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

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On Sep 2018




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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
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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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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.
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Professor and Head
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Saraswati Dental College
Lucknow
On Sep 2018




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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 : 2021 | Month : August | Volume : 15 | Issue : 8 | Page : EC05 - EC11 Full Version

Primary Ovarian Non-Hodgkin LymphomaA Diagnostic Challenge with Clinicopathological Study of Eight Cases


Published: August 1, 2021 | DOI: https://doi.org/10.7860/JCDR/2021/50649.15235
Nikita Mulchandani, Suma Mysore Narayana, Chennagiri S Premalata, Mohit Agrawal, Venkateshaiah Reddihalli Pallavi

1. Registrar, Department of Pathology, Apollo Cancer Centre, Chennai, Tamil Nadu, India. 2. Associate Professor, Department of Pathology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India. 3. Professor and Head, Department of Pathology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India. 4. Senior Resident, Department of Pathology, Kodagu Institute of Medical Sciences, Madikeri, Karnataka, India. 5. Professor and Head, Department of Gynaecologic Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India.

Correspondence Address :
Dr. Mohit Agrawal,
Senior Resident, Department of Pathology, Kodagu Institute of Medical Sciences, Madikeri-571201, Karnataka, India.
E-mail: mohit.medico@gmail.com

Abstract

Introduction: The involvement of the Female Genital Tract (FGT) by lymphoma is extremely rare, with ovaries being most commonly affected. Less than 1% of lymphomas present with ovarian involvement and less than 1.5% of ovarian neoplasms are of lymphoid origin. Secondary involvement of ovary by systemic lymphoma is more common than Primary Ovarian Lymphomas (POL) which is usually Primary Ovarian Non-Hodgkin lymphoma (PONHL) of B-cell lineage.

Aim: To understand the clinicopathological and immuno-morphological features of Primary Ovarian Non-Hodgkin lymphoma.

Materials and Methods: This was a descriptive retrospective study conducted at Department of Pathology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka. India, for a duration of 14 years between July 2006 to June 2020. Eight cases of PONHL were identified from departmental archives and clinicopathological and Immunohistochemistry (IHC) findings of these tumours were analysed.

Results: The PONHL constituted 0.4% of all Non-Hodgkin lymphoma (NHL) reported during the study period. The patients age ranged from 13-60 years with a mean age of 34 years. Among eight cases of PONHL, two cases were of Diffuse Large B-Cell Lymphoma (DLBCL), followed by one case each of High-Grade B-Cell Lymphoma, Not Otherwise Specified (HGBL, NOS), Follicular Lymphoma (FL), Burkitt Lymphoma (BL), Plasmablastic Lymphoma (PBL), Precursor B-Lymphoblastic Lymphoma (B-LBL), and precursor T-Lymphoblastic Lymphoma (T-LBL). Seven cases were staged IE (Ann Arbor staging system) while one case was designated as stage IIE.

Conclusion: This was probably the first study on PONHL from India. The diagnosis of PONHL is challenging unless there is a high index of suspicion as these patients present with non specific pelvic symptoms and can be misdiagnosed as other epithelial, stromal or germ cell ovarian neoplasm which differs in treatment and prognosis. Histological examination with IHC and molecular testing are essential to establish a diagnosis.

Keywords

Extra-nodal, Female genital tract tumours, High-grade B-cell lymphoma, Ovarian lymphoma, Ovarian solid tumours

The involvement of the Female Genital Tract (FGT) by lymphoma is extremely rare, with ovaries being most commonly affected, followed by the uterine cervix, uterine corpus, vagina, vulva, and Fallopian Tubes (FT) (1),(2),(3). Less than 1% of lymphomas present with ovarian involvement and less than 1.5% of ovarian neoplasms are of lymphoid origin (4). Ovarian lymphoma seldom occurs as a primary neoplasm arising from the ovary. The secondary involvement of ovaries, as an initial clinical manifestation of occult nodal disease, or as a manifestation of widely disseminated systemic lymphoma is more common (2),(5).

