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476 Archives ofDisease in Childhood 1995; 73: 476-479

PERSONAL PRACTICE Arch Dis Child: first published as 10.1136/adc.73.5.476 on 1 November 1995. Downloaded from

Lymphadenopathy

Bruce Morland

Lymph node enlargement is a common finding < 1 cm diameter are invariably of non-specific on routine of children. aetiology,' others agree with '1 cm rule', but The dilemma facing general practitioners is add that epitrochlear nodes >05 cm, and when to refer to paediatricians; the dilemma inguinal nodes > 1-5 cm should be regarded as for paediatricians is deciding how extensively abnormal nodal dimensions in these anatom- to investigate children. While the majority of ical sites.2 3 Full examination of all nodal cases will have a benign, rapidly resolving sites should be undertaken to determine iflym- course, the well recognised associations of phadenopathy is localised or generalised. The and potentially life threaten- distinction between localised or generalised ing such as cause worry and lymphadenopathy is important, as a specific anxiety to both families and doctors caring for pathological cause is more likely to be found in children. This concern may in itself initiate patients with generalised lymphadenopathy.I an inappropriately rapid or over aggressive The descriptive character ofthe (s) attempt at determining the diagnosis. An (firm, rubbery, fixed), is at best subjective and organised approach to children with lym- at worst quite misleading. Far from being phadenopathy will help the clinician make pathognomonic of malignant nodes, many appropriate decisions regarding treatment and inflammatory lesions especially if associated further investigation. with fibrotic reaction can 'feel sinister'. Abdominal palpation should determine the presence of liver or splenic enlargement. History Features of anaemia, petechiae, or bleeding A detailed history should focus both on diag- will point.towards a marrow infiltrative nostic clues, and to features suggestive of more such as leukaemia. The skin should be exam- sinister pathology. Duration of lymphadeno- ined for infective lesions or exanthematous

pathy may be helpful, most infectious causes rashes. A careful ear, nose, and throat exami- http://adc.bmj.com/ producing a short (less than two week) history. nation, especially in children with cervical Long standing lymphadenopathy may be lymphadenopathy, with particular emphasis on caused by a variety of diseases including infec- nasal discharge, obstruction, or depression of tions (HIV, Epstein-Barr , tuberculosis, the soft palate helps to define possible source etc), malignancy, , and auto- of while considering some of the immune disease, but while very long standing commoner malignant head and tumours (over one year) lymph node enlargement is such as non-Hodgkin's , rhabdo- likely to be pathological, it is unlikely to be due myosarcoma, and . on September 27, 2021 by guest. Protected copyright. to malignancy. Attention should be made to associated rashes (exanthemata), travel, and exposure to pets (particularly cats). Associated Generalised lymphadenopathy constitutional symptoms should be sought: The presence of generalised lymphadenopathy weight loss (> 10% over six months), fever and should always alert the clinician to the night sweats, pruritis, and myalgia/arthralgia. presence of significant pathology. Detailed While the presence of such symptoms is history and examination will help narrow important, they are not specific, as frequently diagnostic possibilities. Any of the common believed, for lymphoma. Only one third of viral exanthemata may produce generalised children with Hodgkin's disease and 10% lymphadenopathy, other infective causes may with non-Hodgkin's lymphoma display con- include , toxoplas- stitutional symptoms. mosis, and HIV infection particularly if lym- phadenopathy has been present for over three months. Lymphadenopathy due to leukaemia Physical examination may be generalised, but other features such as Department of While the child with isolated lymphadenopathy anaemia, bleeding, or bruising are likely to be Oncology, associated with erythema, tenderness, and present. Similarly generalised lymphadeno- Birmingham inflammation poses little diagnostic dilemma, pathy from other systemic malignancies such Children's Hospital, the non-inflamed node is more of a as lymphoma or are likely to be Ladywood Middleway, chronic, Birmingham challenge. The first point is to decide whether associated with other clinical findings (for B16 8ET nodes are abnormally enlarged. Unfortunately example the presence of an abdominal mass). in the literature to A number of rarer causes of Correspondence to: there is little guidance help. generalised Dr Morland. While some authors suggest lymph nodes lymphadenopathy should also be considered in Lymphadenopathy 477

