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  Table of Contents    
CASE REPORT  
Year : 2013  |  Volume : 56  |  Issue : 4  |  Page : 440-442
Nodular lymphocyte predominant Hodgkin lymphoma and diphenylhydantoin: Report of a case and review of the literature


1 Department of Pathology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India
2 Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India

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Date of Web Publication18-Jan-2014
 

   Abstract 

A variety of lymphoma types have been reported in patients being treated with anticonvulsant therapy. Non-Hodgkin lymphomas have been reported twice as frequently as Hodgkin lymphomas. Association of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) with dilantin therapy is extremely uncommon. We report a case of Hodgkin lymphoma in a 25-year-old male patient who had been treated with diphenylhydantoin sodium for generalized tonic clonic seizures for 15 years. Patient presented with left cervical and axillary lymphadenopathy persisting for more than 2 years after cessation of treatment with diphenylhydantoin. Computerized tomography scan of thorax, abdomen and pelvis revealed no significant lymphadenopathy or any organomegaly. Diagnosis of NLPHL was made on excision biopsy of the cervical lymph node. Although the association between diphenylhydantoin therapy and the development of immunosuppression and lymphoma is well-documented, the role of the drug in the etiology of these disorders is still controversial.

Keywords: Diphenylhydantoin, nodular lymphocyte predominant Hodgkin lymphoma, lymphadenopathy, generalized tonic clonic seizures

How to cite this article:
Sharma S, Menon H, Sengar M, Gujral S. Nodular lymphocyte predominant Hodgkin lymphoma and diphenylhydantoin: Report of a case and review of the literature. Indian J Pathol Microbiol 2013;56:440-2

How to cite this URL:
Sharma S, Menon H, Sengar M, Gujral S. Nodular lymphocyte predominant Hodgkin lymphoma and diphenylhydantoin: Report of a case and review of the literature. Indian J Pathol Microbiol [serial online] 2013 [cited 2019 Dec 9];56:440-2. Available from: http://www.ijpmonline.org/text.asp?2013/56/4/440/125364



   Introduction Top


Phenytoin has been causally implicated in three human cancers: lymphoma, myeloma and neuroblastoma. [1] Among various lymph node abnormalities four distinct categories of lymphadenopathy have been described: Lymphoid hyperplasia, pseudolymphoma, pseudo-pseudolymphoma and lymphoma. These presentations vary from a benign symptom complex, with enlarged lymph nodes, that is reversible upon drug discontinuance to a true malignant lymphoma that is progressive and ultimately fatal. [2] Current understanding categorizes these occurrences into three groups: The anticonvulsant hypersensitivity syndrome, phenytoin-induced pseudo-lymphoma and true lymphoma. Anticonvulsant hypersensitivity syndrome is a severe adverse drug reaction with multiorgan involvement. Aromatic anticonvulsants are the most frequently involved drugs. [3] Phenytoin is linked to a hypersensitivity syndrome that manifests with fever, rash and lymphadenopathy. Patients receiving phenytoin may develop pseudolymphoma or, more rarely, malignant lymphoma with mycosis fungoides-like lesions. [4] Although in general self-limiting, the syndrome may be life-threatening, particularly among patients who develop severe cutaneous eruptions or hepatitis. Early recognition of the syndrome is essential, as immediate discontinuation of the offending antiepileptic agent is the most important step in improving outcome. [5] The lymphoid reaction pattern most commonly seen in this syndrome is a benign lymphoid follicular hyperplasia. In contradistinction to the anticonvulsant hypersensitivity syndrome, phenytoin-induced pseudolymphoma is considered to be a late effect of phenytoin therapy, which can occur years after initiating treatment. This term applies to those patients with histological and clinical features suggestive of lymphoma. These patients have an atypical lymph node hyperplasia that distorts or effaces the normal lymph node architecture with an atrophic germinal center. Fever, hepatitis and eosinophilia are generally absent. Over the last 30 years, the classification of pseudolymphomas and lymphomas has undergone significant change, especially following the application of sophisticated immunostaining and gene rearrangement analysis. [6] Pseudolymphoma syndrome (PLS) is rare but may lead to death if presents with extensive skin lesions, severe hepatitis, agranulocytosis and neutropenia. PLS may also give rise to harmful effects if misdiagnosed as malignant lymphoma. [7] It is therefore critical to distinguish PLS from true lymphomas in order to avoid unnecessary treatment that can potentially be harmful.