Almost all PONHL of B-cell lineage, with DLBCL being the most common type followed by FL and BL (3),(6).

The literature on PONHL is sparse and limited to case reports and a few case series. This was the first case series from India describing eight cases of PONHL. Given the rarity of POL, this case series aimed towards understanding the clinicopathological and immunomorphological features of PONHL. The findings of this study were compared with the previously published studies in the English medical literature.

Material and Methods

This was a descriptive retrospective study conducted at Department of Pathology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India for a duration of 14 years between July 2006 to June 2020. This study strictly followed the Ethical principles laid down by the Institutional Scientific Review Board and Ethical Committee. Eight cases of PONHL were identified from departmental archives between study periods. The cases included both the institutional surgical specimens and review cases.

Inclusion and Exclusion criteria: Cases collected in this study were in accordance with the criteria suggested by Fox H et al., which states that: (a) the lymphoma should be confined to the ovary or regional lymph nodes or structures at diagnosis, without evidence of lymphoma elsewhere; (b) bone marrow and peripheral blood should not contain any abnormal cells; and (c) remote involvement should occur at least several months after ovarian involvement (7).

Study Procedure

The clinical and radiological findings were retrieved from Medical Records Department. Haematoxylin and Eosin (H&E) stained slides of all cases from the routinely processed Formalin-Fixed Paraffin-Embedded (FFPE) tissue was reviewed. IHC was performed using the Horseradish Peroxidase (HRP) polymer method, with 3, 3’-diaminobenzidine tetrahydrochloride (DAB) as a chromogen. The FFPE tissues were sectioned at 4-micron thickness and taken on silane coated slides, dewaxed and heat-induced antigen retrieval was done using the multi-epitope retrieval system, blocked with 2% skimmed milk blocking solution and then incubated with a primary antibody. The bound primary antibody was detected by the addition of secondary antibody conjugated with HRP polymer and DAB chromogen. The slides were counterstained with haematoxylin and covered in a mounting medium. The following antibodies were used depending on the differential diagnosis based on histomorphological features: CD45, CD20, CD79a, CD3, CD7, CD4, CD8, BCL2, BCL6, CD10, MUM1, CD138, MPO, TdT, EMA, and Ki67. Positive external controls (tonsillar tissue, thymic tissue and known case of myeloid sarcoma) were used along with test samples. Each tumour was typed according to the World Health Organisation (WHO) classification (2). Bone marrow biopsy was done in all cases for the staging of lymphoma. Basic haematological, biochemical, and serological test results were obtained from case files.

Statistical Analysis

Descriptive statistics were used to analyse the results.

Results

Primary ovarian NHLs constituted 0.4% of all NHLs reported during the study period. Among eight cases of PONHL, two cases were of DLBCL, followed by one case each of High-Grade B-Cell Lymphoma, Not Otherwise Specified (HGBL, NOS), Follicular Lymphoma (FL), Plasmablastic Lymphoma (PBL), B-Lymphoblastic Lymphoma (B-LBL), and precursor T-Lymphoblastic Lymphoma (T-LBL). The clinical and histochemical features have been summarised in (Table/Fig 1).

Clinicopathological Characteristics

The patients ranged in age from 13-60 years with a mean age of 34 years. All eight cases presented with pain in the abdomen with six patients also complaining of a pelvic mass. Three patients had a history of vaginal bleeding/menorrhagia. While seven tumours were unilateral, one patient presented with bilateral tumour masses (Table/Fig 1), case no. 7). Of the seven unilateral tumours, five were right-sided and two involved the left ovary. Ultra-sonographic findings were non specific and suggestive of predominantly solid neoplasm in five cases and solid cystic neoplasm in three cases. Seven cases were localised to the ovary (Ann Arbor stage IE) and one case was designated as stage IIE because of involvement of the omentum and mesenteric lymph node (case no. 3). There was no evidence of generalised lymphadenopathy. Bone marrow and peripheral blood were not involved by lymphoma in any case. Serum LDH and CA125 levels were elevated in all cases with the mean values being 1473 U/L and 134 U/mL, respectively. One case was positive for HBsAg (case no. 2).

