| Abstract|| |
Introduction: Primary extranodal lymphoma (pENL) refers to group of disorders arising from tissues other than lymph nodes and even from sites, which normally do not contain lymphoid tissue. This study was undertaken to ascertain the prevalence, anatomical distribution, and histological subtypes of extranodal non-Hodgkin lymphoma (NHL) from a tertiary care institute in Southern India. Materials and Methods: This was a cross-sectional study conducted in the Department of Pathology over a period of 3-years. Detailed clinical history, routine complete blood count, microbiological status was obtained from the medical records. Hamatoxylin and eosin slides were reviewed and immunohistochemistry was performed using a panel of antibodies depending on the morphology. All cases were classified based upon morphologic and immunophenotypic criteria according to World Health Organization 2008 classification. Results: Primary extranodal NHL constituting 22.6% (68/300) of all NHL and the majority of patients were from higher age group with peak incidence seen in fourth to fifth decade of life. In the pediatric population, the most common site is ileo-caecal region (42.8%) and the most common morphology is lymphoblastic lymphoma (42.8%). Similarly in the adult population head and neck was the most common site constituting 36% and diffuse large B-cell lymphoma is the most common morphological subtype comprising 54% of all extranodal lymphomas. Conclusion: Although the reported incidence of pENL is low in India compared to other parts of the world, the possibility of pENL should always be kept in mind even though it arises in an extranodal site.
Keywords: Extranodal, non Hodgkinlymphoma, primary
|How to cite this article:|
Mishra P, Das S, Kar R, Jacob SE, Basu D. Primary extranodal non-Hodgkin lymphoma: A 3-year record-based descriptive study from a tertiary care center in Southern India. Indian J Pathol Microbiol 2015;58:296-300
|How to cite this URL:|
Mishra P, Das S, Kar R, Jacob SE, Basu D. Primary extranodal non-Hodgkin lymphoma: A 3-year record-based descriptive study from a tertiary care center in Southern India. Indian J Pathol Microbiol [serial online] 2015 [cited 2020 Jun 5];58:296-300. Available from: http://www.ijpmonline.org/text.asp?2015/58/3/296/162834
| Introduction|| |
Non-Hodgkin lymphoma (NHL) is a group of lymphoproliferative, malignant disorders arising in lymph nodes with heterogeneous, histological, and clinical characteristics.  At least one-quarter of NHL arise from tissues other than lymph nodes and even from sites, which normally do not contain lymphoid tissue. These forms are referred to as primary extranodal lymphomas , (pENL). Extra nodal lymphoma diagnosis is a frequent challenge to the pathologists, due to their morphological mimics, molecular alteration, and clinical presentations.
Despite this relative prominence of extranodal presentations, the literature on their incidence and on most of the specific types and sites is scant and often contradictory. This is primarily because these tumors, numerous when considered together, are distributed, so widely throughout the body that it is difficult to assemble adequate series of any given site.  Over the past twenty years lymphomas arising in the extra nodal sites have shown a rapid increase in incidence especially in central nervous system, gastrointestinal tract (GIT) and the skin.  This may be attributed to immunosupression due to AIDS or immunosuppressive treatments, infections such as Helicobacter pylori, Chlamydia psittaci, Borrelia burgdorferi, and Campylobacter jejuni, autoimmune disorders and environmental factors.  The types of lymphoma encountered vary widely from one extranodal site to another. Extra nodal lymphoma is further classified as primary and secondary. Secondary indicating that the lymphoma first presented in an extra nodal site  and subsequently involved the nodes.
