| Abstract|| |
Background: Necrotizing lymphadenitis represents a group of diseases characterized by non-granulomatous inflammation and necrosis of the lymph node, caused by a variety of infective and inflammatory diseases, most common being Kikuchi-Fujimoto disease, acute Epstein Barr viral infection and systemic lupus erythematosis (1). Objectives: To study the morphological features in lymph nodes in cases of necrotizing lymphadenitis, to correlate them with specific etiological conditions.Materials and methods-58 cases of necrotizing lymphadenitis were reviewed and categorized into different etiological sub types, i.e. acute EBV lymphadenitis, lupus lymphadenitis and the rest as Kikuchis lymphadenitis. Morphological features studied were presence of vascular proliferation, periadenitis, foamy macrophage, neutrophil and plasma cell infiltrate. Clinical follow up was done. Results: 62.2% of cases were Kikuchis lymphadenitis. Both lupus and Kikuchis had a female preponderance (78% and 62% respectively). Among the morphological parameters, plasma cell infiltration and vascular proliferation showed significant association with lupus lymphadenitis. Kikuchis and EBV lymphadenitis showed self-limiting course, with only 2 cases of Kikuchis developing recurrence .4 cases developed complications. All cases of lupus lymphadenitis needed long term therapy. Conclusion: Kikuchis lymphadenitis is the most common cause of necrotizing lymphadenitis, followed by lupus and acute EBV lyphadenitis.Young females were commonly affected in the first 2 groups. It is worthwhile to classify the cases of necrotizing lymphadenitis into etiological subgroups as the prognosis and treatment differ (2). Among the morphological features studied, plasma cell infiltrate and vascular proliferation were significantly associated with lupus lymphadenitis, hence can be used to predict etiology.
Keywords: Etiology, lymphadenits, morphology, necrotizing
|How to cite this article:|
Nair IR, Balan S, Phalak P, Daniel M. Clinicopathologic spectrum of necrotizing lymphadenitis. Indian J Pathol Microbiol 2020;63:60-3
| Introduction|| |
Necrotizing lymphadenitis represents a group of diseases characterized by nongranulomatous inflammation and necrosis of the lymph node. This is caused by a variety of infective and inflammatory diseases, most common being Kikuchi-Fujimoto disease More Details, acute Epstein-Barr viral (EBV) infection, and systemic lupus erythematosis (SLE/lupus lymphadenitis), and excludes Mycobacterial infections such as tuberculosis (TB). Clinically, patients present with features like fever and painful lymphadenitis which make them mimic the more common TB and lymphomas.
Kikuchi-Fujimoto disease is a self-limiting condition of unknown etiology., Acute EBV lymphadenitis is seen in the acute phase of viral infection, whereas lupus lymphadenitis occurs in patients with SLE. The differentiation of these entities is crucial as the treatment and long-term prognosis differ among them. Also, the exclusion of TB and lymphoma is also of clinical relevance as they necessitate specific therapy. We categorized necrotizing lymphadenitis cases into etiological subgroups using serological tests for EBV and SLE. An attempt to study the morphologic features in the lymph node biopsies significantly associated with each etiological subtype was also made so that a pathologic classification can be done.
| Materials and Methods|| |
This is a retrospective study. A total of 58 cases of necrotizing lymphadenitis (pathologic diagnosis, irrespective of etiology) diagnosed on lymph node biopsies during the 3-year period from January 2014 to December 2016, in the Department of Pathology, were reviewed and the morphologic findings were recorded. (Based on a previous study, with a prevalence of Kikuchi lymphadenitis as 42.5%, minimum sample size estimated was 43, with 98% confidence and 15% allowable error). All cases of granulomatous/suppurative lymphadenitis and neoplasms were excluded. Based on the ancillary tests done, the cases were then categorized into different etiological subtypes like acute EBV lymphadenitis (EBV immunoglobulin M positive) and lupus lymphadenitis (antinuclear antibody (ANA) and ds DNA positive). Rest of the cases with negative results for both of these serological tests were classified as Kikuchi lymphadenitis (as specific test is not available, by excluding other 2 aetiologies and other infections). All cases which were proved to be TB by the ancillary tests like acid-fast staining/TB PCR or culture were excluded. Similarly, all fungal/parasitic (special stains: Periodic acid stain/ Gomori Methenamine Silver stain, culture positive) lymphadenitis were also not included. Institutional ethical committee clearance was obtained.
