Karamsad
National Joint Coordinator - Advanced IAP NNF NRP Program
Ex-Member, Governing Body, National Neonatology Forum, New Delhi
Ex-President - National Neonatology Forum Gujarat State Chapter
Department of Pediatrics, Pramukhswami Medical College, Karamsad, Anand, Gujarat.
On Sep 2018




Dr. Kalyani R

"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



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Professor and Head
Department of Pathology
Sri Devaraj Urs Medical College
Sri Devaraj Urs Academy of Higher Education and Research , Kolar, Karnataka
On Sep 2018




Dr. Saumya Navit

"As a peer-reviewed journal, the Journal of Clinical and Diagnostic Research provides an opportunity to researchers, scientists and budding professionals to explore the developments in the field of medicine and dentistry and their varied specialities, thus extending our view on biological diversities of living species in relation to medicine.
‘Knowledge is treasure of a wise man.’ The free access of this journal provides an immense scope of learning for the both the old and the young in field of medicine and dentistry as well. The multidisciplinary nature of the journal makes it a better platform to absorb all that is being researched and developed. The publication process is systematic and professional. Online submission, publication and peer reviewing makes it a user-friendly journal.
As an experienced dentist and an academician, I proudly recommend this journal to the dental fraternity as a good quality open access platform for rapid communication of their cutting-edge research progress and discovery.
I wish JCDR a great success and I hope that journal will soar higher with the passing time."



Dr Saumya Navit
Professor and Head
Department of Pediatric Dentistry
Saraswati Dental College
Lucknow
On Sep 2018




Dr. Arunava Biswas

"My sincere attachment with JCDR as an author as well as reviewer is a learning experience . Their systematic approach in publication of article in various categories is really praiseworthy.
Their prompt and timely response to review's query and the manner in which they have set the reviewing process helps in extracting the best possible scientific writings for publication.
It's a honour and pride to be a part of the JCDR team. My very best wishes to JCDR and hope it will sparkle up above the sky as a high indexed journal in near future."



Dr. Arunava Biswas
MD, DM (Clinical Pharmacology)
Assistant Professor
Department of Pharmacology
Calcutta National Medical College & Hospital , Kolkata




Dr. C.S. Ramesh Babu
" Journal of Clinical and Diagnostic Research (JCDR) is a multi-specialty medical and dental journal publishing high quality research articles in almost all branches of medicine. The quality of printing of figures and tables is excellent and comparable to any International journal. An added advantage is nominal publication charges and monthly issue of the journal and more chances of an article being accepted for publication. Moreover being a multi-specialty journal an article concerning a particular specialty has a wider reach of readers of other related specialties also. As an author and reviewer for several years I find this Journal most suitable and highly recommend this Journal."
Best regards,
C.S. Ramesh Babu,
Associate Professor of Anatomy,
Muzaffarnagar Medical College,
Muzaffarnagar.
On Aug 2018




Dr. Arundhathi. S
"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
The journal has a monthly publication and the articles are published quite fast. In time compared to other journals. The on-line first publication is also a great advantage and facility to review one's own articles before going to print. The response to any query and permission if required, is quite fast; this is quite commendable. I have a very good experience about seeking quick permission for quoting a photograph (Fig.) from a JCDR article for my chapter authored in an E book. I never thought it would be so easy. No hassles.
Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help one’s reviewing skills.
My best wishes to Dr. Hemant Jain and all the editorial staff of JCDR for their untiring efforts to bring out this journal. I strongly recommend medical fraternity to publish their valuable research work in this esteemed journal, JCDR".



Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


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

Important Notice

Original article / research
Year : 2023 | Month : June | Volume : 17 | Issue : 6 | Page : EC20 - EC24 Full Version

ALK-positive Large B-cell Lymphoma: A Clinicopathologic Retrospective Descriptive Study from a Tertiary Care Cancer Centre in India


Published: June 1, 2023 | DOI: https://doi.org/10.7860/JCDR/2023/62619.18104
Jayasudha Arundhathi Vasudevan, Rekha A Nair, Priya Mary Jacob, CM Simi, NP Prakash, Aleyamma Mathew

1. Associate Professor, Department of Pathology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India. 2. Director, Department of Pathology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India. 3. Associate Professor, Department of Pathology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India. 4. Assistant Professor, Department of Pathology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India. 5. Additional Professor, Department of Medical Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India. 6. Professor and Head, Department of Cancer Epidemiology and Biostatistics, Regional Cancer Centre, Thiruvananthapuram, Kerala, India.

Correspondence Address :
Dr. Jayasudha Arundhathi Vasudevan,
Associate Professor, Department of Pathology, Regional Cancer Centre, Thiruvananthapuram-695011, Kerala, India.
E-mail: drjayasiv@gmail.com

Abstract

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.

Keywords

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.

Material and Methods

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.

Results

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.

Discussion

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.

Conclusion

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.

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DOI and Others

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

PLAGIARISM CHECKING METHODS:
• Plagiarism X-checker: Jan 05, 2023
• Manual Googling: Feb 09, 2023
• iThenticate Software: Apr 18, 2023 (8%)

ETYMOLOGY: Author Origin

EMENDATIONS: 8

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