In addition to the variation in the incidence, there may be regional and geographical differences in response to treatment, prognosis and survival for various types of lymphomas. Although there are numerous reports dealing with extranodal NHL originating in almost every organ of the body, the literature on pENL as a group is limited. This study was undertaken to ascertain the prevalence, anatomic distribution and histological subtypes of extranodal NHL from a tertiary care institute in Southern India.
| Materials and Methods|| |
This was a cross-sectional study conducted in the Department of Pathology over a period of 3-year. During this period, 300 NHL were diagnosed. Of them, 68 cases were pENLs. Tissue was processed routinely in 10% formalin and 5 μ paraffin sections were stained with hamatoxylin and eosin. Immunohistochemistry (IHC) was performed using a panel of antibodies depending on the morphology. Immunohistochemical analyses were performed manually on the paraffin embedded tissue sections by using a panel of monoclonal antibodies. Antigen retrieval was done by pretreatment of paraffin sections by heating in a Pascal pressure cooker in 0.01 M citrate buffer (pH6.0). The panel of antibodies used for IHC includes pancytokeratin, leukocyte common antigen, CD3, CD4, CD5, CD7, CD8, CD19, CD20, CD23, CD10, CD15, CD30, CD99, CD56, Bcl2, Bcl6, Tdt, anaplastic lymphoma kinase-1 (ALK-1), cyclinD1, Ki67 and epithelial membrane antigen (EMA). Molecular diagnostic techniques such as cytogenetics/fluorescence in situ hybridization were not performed in any of the cases due to lack of facilities. Data pertaining to patients' demography, ethnicity, occupation, clinical presentation, immune status, routine complete blood count, and microbiological (HIV, EBV, H.pylori , HCV, and HBV) status were obtained from the medical records.
Since cutaneous lymphoma itself constitutes a diverse group of lymphomas we have excluded it from our analysis for convenience. The definition of pENL remains somewhat controversial, especially in patients where both nodal and extranodal sites are involved, and there are different proposals defining this disease. ,, We adopted the proposal by Krol et al. who used a liberal definition of primary extranodal NHL that includes all patients who present with NHL that apparently originated at an extranodal site, even in the presence of disseminated disease, as long as the extranodal component was clinically dominant. Another problem concerns the debate about whether tonsil and Waldeyer's ring (WR) should be considered as nodal or extranodal lymphoma sites.  In many respects, they could be considered of nodal origin, but they have historically been included among the extranodal types ,,, and therefore, we have included them as an extranodal site. Primary nodal NHL with secondary extranodal involvement and plasmacytomas were also excluded from the study. All cases were classified based upon morphologic and immunophenotypic criteria according to World Health Organization (WHO) 2008 classification.  Clinical stage was defined according to the Ann Arbor classification. 
| Result|| |
Primary extranodal NHL constituting 22.6% (68/300) of all NHL diagnosed over a period of 3-year were included in the study. Our study included 38 males and 30 females, with a male: Female ratio of 1.3:1. Majority of our patients were from higher age group with peak incidence seen in fourth to fifth decade of life (age range 2-75 years) [Figure 1]. The different sites that were involved in pENL is shown in [Figure 2].
|Figure 2: Anatomic distribution in primary extranodal non-Hodgkin lymphomas|
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In the pediatric population, there were seven cases. The age ranged from 0 to 10 years with male: Female ratio of 2.5:1. Sites involved were ileo-caecal region in 3 cases, renal in 2 cases, mediastinum and maxillary sinus in one case. Histologically, there were three cases of lymphoblastic lymphoma (LL), two cases of Burkitt lymphoma (BL) and one case each of Maltoma and diffuse large B-cell lymphoma (DLBCL).
Head and neck was the most common site of pENL in our study constituting 36%, followed by GIT 29%, soft tissue 9% and kidney/renal system 6%. Brain, mediastinum and testis comprised 4% each. The least common site being breast, adrenal, ovary and bone accounting for 2% each; B-cell lymphomas were seen in 82% of cases where as T-cell was seen in 18% of cases. Classifying according to the WHO 2008 classification, DLBCL was the commonest histological subtype comprising 54% of all extra nodal lymphomas followed by peripheral T-cell lymphoma (PTCL) 13%, Maltomas 12%, LL 6%, and BL 4%. Plasmablastic lymphoma, natural killer (NK)/T-cell lymphoma and DLBCL/BL gray zone lymphoma comprised 3% each. ALCL was seen in one case (2%) [Table 1].