the list of differential diagnoses. A wide range biopsies in children reported about one sixth of of autoimmune and connective tissue disease cases being due to malignancy.'2 Of 13 malig- may be associated with generalised lympha- nant cases in this report, nine were due to Arch Dis Child: first published as 10.1136/adc.73.5.476 on 1 November 1995. Downloaded from denopathy. Drugs (particularly phenytoin and Hodgkin's disease, three non-Hodgkin's lym- carbamazepine) are reported to be associated phoma, and one Langerhans' cell histiocytosis. with lymphadenopathy, but this complication Although other malignancies such as soft tissue appears to be very rare.4 X linked lymphopro- sarcomas may involve locoregional nodes, it is liferative disease is characterised by a rapidly uncommon for lymphadenopathy to be present progressive and often fatal Epstein-Barr virus without additional physical signs due to the infection mimicking severe infectious mono- primary tumour. nucleosis.5 The Sezary syndrome is a form of cutaneous T cell non-Hodgkin's lymphoma with similarities to mycosis fungoides.6 Rarer pathologies Although more typically a disease of older A seemingly bewildering assortment of reactive patients, it has been reported to occur in , lymphadenitides, and lym- children and is associated with generalised phoproliferative disorders underlies a small lymphadenopathy. proportion of children with enlarged lymph nodes.'3 A few warrant further discussion as confusion with malignant nodes is not Regional lymphadenopathy uncommon.14 Due to the anatomical arrangement of the Rosai-Dorfmann disease (sinus histiocytosis and drainage, regional with massive lymphadenopathy) 15 may present lymphadenopathy usually represents the with alarming, bulky, and often matted lymph clinical manifestation of local pathological nodes. The majority of cases present with processes. Infection is undoubtedly the com- , although other monest cause of localised lymphadenopathy, nodal sites and extranodal involvement (skin, and careful examination of the skin, ear, nose, soft tissues, bone, central nervous system) can and throat, teeth, scalp, etc will help define the be seen. Although the disease is usually seen in source of infection in a proportion of children. young adults, cases in children have been Common infecting organisms will be strepto- reported.16 Constitutional symptoms such as coccal and staphylococcal species.7 Axillary fever and malaise may be present in a propor- and cervical lymphadenopathy should always tion of cases. Common laboratory findings are prompt questioning about pets, as cat scratch raised erythrocyte sedimentation rate (ESR), disease is commonly associated with this hypergammaglobulinaemia, and anaemia. pattern of lymph node enlargement.8 Long Although the lymph nodes undergo spon- standing lymphadenopathy may suggest tuber- taneous regression with time, mortality from culosis and a history of contact should be progressive disease in vital sites is recognised.'7 sought. Tuberculin skin testing may help in A variety of therapeutic interventions have clarification, however, both false positive and been tried in order to halt the progression of false negative results may lead to confusion.9 this disease including corticosteroids, a variety http://adc.bmj.com/ In developed countries, lymphadenopathy of chemotherapeutic agents, immunosuppres- due to mycobacteria is likely to be non- sants such as cyclosporin, and radiotherapy. tuberculous and one recent report has suggested All have been shown to have some effect in the incidence of avium and individual patients, but at best the responses Mycobacterium malmoense in children are variable, and no consistent approach can is increasing.10 The cervical, submandibular, be recommended other than observation in the and preauricular nodes are usually involved, majority of cases. A small number of cases will on September 27, 2021 by guest. Protected copyright. and in most cases the lymphadenopathy is uni- develop persistent, non-progressive disease, or lateral. Systemic illness appears to be unusual. demonstrate a chronically relapsing picture Diagnosis may be made by Mantoux testing over several years. with different mycobacterium species antigens, Kikuchi's disease (histocytic necrotising however, results may not be conclusive. In addi- lymphadenitis) was first described in Japan but tion cross reactivity with tuberculin purified is now recognised to occur world wide,'8 protein derivative may further confuse the situa- usually in young adults, but also reported in tion by producing both false positive and false children. 19 The disease is benign and selflimit- negative results. The diagnostic test of choice is ing, however, the pattern of lymphadenopathy excisional biopsy with the specimen being sent and prominent constitutional symptoms com- for both mycobacterial culture and for routine monly leads to confusion with malignant lym- histology. Excision is likely to be curative, as phomas. are usually antituberculous drug treatment seems to have involved, although other nodal sites (including no role in the treatment of non-tuberculous generalised lymphadenopathy) may be seen. mycobacterial infection. Incision and drainage Nodes are commonly tender to touch, classical or needle biopsy produces sinus formation and rubbery or firm, but not matted together. A scarring in a significant number of children." prodromal flu-like illness may precede the Regional lymphadenopathy may of course onset of lymphadenopathy and fever is be due to malignancy. Indeed such as commonly reported. Laboratory findings Hodgkin's disease commonly present with include raised ESR and leucopenia. Due to the enlarged nodes. Overall the incidence of self limiting nature of the disease a conserva- cancer induced lymphadenopathy is small. tive approach should be taken with sympto- One series presenting data on lymph node matic antipyretic treatment. The majority of 478 Morland

