J Clin Pathol 1984;37:1119-1122

Herpes simplex lymphadenitis: a case report andreview of the published workM LAPSLEY,* P KETTLE,t J M SLOAN*

From the Departments of *Pathology and tHaematology, Royal Victoria Hospital, Belfast BT12 6BA

SUMMARY Viral lymphadenitis may lead to a histological appearance that can simulate malig-nancy. The histological features of herpes simplex lymphadenitis have not previously beendescribed in detail. We report a case of proved herpes simplex lymphadenitis in a 30 year old manwhich was characterised by a pronounced proliferation of immunoblasts. The microscopicalfindings are described and the published work is reviewed.

Infectiops mononucleosis had long been recognisedas a major source of difficulty in diagnosis in lymphnode histopathology,' but other viral infections maygive rise to similar problems. Problems in interpreta-tion arise because of distortion and apparenteffacement of lymph node architecture and becauseof the large numbers of large dividing cells seenunder high power examination. These problems areoften further compounded by lack of experience ininterpreting biopsy material from patients sufferingfrom viral illness, since lymph node excision is notusually deemed necessary from a clinical point ofview.We report a case of lymphadenitis in a 30 year old

man with serologically proved herpes simplex infec-tion, which was characterised by pronouncedimmunoblastic proliferation.

Case report

CLINICAL FEATURESA 30 year old man presented with a short history ofincreasing tiredness and general malaise, with awidespread rash. He had no night sweats and nopruritus, and he was not taking any drugs. There wasno history of immunisation. His children were con-valescing from a rash which had been diagnosed clin-ically as varicella.By the time of examination the rash had faded

considerably. There were a few raised papules onthe trunk and limbs with occasional raisederythematous areas. There was generalised lym-phadenopathy, but all the nodes were less than 05cm in diameter. There was no hepatosplenomegaly,

Accepted for publication 17 July 1984

and he was not feverish. No cold sores or herpeticwhitlow were identified.

His haemoglobin concentration was 15-6 g/dl andhis white cell count 8-2 x 109/1, with a normal differ-ential count. The erythrocyte sedimentation ratewas 2 mm in the first hour. Biochemical screeningshowed no abnormality, and serum immunoglobulinvalues were normal. Bone marrow trephine biopsywas normal. There was no hilar lymphadenopathyon chest radiography, and computed tomography ofthe abdomen showed a few small pelvic lymphnodes, which were not thought to be important.

Serological screening showed no change in titre tovaricella zoster or cytomegalovirus. There was, how-ever, a rise in titre to herpes simplex to 1/640, whichfell to 1/160 two months later. Further typing wasnot performed. The result of a Paul Bunnell test wasnegative.About eight months after referral the patient is

well and asymptomatic. The lymph nodes haveregressed without treatment.A lymph node biopsy was performed shortly after

the onset of symptoms, and the findings are pre-sented.

PATHOLOGICAL FINDINGSThe lymph node was fixed in formalin, processed,and embedded in wax. Sections were cut and stainedwith haematoxylin and eosin. Giemsa, periodic acidSchiff, and reticulin (Foot) stains were also per-formed. Further paraffin sections were stained forcytoplasmic immunoglobulin light and heavy chainsby an immunoperoxidase method.The lymph node structure was distorted, but the

sinus architecture was preserved. There was pro-nounced expansion of the paracortical regions, andseveral atrophic germinal centres remained around

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Lapsley, Kettle, Sloan

Fig. 1 Lymph node showingi expansion ofthe parafollicular areas,

preservation of small atrophicgerminal centres, and remaining

z medullary sinuses. Originalmagnification x40.

Fig. 2 Infitrate in interfollicular areas.There is an intimate mixture ofimmunoblasts, centroblasts, smalllymphocytes, and occasional histiocytes.A small venule is present and hasprominent endothelial cells. Originalmagnifiation x400.

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Herpes simplex lymphadenitis

the periphery of the node (Fig. 1). The interfollicu-lar infiltrate was composed of a mixture of cells.There were abundant immunoblasts, which are largecells with pyroninophilic cytoplasm and a vesicularnucleus containing a single large eosinophilic nuc-leolus. Many of these were in mitosis. Intimatelyinterspersed between these were many lymphocytes,with occasional plasmacytoid cells and macrophages(Fig. 2). There was no sheeting of immunoblasts.The endothelial cells of the epithelioid venules wereprominent, but the small blood vessels did not showan arborising pattern. There was no necrosis, and noextension of lymphoid cells through the capsule ofthe node. There was no invasion of blood vesselwalls. Immunoperoxidase studies showed only mini-mal production of both light chains. No heavychains were produced. An immunoperoxidase stainfor herpes simplex type II was negative. Unfortu-nately, fresh unfixed material was not available forlymphoid cell surface marker studies.