We studied the lymph node biopsy tissues which were formalin-fixed, paraffin-embedded, cut into 4-μm thick sections and stained with haematoxylin and eosin. Representative sections were also stained with histo chemical stains like Periodic acid Schiff's and reticulin stain. Morphologic features like the presence of vascular proliferation, periadenitis, and infiltration with foamy macrophages, neutrophils, and plasma cells were recorded and the association of each of these variables with the specific subtypes were assessed., Clinical details of all the cases were collected from electronic medical records and patients were followed up for a minimum period of 6 months.
| Results|| |
A total of 58 cases of necrotizing lymphadenitis diagnosed pathologically were further categorized based on serological tests. 15.5% (9/58) proved to be lupus lymphadenitis and 17.2% (10/58) EBV lymphadenitis. Rest of the cases (62.2%) with negative serological tests were classified as Kikuchi lymphadenitis.
Lupus cases had a female preponderance (78%), with age ranging from 18 to 61 years. (median age = 26 years; interquartile range (IQR)=33). Kikuchi lymphadenitis also was seen mostly in young females (62%), with a median age of 22 (IQR = 17.25) years, most of patients being <40 years (range, 8–52 years). Males (75%) with a median age of 28 years (range, 6–57 years; IQR = 42) were commonly affected by EBV lymphadenitis. 21% of patients were in the pediatric age group (mean age = 12 years; range, 6–18), with 8 having Kikuchi lymphadenitis, 3 EBV, and 1 lupus lymphadenitis.
Morphologically, all cases showed reactive lymphadenopathy with nongranulomatous necrotizing inflammation [Figure 1]. Necrosis with karyorrhectic debris was seen along with foamy histiocytes, in variable numbers. Among the morphologic parameters, plasma cell infiltration [Figure 2] (seen in 7/9 cases of lupus lymphadenitis, χ2 test, P value < 0.003) and vascular (venules/arteriolar) proliferation [Figure 3] (seen in 6/9 of SLE patients, χ2 test, P value = 0.013) were found to be significantly associated with lupus lymphadenitis. None of the other subtypes of lymphadenitis showed statistically significant association with any of the specific morphologic features studied. Foamy macrophages were seen more in Kikuchi disease, neutophils were occasionally seen in EBV and lupus lymphadenitis, but were absent in Kikuchi lymphadenitis. Periadenitis was more in EBV lymphadenitis. Fibrinoid necrosis of vessels was seen only in 2 cases of lupus lymphadenitis. Azzopardi phenomenon and hematoxylin bodies, though mentioned as pathognomonic, were seen in none of the lupus cases [Table 1].
|Table 1: Morphologic variables in different aetiological subtypes (statistically significant ones highlighted)|
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On follow-up for 6 months, all cases of Kikuchi lymphadenitis showed self-limiting course, with only 2 cases developing recurrence, 1 after 7 months, and second after 11 months of first episode. 90% of the patients were treated and resolved with supportive measures like antibiotics, antipyretics, and nonsteroidal anti-inflammatory drugs. EBV lymphadenitis also responded to supportive measures. The lupus patients received therapy as per the SLE protocol. The 2 patients with recurrent Kikuchi disease were offered long-term immunosuppression with low-dose mycophenolate mofetil, 1 agreed to take up, whereas the other patient offered to stay on follow-up. 4 developed complications, 3 had secondary hemophagocytic lymphohistiocytosis (2 Kikuchi disease and 1 EBV) and 1 Kikuchi disease had aseptic meningitis, all were treated with steroids.
| Discussion|| |
Necrosis in lymph nodes can be seen in a variety of neoplastic and non-neoplastic conditions. The most common non-neoplastic cause is TB, where granulomas with caseation type necrosis is seen. Neoplastic nodes can also undergo necrosis, for example, Hodgkin's lymphoma, nodular sclerosis subtype. Necrotizing lymphadenitis is characterized by nongranulomatous, noncaseating necrosis along with mixed inflammatory infiltrate composed of variable number of plasma cells, histiocytes, and neutrophils.
It is caused by a group of clinically and morphologically similar conditions, with different etiology, treatment, and prognosis, the most common cause being Kikuchi disease (62.2% in our study) followed by EBV and lupus lymphadenitis. In a similar study done in Thailand, 42.5% were Kikuchi lymphadenitis.