diagnosis is likely to be a biopsy preceded by Is lymphadenopathy abnormal ? a few simple investigations. These should include a full blood count and differential Arch Dis Child: first published as 10.1136/adc.73.5.476 on 1 November 1995. Downloaded from Yes white cell count, tuberculin skin test, and chest Significant physical signs or symptoms ? radiography (particularly important to exclude mediastinal masses before general anaes- No Yes thesia). ESR is a very non-specific test and is of limited benefit as it is commonly raised in a Observe wide range inflammatory, reactive, and malig- ? use antibiotics nant conditions. Similarly a normal ESR does not necessarily exclude significant pathology. Lymph node fine needle aspiration may have a 3 weeks role, but experience in the technique is limited, and interpretation of samples requires a degree of expertise and can at times be very mislead- Reassess Node(s) increasing in size ing. The procedure of choice is either inci- 3 weeks \ sional or excisional . Pathological diagnosis can be notoriously Reassess Node(s) unchanged difficult, and appropriate handling of biopsies, and experienced pathological opinion, is vital. 4 weeks Certainly if the possibility of malignancy is Reassess Node(s) not resolved being considered, advice from a paediatric completely oncologist should be sought before biopsy. Flow chartfor the management ofchildren with lymphadenopathy. Complex immunohistochemistry, cytogenetic analysis, and molecular biology studies can be vital clues in clinching or excluding the cases will resolve within a few weeks but a few possibility of cancer and also help define a wide will persist for some months or up to a year. range of non-malignant entities. All these presents with a combina- techniques rely on fresh biopsy material, and tion of fever, rash, changes to the peripheral the days of a wedge of tissue fixed in formalin extremities, mucosal changes, conjunctival in the operating theatre are numbered. injection, and cervical lymphadenopathy. The Unfortunately inappropriate handling of association with coronary artery disease and biopsy material still frequently occurs. These sudden death makes recognition of the disease issues may be compounded by the present important.20 Diagnosis is rarely a problem if nature of contracting within the health service the full spectrum of clinical features is present, and the incentive to deal with these children 'in however, cases presenting with fever and house' rather than to refer or consult specialist cervical lymphadenopathy mimicking infective centres early in the diagnostic process. This lymphadenitis have been reported.21 can result in further delays in diagnosis and the need for repeat biopsies. Appropriate consulta- http://adc.bmj.com/ tion and referral at an early stage can avoid Management oflymphadenopathy many of the pitfalls outlined above. With an organised approach, careful history taking and physical examination, the majority of children with lymphadenopathy will not Conclusions pose a diagnostic dilemma. The presence of Lymphadenopathy is a common finding in