Gross Appearance

Tumour size was ranging from 8 to 26 cm (mean=10.75 cm) in maximum dimension. Grossly, the ovarian capsule was intact in seven cases and breeched in one (case no. 3). All tumours were predominantly solid with occasional cystic areas (Table/Fig 2). The solid areas were firm to fleshy in consistency. Haemorrhagic and necrotic areas were seen in six cases. Ipsilateral FT were unremarkable in six cases and showed tumour deposits in one case (case no. 3).

Histopathological and Immunohistochemical Findings [Table-3]a-f, [Table-4]a-d

Both cases of DLBCL (case no. 1, and 2) showed diffuse sheets of large lymphoid cells (centroblastic type) with a moderate amount of cytoplasm and nucleus size more than twice of normal lymphocyte. The nuclear contours were irregular or round with vesicular to granular chromatin and solitary or multiple nucleoli and frequent mitosis (Table/Fig 3)a, [Table-4]a. Among these two DLBCL cases, one was Germinal Centre B-cell (GCB) type (CD10+, BCL6+, and MUM1+ in <30% of neoplastic cells) (Table/Fig 3)b-e, while other was of the Activated B-Cell (ABC) type (MUM1+, BCL6+, and CD10-) (Table/Fig 4)b-d. The neoplastic lymphoid cells had replaced the ovarian stroma. Both cases had a high proliferative index which varied from 70% to 90% (Table/Fig 3)f.

The third case showed diffuse sheets of medium sized neoplastic lymphoid cells with scattered large cells and intermixed tingible body macrophages imparting a starry sky pattern. The morphological features of this case were intermediate between DLBCL and BL (Table/Fig 5)a. On IHC, the tumour cells were immunoreactive for LCA, CD20, CD10 and BCL6. Fluorescence In-Situ Hybridisation (FISH) for I#IC-MYCI?I rearrangement was performed to rule out BL. FISH showed 2 to 8 fusion signals of break-apart probe in most of the neoplastic nuclei and hence was interpreted to be negative for I#IC-MYCI?I rearrangement (Table/Fig 5)b. The molecular tests to identify double-hit (MYC, BCL2 or BCL6) or triple-hit lymphoma (MYC, BCL2 and BCL6) signatures could not be performed. Hence, we labelled this neoplasm as HGBL, NOS.

One case of FL (case no. 4) showed closely packed irregular follicles with randomly distributed centroblasts and centrocytes (Table/Fig 6)a. There were average seven large nucleolated cells per high power field, rendering it grade 2 FL. The neoplastic lymphoid cells were positive for CD20, CD10, BCL2, and BCL6 (Table/Fig 6)b-d.

The BL case (case no. 5) was composed of a monotonous population of medium sized neoplastic cells and tingible body macrophages giving a starry sky appearance (Table/Fig 7)a. These cells had round to slightly irregular nuclear contours, with vesicular chromatin and high mitotic rate. These neoplastic cells were positive for CD20 and CD10 and negative for TdT. The Ki67 proliferating index was approaching 100% (Table/Fig 7)b-d.

There was one case each of precursor B-LBL and T-LBL respectively. Both cases showed sheets of small to medium sized tumour cells with round to oval, indented nuclei with coarsely clumped chromatin with indistinct to prominent nucleoli. Numerous mitoses were present. While the B-LBL case was positive for CD20 and TdT and the T-LBL case was positive for CD3 and TdT. Both cases showed a Ki67 index of >90% (Table/Fig 8)a-d, [Table-9]a-d.

One case of PBL showed sheets of large plasmacytoid cells with large vesicular nuclei, prominent nucleoli with abundant cytoplasm (Table/Fig 10)a-d. These cells were immunoreactive for CD38, CD138, and MUM1.