Kikuchi-Fujimoto disease is a type of self-limiting lymphadenitis of unknown etiology. Clinically, it presents with fever, tender lymphadenitis, and systemic symptoms with only occasional complications. As already described, our cases also showed preponderance in young females, with a mean age of 22 years, slightly lower than the mean age of 30 years in a case series reported by Dumas et al. Male to female ratio was 2.2:1 and cervical nodes were the most common site affected. Similar findings were observed in the same study. Classic morphologic pictures of necrosis with karyorrhectic debris, plasmacytoid lymphocytes, and crescentic histiocytes were seen in all these cases. Of the 3 histologic stages described, that is, proliferative, necrotizing and xanthomatous, proliferative phase mimics anaplastic and Hodgkin's lymphomas because of the presence of large immunoblasts with pleomorphic vesicular nuclei and prominent nucleoli. CD30 immunohistochemistry positivity in these cells is a potential pitfall, suggesting an erroneous diagnosis of lymphoma. Studies on reactive immunoblastic proliferation have shown expression of CD30 in T/B reactive immunoblasts in up to 42% of cases. But the lack of CD15 and absence of loss of other B-cell markers help to differentiate these cases. The background reactive T lymphocytes may show aberrant loss of T-cell markers. Admixed plasmacytoid cells express CD123, which serve as an important diagnostic clue. A high index of suspicion is based on the features like partly preserved nodal architecture, reactive follicles, polymorphous population of cells, and tiny areas of necrosis guide to an accurate diagnosis.
SLE is an autoimmune systemic disease, with around 30% of patients developing lymphadenitis. Young females are commonly affected, as seen in our study, with a mean age of 29 years (24 years in a study by Sharma et al. from Scotland). Male to female ratio was 1:3. Lymphnode biopsies showed reactive follicular hyperplasia, immunoblasts, plasma cells, and proliferating vascular channels. Fibrinoid necrosis was rarely found. Hematoxylin bodies and Azzopardi phenomenon are other commonly described findings. Baenas et al. had reported that Kikuchi lymphadenitis can coexist with SLE, which makes it more aggressive, warranting long-term therapy and follow-up. Other studies have also shown the development of Kikuchi lymphadenitis before or after SLE diagnosis. But none of our patients with Kikuchi lymphadenitis had such an association on follow-up, suggesting it to be a distinct disease.
Acute EBV lymphadenitis is also seen in young adults, as concurred by our study, with a mean age of 28 years. Unlike the other 2 conditions, this showed a male preponderance, with a M:F ratio of 4:1. (1.6:1 as seen in the study done by Jalal Ali Bilal). Systemic symptoms were seen in half of the patients. Lymph node biopsy showed typically paracortical hyperplasia with mottling, small areas of necrosis and immunoblast proliferation. Serological tests for EBV-IgM is confirmatory. However, EBER-ISH (more specific and sensitive) or IHC for EBV-LMP-1 can also be done on the lymph node tissue. The large B immunoblasts can also show expression of CD30, but usually express the B-cell markers like CD20 and PAX-5 and lack CD15. Moreover, the background cells are mostly CD8 positive T lymphocytes. Nodular lymphocyte-predominant Hodgkins lymphoma may be a morphologic mimicker, but it lacks the EBV expression in the large neoplastic cells.
As all these conditions can have similar clinical features, it is important to differentiate between them, to initiate appropriate treatment. A lymph node examination can exclude neoplastic conditions like lymphomas and the more common typical Mycobacterial infection.
Necrosis in the lymph node is caused by different mechanisms in all these conditions. In Kikuchi lymphadenitis, plasmacytoid dendritic cells secrete interferon, which activates cytotoxic T cells and induces necrosis. In EBV lymphadenitis, rapid destruction of virus-infected cells by T cells is considered to be the causative factor. Lupus lymphadenitis being an immune-mediated disease, necrotizing vasculitis, and autoantibodies induces the cell necrosis.
Plasma cells are seen more in lupus cases, as it is an immune-mediated disorder. Whereas, another significant finding, vascular proliferation is considered to be initiated by fibroblastic reticulum cells in the stroma which stimulate secretion of Vascular endothelial growth factor (VEGF).
The clinical outcome of the 3 groups of patients was also different. All cases of Kikuchi lymphadenitis resolved with supportive measures in 1–4 months. This is similar to other clinical studies, where the duration of disease was around 1–2 months. 5.5% of our cases developed complications, which is slightly higher than other reports available (3%). Two patients had recurrence and were on long-term treatment and follow-up. Recurrences are reported, as late as 12 years. Another series by Dumas et al. showed disease recurrence in 17% of cases.