Tonsil was the most common site in the head and neck region (36%) followed by orbit, nasal, palate, nasopharynx, base of tongue and thyroid [Figure 3]. In the GIT, stomach was the most commonly involved site comprising >50% followed by the small intestine, ileo-caecal region and colon [Figure 4].
|Figure 3: Site distribution of primary extranodal head and neck lymphomas|
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|Figure 4: Site distribution of common histological subtypes in primary extranodal lymphomas of gastrointestinal tract|
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In one case of gastric lymphoma of mucosaassociated lymphoid tissue H. pylori was detected in gastric biopsy on routine Giemsa staining. Epstein-Barr virus-latent membrane protein was weakly positive in a single case of NK/T-cell lymphoma of the hard palate. Seropositivity for HIV was also seen in one case of DLBCL of nasopharynx.
Bone marrow infiltration was seen in 5 cases (7.3%) primaries being 2 cases each from orbit and GIT and one from kidney. Bone marrow examination showed hemophagocytic syndrome in a case of NK/T-cell lymphoma of the small intestine.
| Discussion|| |
Primary extra nodal lymphomas are a heterogeneous group of tumors because of its difference in epidemiology and etiology in different areas around the world. Studies from Western countries have reported the occurrence of extranodal NHL as 24-48% of all NHL ,,, in contrast to Asian studies (Pakistan [42%], Kuwait (45%), Japan (46.6%), Korea [55%], Thailand [58.7%], and China (44.9-61.4%)). ,,,, Compared to these data from other Asian countries, the prevalence in our series (22.6%) is much lower, which may be due to shorter duration of the study. However, a more tenable explanation for the varying frequency of extranodal lymphomas may be due to variation in genetic and ethnic factors, as well as the diverse definition criteria.
[Table 2] compares the incidence of various site specific extra nodal Hodgkin lymphoma in different geographical regions. The GIT is the predominant site of extranodal NHL accounting for almost one-third of all primary extranodal NHL, but this incidence may vary in different areas. Within the GIT, primary gastric NHL is by far the most common, comprising 50-60% of all GIT-NHL, and therefore, considered the most common site of extranodal lymphoma involvement in Korea  and India.  However, head and neck region including WR have been reported to be the most common sites of origin of pENL in various studies from China  and Taiwan. 
In India, the incidence of pENL and the sites varies widely. A study from Northern India by Singh et al.  showed extranodal lymphomas constitute 44% with the most common site being the head and neck, whereas a study conducted by Padhi et al.  from Southern India showed extranodal lymphomas constituted 22% and the most common site being the central nervous system. Western India shows incidence of 28% and GIT being the most common site that is affected. Our study showed incidence of 22.6% with head and neck being the most common site of pENHL. It is difficult to explain such diversities. These regional variation could again be attributed to differences in genetic and geographical factors, and more importantly these are all hospital-based studies and hence not truly representative of population demographic profile.
Diffuse large B-cell lymphoma (54%) was the most common histological subtype followed by PTCL (13%) and Maltoma (11%) in the extranodal site. Follicular lymphomas were conspicuously absent in the extranodal sites, possibly as suggested by Biagi and Seymour,  that geographic variation and molecular expression profiling in follicular lymphomas could be a possible explanation.
Non-Hodgkin lymphoma of the GIT was the second common site to be involved in our study, stomach being the commonest site. DLBCL was the most common histological subtype followed by Maltomas. We had three cases of PTCL, two cases of BL and one case of NK/T-cell lymphoma. This pattern was similar to the western population  as well as from India.  One case of gastric Maltoma had a history of H. pylori gastritis.
Primary brain lymphomas account for <2% of extra nodal lymphomas, but the incidence is increasing in immunocompromised and immunodeficient hosts.  Our study showed an incidence of 4% of primary brain lymphomas and all the patients were immunocompetent. Testicular lymphoma is common beyond the age of 60-year, is usually bilateral, and the predominant histological type is DLBCL.  However, we have some interesting findings regarding testicular lymphomas in our study. We had three cases of testicular lymphomas of which in two cases the patients age was <30 years and the histological subtypes were DLBCL in two cases, and one case showed PTCL. Primary ovarian lymphomas are rare, and patients have a poor prognosis with 5-year survival rate of <25%.  In this study, we had one case of ovarian lymphoma, which histologically was B-cell NHL morphologically intermediate between Burkitt lymphoma and DLBCL. Primary bone lymphomas account for 3-5% of extra nodal lymphomas  and the majority are intermediate to high-grade B-cell lymphoma.