Treatment and Follow-up

Varying combinations of surgery, Chemotherapy (CT), and Radiotherapy (RT) were used to treat these patients. Five of the eight cases underwent transabdominal hysterectomy with bilateral salpingo-oophorectomy (TAH+BSO), whereas the remaining three patients underwent unilateral salpingo-oophorectomy with tumour debulking surgery. Five patients received adjuvant CT and one received a combination of CT and RT. The chemotherapeutic regimen consisted of R-CHOP (Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Clinical follow-up ranged from five months to seven years (mean four years). Three patients were alive and disease-free at the last follow-up and one patient is undergoing treatment. Also, while two patients succumbed to disease, the remaining two patients refused further treatment after surgery and were lost to follow-up.

Discussion

Primary lymphomas of the FGT are rare with ovaries being the most common site to be involved (2). This can be seen in the study by Nasioudis D et al., who reviewed 697 cases of primary lymphomas of FGT and concluded that POL constituted 37% of cases followed by cervix (21.4%), and uterus (16.5%) (3).

Histogenesis of PONHL is unclear but it is considered to arise from hilar lymphoid tissue, from lymphocytes in an inflammatory infiltrate in ovarian stroma, or from lymphoid tissue in a teratoma of ovary (7),(8),(9),(10). The present study reported eight cases of PONHL according to criteria suggested by Fox H et al., (7). However, Paladugu RR et al., found these criteria to be insufficiently stringent and suggested that there should be 60 months of disease free interval following surgical treatment of the ovarian lesion (11). This criterion is difficult to apply practically and makes the possibility of lymphomas to arise primarily in the ovary exceedingly rare. For instance, Chorlton I et al., reported 54 cases of POL, of them only five tumours can be eligible for this diagnosis if this criterion is adopted (12). Similarly, only two tumours in this series would qualify this criterion.

Lymphomas of the ovary affect patients of any age, but most often in the third and fourth decade (6). In this study patients age ranged from 13 to 60 years with a mean age of 34 years (Table/Fig 11). Patients of ovarian lymphoma usually present with complaints of abdominal pain, pelvic mass, abnormal vaginal bleeding, and ascites (13),(14). B-symptoms like fever, night sweats, fatigue, or weight loss are seen in 10%-33% of the patients (6),(15). Also, most of the PONHL patients present with elevated CA125 and LDH similar to other ovarian neoplasms (14),(16). CA125 and LDH levels were elevated in all cases whereas B-symptoms were not seen in patients of the present study. Vang R et al., reported that unilateral ovarian involvement was commoner than bilateral involvement with no predilection to side, in localised stage I?SUB?E#SUB# diseases (4). All eight cases of PONHL in this study were low stage NHLs, seven of which presented with unilateral disease.

Macroscopically, ovarian lymphomas have been reported as unilateral or bilateral mass forming solid tumours which vary in size from 4 to 20 cm (median size 8-12 cm) (5),(14),(16). The common differential diagnosis of solid ovarian tumours includes Brenner tumours, teratomas, dysgerminomas, ovarian fibromas, ovarian thecomas, granulosa cell tumours, and Krukenberg tumours (17),(18). It is necessary to differentiate PONHL from advanced epithelial carcinoma as both can present with similar clinical features like elevated tumour markers and ascites (19),(20). Lymphoblastic Lymphoma (LL) can be confused with other small round cell tumours so an optimal panel of IHC should be used to classify ovarian lymphoma (21).

Commonly, lymphomas of the ovaries are of B-cell lineage with previous studies revealing DLBCL to be the most common subtype of PONHL followed by BL and FL, a finding consistent with this series (Table/Fig 11) (3),(4),(5),(7),(14),(15),(16),(17),(22).