   Case Report Top


This was a case report of a 25-year-old male patient who was presented with the complaints of the left cervical and axillary lymphadenopathy of more than 2 years duration. He was being treated for generalized tonic clonic seizures with dilantin from year 1990 to year 2010. The lymph nodes appeared in year 2010 and persisted for more than 2 years even after cessation of treatment with dilantin. There was no history of fever, weight loss or night sweats. At the time of the initial consultation at our institution, the patient's physical examination was significant for palpable cervical and axillary lymphadenopathy of the left side. The largest node was a left level II cervical node measuring 2.9 cm × 2.0 cm on computerized tomography scan. There was no hepatosplenomegaly. His complete blood count showed a total leucocyte count of 6,480/μL, a platelet count of 174,000/μL and hemoglobin of 14.3 g/dL. Patient was seronegative for human immunodeficiency virus, hepatitis B surface antigen and hepatitis C virus. Routine biochemical tests were within normal limits with normal lactate dehydrogenase and β2 microglobulin levels of 149 U/L and 1.64 mg/L respectively. An excision biopsy of the cervical lymph node revealed partially effaced nodal architecture consisting of a nodular pattern of proliferation [Figure 1]a . These large size nodules consisted of diffuse infiltrates predominantly small lymphocytes admixed with histiocytes and intermingled large mononuclear cells and occasional multinuclear cells. These large size cells had moderate to abundant cytoplasm and a folded popcorn shaped nuclei (Langerhans and histiocytic cells) [Figure 1]b. Immunohistochemical studies revealed that the nodules were rich in CD20 positive small B cells, which also highlighted large size tumor cells within the nodule [Figure 1]c. The large cells in addition expressed CD45 [Figure 1d], OCT2 [Figure 1]f and BOB1, whereas negative for CD30 [Figure 1]e and CD15. Stains for CD3 revealed rosetting of the large size tumor cells. Stains for CD23 revealed a mottled follicular dendritic cell pattern [Figure 2]. Diagnosis of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) was rendered. Bone marrow biopsy and aspirate revealed a normocellular marrow with adequate trilineage maturing hematopoiesis. As the patient was asymptomatic (Stage IIA), he is being kept on observation and regular follow-up.
Figure 1: (a) Lymph node biopsy showing a single large tumor nodule composed of dark small lymphocytes, pale histi ocytes and L and H cells (H and E, ×100) , (b) Higher magnifi cati on of the same showing large multi lobated L and H cells (H and E, ×400), (c) immunohistochemical (IHC) stain for CD20 highlights many small reacti ve B lymphocytes and large L and H cells (IHC, ×200), (d) The L and H cells are positi ve for CD45 (IHC, ×400), (e) The L and H cells are negati ve for CD30 (IHC, ×200), (f) IHC stain for octamer binding transcripti on factor 2 [Oct 2] highlights many small B cells and large L and H cells (IHC, ×200)

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Figure 2: Immunohistochemical (IHC) stain for CD23 highlighti ng loose follicular dendritic cell pattern in nodular lymphocyte predominant Hodgkin's lymphoma (IHC, ×100)

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   Discussion Top


Lymphadenopathy in association with the use of hydantoin derivatives like phenytoin was first described in 1940. Over the years, there have been multiple case reports and small series published describing this occurrence and variously terming it Dilantin-associated lymphadenopathy, phenytoin-induced pseudolymphoma and anticonvulsant hypersensitivity syndrome. [8]