Most of the thyroid lymphomas have localized stage IE or IIE disease and the prognosis worsens with penetration of the thyroid capsule, tumor bulk, advanced stage and intermediate to high-grade histological types.  In this study, one case of thyroid lymphoma was seen, and it did not show bone marrow infiltration. Primary adrenal lymphoma is very rare  and accounts for 0.1% of all NHL. It is characterized by a high-incidence of bilateral involvement and histologically of diffuse large B-cell type. We had one case of primary adrenal lymphoma that was incidentally detected on radioimaging and histopathology revealed primary extranodal DLBCL of the adrenals.
| Conclusion|| |
Primary extranodal lymphomas constitute a diverse group of hematolymphoid malignancies. The incidence of pENL is low in India compared to data from other parts of the world. The diagnosis is a frequent challenge to the pathologists, due to their morphological mimics, and varied clinical presentations. Therefore, the possibility of pENL should be kept in mind even though it arises in an extranodal site. Further studies throwing light on the genetic profile of lymphomas and treatment outcome are required to understand the biological variations of this group of diseases.
| References|| |
Evans LS, Hancock BW. Non-Hodgkin lymphoma. Lancet 2003;362:139-46.
Zucca E, Roggero E, Bertoni F, Cavalli F. Primary extranodal non-Hodgkin′s lymphomas. Part 1: Gastrointestinal, cutaneous and genitourinary lymphomas. Ann Oncol 1997;8:727-37.
Zucca E, Roggero E, Bertoni F, Conconi A, Cavalli F. Primary extranodal non-Hodgkin′s lymphomas. Part 2: Head and neck, central nervous system and other less common sites. Ann Oncol 1999;10:1023-33.
Rehman SA, Sidique M, Ahmad G, Naiz M. Extra nodal lymphoma. Prof Med J 2005;12:223-9.
Freeman C, Berg JW, Cutler SJ. Occurrence and prognosis of extranodal lymphomas. Cancer 1972;29:252-60.
Dawson IM, Cornes JS, Morson BC. Primary malignant lymphoid tumours of the intestinal tract. Report of 37 cases with a study of factors influencing prognosis. Br J Surg 1961;49:80-9.
Krol AD, le Cessie S, Snijder S, Kluin-Nelemans JC, Kluin PM, Noordijk EM. Primary extranodal non-Hodgkin′s lymphoma (NHL): The impact of alternative definitions tested in the Comprehensive Cancer Centre West population-based NHL registry. Ann Oncol 2003;14:131-9.
Cavalli F. Extranodal lymphomas. In: Magrath IT, editor. The non-Hodgkin′s Lymphomas. 2 nd
ed. London: Arnold; 1997. p. 1007-27.
Otter R, Gerrits WB, vd Sandt MM, Hermans J, Willemze R. Primary extranodal and nodal non-Hodgkin′s lymphoma. A survey of a population-based registry. Eur J Cancer Clin Oncol 1989;25:1203-10.
d′Amore F, Christensen BE, Brincker H, Pedersen NT, Thorling K, Hastrup J, et al.
Clinicopathological features and prognostic factors in extranodal non-Hodgkin lymphomas. Danish LYFO Study Group. Eur J Cancer 1991;27:1201-8.
Chan JK, Ng CS, Lo ST. Immunohistological characterization of malignant lymphomas of the Waldeyer′s ring other than the nasopharynx. Histopathology 1987;11:885-99.
Isaacson PG. The pathology and biology of non-Hodgkin′s lymphoma. In: Peckham M, Pinedo HM, Veronesi U, editors. Oxford Textbook of Oncology. Oxford: Oxford Medical Publications; 1995. p. 1768-8.
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pilleri SA, Stein H, et al
. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4 th
ed. Lyon, France: IARC; 2008.
Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the Committee on Hodgkin′s disease staging classification. Cancer Res 1971;31:1860-1.