Histologically, ovarian DLBCL shows centroblast, immunoblast, and/or multilobed cells arranged in diffuse sheets, nests, and cords associated with sclerosis (16),(17),(20). In present study, two cases showed typical immuno-morphological features of DLBCL while one case showed morphological features intermediate between DLBCL and BL which warranted further molecular analysis to classify this lymphoma as double-hit/ triple-hit lymphoma (HGBL with MYC and BCL2 and/or BCL6 rearrangements) or HGBL, NOS (HGCL that lack defined genetic rearrangements or unable to classify as DLBCL or BL). This case was labelled as HGBL, NOS as molecular test could not be performed due to poor economic status of patient. DLBCL-GCB type is commoner than ABC type as describe by Xu H et al., who reported seven cases of GCB subtype in their study on nine ovarian DLBCLs (23). Molecular pathogenesis of DLBCL shows clonal rearrangement of IG genes. Cao XX et al., suggested that 50% of cases have I#IMYD88 I?Ip.Leu256Pro mutation and 25% have CD79BB p.Tyr196 mutation (with or without I#IMYD88 I?Ip.Leu256Pro) (24). Khattar P et al., conducted a molecular analysis of ovarian DLBCL and concluded that most I#IMYD88 I?Imutated cases had an NGCB immunophenotype while somatic mutations of EZH2 and GNA13 are restricted to GCB DLBCL cases (18). Xu H et al., also stated that I#INOTCH3 I?Iand HDAC4 mutations are commonly identified in the GCB subtype of DLBCL involving the ovaries but not in the conventional type (23).

Histologically, primary ovarian FL shows mixed diffuse and follicular growth patterns and high grade cytological features as compared to secondary involvement by systemic disease (2). Özsan N et al., studied 16 cases of ovarian FL and concluded that FL presenting in the ovary comprised of two distinct biological subsets: one group showed features of nodal FL, including presentation as an advanced-stage disease with low histologic grade, BCL2 immunoreactivity, and presence of IGH@/BCL2 translocation. The second group included cases that presented with the disease usually confined to one ovary, showing a higher histologic grade, loss CD10 and BCL2 immunoreactivity and absence of IGH@/BCL2 fusion. This latter group may represent the true primary ovarian FL as it shows distinct biological and immunologic characteristics similar to higher-grade/low-stage FL presenting at other extra-nodal sites (25). Ovarian FL in the present study can be categorised in the second group as it was confined to one ovary with histological grade 2.

BL is an aggressive undifferentiated B cell NHL which accounts for 5-20% of FGT lymphomas (2). It is characterised by frequent extra-nodal site presentation, an extremely rapid growth rate with a short doubling time, and usually I#IMYC I?Itranslocation (3),(4),(22). Stepniak A et al., reviewed 21 cases of primary ovarian BL and formulated 4 factors suggestive of primary ovarian BL which include: young age at presentation, bilateral ovarian involvement, rapid progression, and high LDH levels (26). While Stepniak A et al., reported that 67% of their primary ovarian BL cases presented with bilateral ovarian involvement, the case of BL in this series involved only the right ovary. Pathogenesis of BL is characterised by deregulation of MYC expression by translocation of I#IMYC I?Ito an I#IIGI?I gene locus. The diagnosis of BL can be made based on of criteria suggested by Haralambieva E et al., (27). These include: a Ki-67 index of ~90%, breakpoints in the MYC gene, CD10 positivity with an absence of BCL2 expression (27).

PBL is a high-grade NHL, usually seen in the oral cavity of immunodeficient patients, usually Human Immunodeficiency Virus (HIV) positive (28). Extra-oral PBL arising in the ovary is very rare and not related to immunodeficiency (29). Epstein-Barr Virus (EBV) is an important aetiological factor is seen in 70% of PBL cases (30). In addition to EBV infection, recent studies have identified the presence of MYC gene rearrangements as an important pathogenic mechanism of PBL (31). The neoplastic cells in PBL are immunonegative for CD20 with the expression of CD138, CD38, CD79a, IRF4/MUM1, cytoplasmic immunoglobulins (most frequently IgG), either kappa or lambda light chain restriction, and a high Ki-67 proliferation index (usually ≥80%) (32). Cases of PBL which are seen in HIV-negative individuals have shown EBV association in 17% of cases (33). The present case of PBL was negative for HIV and did not express EBER by ISH.