John et al. [8] reported cases of phenytoin induced pseudolymphoma mimicking angioimmunoblastic T cell lymphoma and cutaneous T cell lymphoma respectively in their studies. In a case series, Abbondazo et al. [9] reported 15 cases of benign histology, 7 cases of NHL and 3 cases of Hodgkin's disease following treatment with dilantin. Creixenti et al. reported a case of Hodgkin's disease following treatment with hydantoin. [2] In various studies, a variety of lymphoma types have been reported in patients being treated with anticonvulsant therapy. Non-Hodgkin lymphomas have been reported twice as frequently as Hodgkin lymphomas. The types of non-Hodgkin lymphomas reported include angioimmunoblastic T-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma and cutaneous anaplastic large-cell lymphoma. [10] The types of Hodgkin lymphoma reported include nodular sclerosis, mixed cellularity and nodular lymphocyte predominant. [9],[10]

The mechanisms underlying the development of lymphadenopathy in patients treated with phenytoin are not completely understood. With regards to the anticonvulsant hypersensitivity syndrome, it has been proposed that abnormal detoxification of reactive metabolites of phenytoin, possibly arene oxide metabolites produced by cytochrome P450, is responsible for the syndrome. Whether the pathophysiology of phenytoin-induced pseudo-lymphoma is similar remains unknown. [1] It is suggested that periodic examination of patients receiving diphenylhydantoin for lymphadenopathy may be useful in detecting early aberrations of the immune system in these individuals.

In summary, this case report describes the presentation of the rare but important syndrome of phenytoin-induced subtype of Hodgkin lymphoma (NLPHL) and adds to the available body of literature describing this entity.

 
   References Top

1.Singh G, Driever PH, Sander JW. Cancer risk in people with epilepsy: The role of antiepileptic drugs. Brain 2005;128:7-17.  Back to cited text no. 1
    
2.Bladé Creixenti J, Segura Porta F, Nogué Xarau S, Soriano Marín E, García San Miguel J. Hodgkin's disease following treatment with hydantoins. Report of a case and review of the literature (author's transl). Med Clin (Barc) 1980;75:24-6.  Back to cited text no. 2
    
3.Mansur AT, Pekcan Yaºar S, Göktay F. Anticonvulsant hypersensitivity syndrome: Clinical and laboratory features. Int J Dermatol 2008;47:1184-9.  Back to cited text no. 3
    
4.Scheinfeld N. Impact of phenytoin therapy on the skin and skin disease. Expert Opin Drug Saf 2004;3:655-65.  Back to cited text no. 4
    
5.Kruspe R, Broussard A, Santanilla J, Gupta S, Espinoza C, Lopez FA, et al. Lymphoma or pseudolymphoma? J La State Med Soc 2002;154:178-81.  Back to cited text no. 5
    
6.Albrecht J, Fine LA, Piette W. Drug-associated lymphoma and pseudolymphoma: Recognition and management. Dermatol Clin 2007;25:233-44, vii.  Back to cited text no. 6
    
7.Choi TS, Doh KS, Kim SH, Jang MS, Suh KS, Kim ST. Clinicopathological and genotypic aspects of anticonvulsant-induced pseudolymphoma syndrome. Br J Dermatol 2003;148:730-6.  Back to cited text no. 7
    
8.Johns ME, Moscinski LC, Sokol L. Phenytoin-associated lymphoadenopathy mimicking a peripheral T-cell lymphoma. Mediterr J Hematol Infect Dis 2010;2:e2010028.  Back to cited text no. 8
    
9.Abbondazo SL, Irey NS, Frizzera G. Dilantin-associated lymphadenopathy. Spectrum of histopathologic patterns. Am J Surg Pathol 1995;19:675-86.  Back to cited text no. 9
    
10.Ioachim HL, Medeiros LJ. Iatrogenic lymphadenopathies. In: Ioachim HL, Medeiros LJ, editors. Ioachim's Lymph Node Pathology. 4 th ed. New York: Lippincott Wolters Kluwer; 2008. p. 256.  Back to cited text no. 10
    

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Correspondence Address:
Sumeet Gujral
Department of Pathology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.125364

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    Figures

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