Kim JM,·Ko YH,·Lee SS, Huh J, Kang TS, Kim CW, et al
. WHO classification of malignant lymphomas in Korea: Report of the third nationwide study. Korean J Pathol 2011;45:254-60.
Yang QP, Zhang WY, Yu JB, Zhao S, Xu H, Wang WY, et al.
Subtype distribution of lymphomas in Southwest China: Analysis of 6,382 cases using WHO classification in a single institution. Diagn Pathol 2011;6:77.
Fujita A, Tomita N, Fujita H, Motohashi K, Hyo R, Yamazaki E, et al.
Features of primary extranodal lymphoma in Kanagawa, a human T-cell leukemia virus type 1 nonendemic area in Japan. Med Oncol 2009;26:49-54.
Singh D, Kumar L, Goyal H, Raina V, Bijlani L, Wadhwa J, et al.
Primary extranodal non-Hodgkin′s lymphoma in Northern India. Proc Am Soc Clin Oncol 2003;22:2457.
Padhi S, Paul TR, Challa S, Prayaga AK, Rajappa S, Raghunadharao D, et al
. Primary extra nodal non Hodgkin lymphoma: A 5 year retrospective analysis. Asian Pac J Cancer Prev 2012;13:4889-95.
Cavalli F, Stein H, Zucca E. Extranodal Lymphomas: Pathology and Management London. Informa: Healthcare; 2008.
Yoon SO, Suh C, Lee DH, Chi HS, Park CJ, Jang SS, et al.
Distribution of lymphoid neoplasms in the Republic of Korea: Analysis of 5318 cases according to the World Health Organization classification. Am J Hematol 2010;85:760-4.
Sukpanichnant S. Analysis of 1983 cases of malignant lymphoma in Thailand according to the World Health Organization classification. Hum Pathol 2004;35:224-30.
Aoki R, Karube K, Sugita Y, Nomura Y, Shimizu K, Kimura Y, et al.
Distribution of malignant lymphoma in Japan: Analysis of 2260 cases, 2001-2006. Pathol Int 2008;58:174-82.
Gross SA, Zhu X, Bao L, Ryder J, Le A, Chen Y, et al.
A prospective study of 728 cases of non-Hodgkin lymphoma from a single laboratory in Shanghai, China. Int J Hematol 2008;88:165-73.
Arora N, Manipadam MT, Pulimood A, Ramakrishna BS, Chacko A, Kurian SS, et al.
Gastrointestinal lymphomas: Pattern of distribution and histological subtypes: 10 years experience in a tertiary centre in South India. Indian J Pathol Microbiol 2011;54:712-9.
Chen WL, Tsai WC, Chao TY, Sheu LF, Chou JM, Kao WY, et al.
The clinicopathological analysis of 303 cases with malignant lymphoma classified according to the World Health Organization classification system in a single institute of Taiwan. Ann Hematol 2010;89:553-62.
Biagi JJ, Seymour JF. Insights into the molecular pathogenesis of follicular lymphoma arising from analysis of geographic variation. Blood 2002;99:4265-75.
Fine HA, Mayer RJ. Primary central nervous system lymphoma. Ann Intern Med 1993;119:1093-104.
Doll DC, Weiss RB. Malignant lymphoma of the testis. Am J Med 1986;81:515-24.
Osborne BM, Robboy SJ. Lymphomas or leukemia presenting as ovarian tumors. An analysis of 42 cases. Cancer 1983;52:1933-43.
Boddie AW Jr, Mullins JD, West G, Bouda D. Extranodal lymphoma: Surgical and other therapeutic alternatives. Curr Probl Cancer 1982;6:1-64.
Burke JS, Butler JJ, Fuller LM. Malignant lymphomas of the thyroid: A clinical pathologic study of 35 patients including ultrastructural observations. Cancer 1977;39:1587-602.
Ezer A, Parlakgumus A, Kocer EN, Colakoglu T, Nursal GN, Yildirim S. Primary adrenal non-Hodgkin′s lymphoma: Report of two cases. Turk J Gastroenterol 2011;22:643-7.
Dr. Debdatta Basu
Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry - 605 006
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]