The LL of the ovary is rarely seen and usually presents as secondary involvement than a primary lymphoma (2). Case studies by Dimopoulos MA et al., Fox H et al., and Paladugu RR et al., reported only one, six, and two cases of LL, respectively (6),(7),(11). Histologically, it shows small to medium sized blasts with scant cytoplasm and convoluted nuclei which are uniformly immunoreactive for TdT. While B- ALL cells are positive for B lineage markers (CD19, CD20, CD79a), and CD10; T- ALL shows positivity for T-cell lineage markers (CD3, CD7), CD1a+, CD10+/-, and/or CD4/CD8 double+ (21),(34). Clonality of IGH or T-cell Receptor (TR) can be demonstrated by molecular analysis (2).

The POL are staged as other extra-nodal NHLs (Ann Arbor staging system) or by Lugano staging system (2),(3). Most studies on ovarian NHL have included both primary and secondary cases of ovarian lymphoma (7),(12),(20). Less than 10% of all ovarian NHLs reported in the literature are presumably PONHLs (6),(17). This distinction is of considerable importance because primary extra-nodal lymphomas have a less aggressive disease course with a five-year survival rate of 80% as compared to lymphomas with secondary involvement of the ovaries, which have a five-year survival rate of only 33% (6).

PONHL treatment relies on histology, type, and clinical staging. Cancer-Directed Surgery (CDS) was performed in 90.3% of ovarian lymphoma cases in a study by Nasioudis D et al., (3). Dimopoulos MA et al., reported and reviewed the treatment aspect of ovarian lymphomas and recommend that they should be treated with curative intent with combination CT regimens appropriate for their specific histology (6).

In the present study, ovarian involvement by systemic NHL/leukaemia was ruled out by the absence of generalised lymphadenopathy, bone marrow, and peripheral blood involvement. Also, of the six patients who agreed to further management, three patients show no evidence of disease on follow-up (median follow-up duration, 5 years). The prognosis is better in patients with localised disease. Various reports in the literature suggest the survival rate of PONHL cases ranges from 0% to 36%, with an average survival time of less than 3 years (6),(15),(18),(19).

Nasioudis D et al., reported five-year Cancer-Specific Survival (CSS) of 70.8% for ovarian lymphoma (3). Inaccurate or delayed diagnosis of ovarian lymphoma contributes to their poor prognosis as compared to nodal lymphoma (7). While unilateral ovarian involvement and/or focal involvement of the ovary may be considered as indicators of good prognosis; the rapid growth of a pelvic mass, severe systemic symptoms, bilateral ovarian tumours, and advanced stage may be indicative of poor prognosis (14),(15),(16),(17).

Limitation(s)

The results of the present study highlight the histopathologic features of PONHL and the prognostic impact of this diagnosis. However, due to the rarity of PONHL, the data needs to be interpreted with caution due to the limited number of patients. Also, further molecular analysis would have been beneficial could not be performed due to poor economic status of patients.

Conclusion

To conclude, PONHL is a very rare disease with the majority of cases showing a B-cell phenotype. We have described probably the first case series of PONHL from India. They present with non specific pelvic symptoms and can be misdiagnosed as other epithelial, stromal, or germ cell ovarian tumours. Tissue biopsy coupled with IHC and molecular testing is essential to establish a diagnosis, especially in young females. Low stage PONHL has a good prognosis if optimally treated with combined CT with or without surgery.

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DOI and Others

10.7860/JCDR/2021/50649.15235

Date of Submission: Jun 02, 2021
Date of Peer Review: Jul 05, 2021
Date of Acceptance: Jul 10, 2021
Date of Publishing: Aug 01, 2021

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: Jun 03, 2021
• Manual Googling: Jul 04, 2021
• iThenticate Software: Jul 05, 2021 (15%)

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