Supportive measures were only offered to the patients with acute EBV lymphadenitis and a spontaneous resolution was seen in all except 1 who developed HLH, in 2–4 weeks' time, as seen in other studies. Lupus patients were treated with immunosuppression, steroids, and other drugs as per SLE protocol and had a chronic disease with a regular follow-up.
| Conclusions|| |
Necrosis in the lymph node does not equate to caseation or TB. Among the 3 etiological subgroups of necrotizing lymphadenitis identified in our series, Kikuchi lymphadenitis was the most common. It is useful to categorize all necrotizing lymphadenitis into these 3 subgroups based on serological tests as the treatment and prognosis differ. In addition, we suggest that a careful assessment of specific features like the presence of plasma cells and vascular proliferation can suggest the diagnosis of lupus lymphadenitis. Other morphologic features should also be looked into, as it might be helpful in identifying significant findings in the lymph node biopsies which can clinch the etiological diagnosis. A study including more number of cases in each entity might identify diagnostically significant pathologic features.
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| References|| |
Iochim HL, Medeiros LJ. Lymph Node Pathology. 4th
ed, Philadelphia: Wolters Kluwer/Lippincott Wilkins & William; 2009.
Fujimoto Y, Kozima Y. Yamaguchi cervical sub-acute necrotizing lymphadenitis: A new clinicopathologic entity. Naika 1972;20:920-7.
Kikuchi M. Lymphadenitis showing focal reticulum cell hyperplasia with nuclear debris and phagocytes. Acta Hematologic 1972;35:379-80.
Sanpavat A, Wannakrairot P, Assanasen T. Necrotizing non-granulomatous lymphadenitis: A clinicopathologic study of 40 Thai patients. Southeast Asian J Top Med Public Health 2006;37:563-70.
Neto R, Salles N, Rossi BK, Manente MF, Andrade de MP, Maurício LN. Lymphadenopathy and systemic lupus erythematosus. Rev Bras Reumatol 2010; 50:96-101.
Gordon C, Amissah-Arthur M-B, Gayed M, Brown S, Bruce IN, D 'Cruz D, et al
. The British society for rheumatology guideline for the management of systemic lupus erythematous in adults. Rheumatology 2018;57;1-45.
Dumas G, Prendki V, Haroche J. Kikuchi-Fujimoto disease retrospective study of 91 cases and review of the literature. Medicine (Baltimore) 2014;93:372-82.
Deaver D, Horna P, Cualing H, Sokol L. Pathogenesis, diagnosis, and management of Kikuchi–Fujimoto disease. Cancer Control 2014;21:313-21.
Wei XJ, Zhou XG, Xie JL, Zheng XD, Zheng YY. Aberrant phenotypes in Kikuchi's disease. Int J Clin Exp Pathol 2014;7:5557-63.
Sharma V, Rankin R. Fatal Kikuchi-like lymphadenitis associated with connective tissue disease: A report of two cases and review of literature. Springerplus 2015;4:167.
Baenas DF, Diehl FA, Lemos PA. Kikuchi Fujimoto disease and systemic lupus erythematosis. Int Med Case Rep J 2016;9:16-167.
Bilal JA. Prevalence and clinical characteristics of primary Epstein–Barr virus infection among children presented with cervical lymphadenopathy. J Clin Diagn Res 2015;9:8-10.
Pittaluga S. Viral-associated lymphoid proliferations. Semin Diagn Pathol 2013;30:130-6.
Pileri SA, Facchetti F, Ascani S. Myeloperoxidase expression by histiocytes in Kikuchi's and Kikuchi-like lymphadenopathy. Am J Pathol 2001;159:915-24.
Chiu CF, Chow KC, Lin TY. Viral infections in patients with Histiocytic necrotizing lymphadenitis in Taiwan. Am J Clin Pathol 2000;113:744-81.
Kojima M, Nakamura S, Itoh H, Yoshida K, Suchi T, Masawa N. Lymphnode necrosis in systemic lupus erythematosis. APMIS 2001;109:141-6.
Taha S, Gamal SM, Nabil M, Naeem N, Labib D, Siam I, et al
. Vascular endothelial growth factor G1612A gene polymorphism and neuropsychiatric manifestations in systemic lupus erythematosis patients. Rev Braz Rheumatol 2017;57:149-53.
Blewitt RW, Kumar SN, Abraham JS. Recurrence of Kikuchi's lymphadenitis after 12 years. J Clin Pathol 2000;53:157-8.
Indu R Nair
Department of Pathology, Amrita Institute of Medical Sciences, Ponekkara, Kochi - 682 041, Kerala
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]