Discussion

Lymph node biopsy is not normally required in thediagnosis of viral illness, and the importance of thehistological appearances lies in the recognition ofthe somewhat alarming pattern as being due to abenign self limiting condition. Many other benignconditions can simulate malignancy in lymph nodes,2including herpes zoster3 and infectious mononuc-leosis.' Postvaccinial lymphadenitis may give a simi-lar picture to viral lymphadenitis,3 although therewas no history of immunisation in this case. To ourknowledge the histological findings in herpes sim-plex lymphadenitis have not previously beendescribed in detail, although Tindle briefly describedherpetic lymphadenitis in general as being character-ised by immunoblastic proliferation.4The histological appearances seen in this patient's

lymph node are similar to those reported after infec-tion by other members of the herpes group, such asinfectious mononucleosis' and herpes zoster infec-tion.3 In all these cases hypercellularity and expan-sion of paracortical areas are the main features.Similar features have been shown in rabbits infectedwith herpes virus of bovine malignant catarrhalfever5; the proliferating cells have been shown to beT lymphoblasts in this disease.6We believe that the changes in this lymph node

were due to a proliferation of T immunoblasts as areaction to herpes simplex virus antigen. Thisinterpretation is supported by the parafollicularlocation of the dividing cells, in between theatrophic germinal centres. This is the T zone of thelymph node.7 In addition, staining for immunoglobu-lin by the immunoperoxidase method showed little

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evidence of immunoglobulin production, which, ifpresent, would suggest B cell function. The Timmunoblast is believed to be the precursor of thecytotoxic T cell.7 Animal studies have suggested thata T cell reaction would be consistent with theimmune response to herpes simplex infection underexperimental conditions. Stimulated mouse T cellscan be specifically sensitised to herpes simplex anti-gen.89 These cells are of the cytotoxic subgroup.Another study has shown that herpes simplex viruscan replicate within activated human T cells.'0 Thus,at least in the mouse, the normal response to herpessimplex infection would seem to include T cell trans-formation and proliferation.Herpes simplex infection in man is well known for

causing cold sores, genital lesions, and encephalitis.Reports of lymphatic complications are rarer, butlymphangitis, usually associated with lym-phadenopathy, has been described after herpes sim-plex infection of the hand."I2 Systemic infectionmay rarely occur in pregnancy after genital herpes,and lymphadenopathy is considered to be an impor-tant sign of generalised infection.'3 Unfortunately,no biopsy material was available to the authors ofthe latter report. It has also been suggested'4 thatgeneralised herpes simplex infection is uncommonand usually fatal and occurs in immunodeficientpatients. Our experience with this case suggests thatthis is not always so.

It is uncertain what the origin of the infection inthe present case was, or indeed why a healthy 30year old man should develop a systemic herpes sim-plex infection in the absence of any localised lesion.His children had been suffering from a febrile illnesswith an associated rash, which was diagnosed clini-cally as varicella. This diagnosis was not proved,however, and the illness may have been the same asthat in our patient.The clinical findings were those of a benign self

limiting condition, and the appearances in the lymphnode would support this. In particular, the preserva-tion of germinal centres and medullary sinuses andthe absence of any sheeting or clumping ofimmunoblasts suggest a benign condition. Finally,should a case such as this be misdiagnosed as malig-nant, a short course of chemotherapy orradiotherapy would be considered "curative," andthe true diagnosis might never be made. The hazardsof cytotoxic therapy and the anxiety generated inboth the patient and his family after a diagnosis ofmalignancy, possibly for many years subsequently,make the recognition of this and similar conditionsof great importance.

We thank Professor JM Bridges for his permissionto report this case.

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Referenc

'Salvador AH, Harrison EG, Kyle RA. Lymphadenopathy due toinfectious mononucleosis: Its confusion with malignant lym-phoma. Cancer 1971;27:1029-40.

2 Dorfman RF, Warnke R. Lymphadenopathy simulating themalignant lymphomas. Hum Pathol 1974; 5:519-50.

3Hartsock RJ. Postvaccinial lymphadenitis. Hyperplasia of lym-phoid tissue that simulates malignant lymphomas. Cancer1968;21:632-49.

4Tindle BH. The haemopoietic system. In: Coulson WF, ed. Sur-gical Pathology. Philadelphia: JB Lippencott Company.1978;903-4.

5 Edington N, Patel J, Russell PH, Plowright W. The nature of theacute lymphoid proliferation in rabbits infected with theherpes virus of bovine malignant catarral fever. Eur J Cancer1979; 15:1515-22.

6 Rossiter PB. Proliferation of T lymphoblasts in rabbits fatallyinfected with the herpes virus of malignant catarral fever. ClinExp Immunol 1983;54:547-53.

7Lennert K. Malignant lymphomas other than Hodgkin's diseaseBerlin: Springer Verlag, 1978;24-51.

8Jennings SR, Rice PL, Pan S, Knowles BB, Trevethia SS. Recog-

Lapsley, Kettle, Sloannition of herpes H-2b simplex virus antigens on the surface ofmouse cells of the haplotype by virus-specific cytotoxic T lym-phocytes. J Immunol 1984; 132:475-81.

Rouse BT, Wagner H. Frequency of herpes simplex virus-specificcytotoxic T lymphocyte precursors in lymph node cells ofinfected mice. Immunology 1984,;51:57-64.

Braun RW, Teute HK, Kirchner H, Munk K. Replication ofherpes simplex virus in human T lymphocytes: characteriza-tion of the viral target cell. J Immunol 1984; 132:914-9.

"Howard WR, Taylor JS, Steck WD. Lymphatic complications ofmanual herpes simplex infection. Cutis 1979;23:580-3.

2 Dorman JM. Herpetic lymphangitis in a student population. JAdolesc Health Care 1982;3:49-50.

Hillard P, Seeds J, Cefalo R. Disseminated herpes simplex inpregnancy: Two cases and a review. Obstet Gynecol Surv1982;37:449-53.

'4 Schaffer R, Ormanns W, Pfeifer U. Post mortem diagnosis ofherpes simplex infections. Verh Dtsch Ges Pathol1981;65:230-4.

Requests for reprints to: Dr M Lapsley, Department ofHistopathology, Guy's Hospital Medical School, LondonBridge, London SE1 9RT, England.

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