unexplained generalised lymphadenopathy, children. Although a myriad of possible diag- on September 27, 2021 by guest. Protected copyright. significant constitutional symptoms, hepatic or noses are possible, very few cases will be splenic enlargement, anaemia, or bleeding associated with significant pathology. tendency should prompt urgent referral to a Untimely, inappropriate, and unnecessary paediatrician. Where the diagnosis is not investigations can be avoided in children pre- immediately obvious and other clinical signs senting with lymphadenopathy and should be are absent, a period of observation should be achieved through good clinical skills and inter- undertaken, and some authors would recom- disciplinary communication and cooperation. mend the initial empirical use of antibiotics during the early follow up period.2 7 Regular 1 Pangalis GA, Vassilakopoulos TP, Boussiotis VA, Fessas P. Clinical approach to lymphadenopathy. Semin Oncol evaluation of both the lymph node(s) and 1993; 20: 570-82. patient's general condition should be under- 2 Grossman M, Shiramizu B. Evaluation of lymphadeno- pathy in children. Current Opinion in Pediatrics 1994; 6: taken. Progressive lymph node enlargement 68-76. over two to three weeks, no diminution in 3 Nesbit ME. Clinical assessment and of the child with suspected cancer. In: Pizzo PA, Poplack lymph node masses after five to six weeks, or DG, eds. Principles and practice of pediatnic oncology. failure or complete resolution by 10 weeks Philadelphia: JB Lippincott, 1993: 108-9. 4 Segal GH, Clough JD, Tubbs RR. Autoimmune and iatro- should prompt further referral and investiga- genic causes of lymphadenopathy. Semin Oncol 1993; 20: tion (figure).3 611-26. 5 Puriilo DT, Cassel CK, Yang JPS, Harper R. X-linked If at the time of referral there are no diag- recessive progressive combined variable immunodefi- nostic clues in the history or the examination of ciency (Duncan's disease). Lancet 1975; i: 935-40. 6 Kuzel TM, Roenigk HH Jr, Rosen ST. Mycosis fungoides the child, an exhaustive battery of detailed and the Sezary syndrome: a review of pathogenesis, diag- investigations is likely to be time consuming, nosis and therapy. J Clin Oncol 1991; 9: 1298-313. 7 Bodenstein L, Altman RP. Cervical lymphadenitis in infants unpleasant for the child, expensive, and of little and children. Seminars in Pediatric Surgery 1994; 3: diagnostic value. The most direct way to a 134-41. Lymphadenopathy

8 Adal KA, Cockerell CJ, Petri WA. Cat scratch disease, 15 Rosai J, Dorfmann RF. Sinus histiocytosis with massive , and other infections due to lymphadenopathy: a newly recognised benign clinico- rochalimaea. N Engl J Med 1994; 330: 1509-15. pathologic entity. Arch Pathol 1969; 87: 63-70. 9 Dandapat MC, Mishra BM, Dash SP, Kar PK. Peripheral 16 Stones DK, Havenga C. Sinus histiocytosis with massive Arch Dis Child: first published as 10.1136/adc.73.5.476 on 1 November 1995. Downloaded from lymph node tuberculosis: a review of 80 cases. Br J Surg lymphadenopathy. Arch Dis Child 1992; 67: 521-3. 1990; 77: 911-2. 17 Foucar E, Rosai J, Dorfmann RF. Sinus histiocytosis with 10 Grange JM, Yates MD, Pozniak A. Bacteriologically con- massive lymphadenopathy: an analysis of 14 deaths occur- firmed non-tuberculous mycobacterial lymphadenitis in ring in a patient registry. Cancer 1984; 54: 1834-40. south east England: a recent increase in the numbers of 18 Dorfmann RF, Berry GJ. Kikuchi's histiocytic necrotising cases. Arch Dis Child 1995; 72: 516-7. lymphadenitis: an analysis of 108 cases with emphasis on 11 White MP, Bangash H, Goel KM, Jenkins PA. Non-tuber- differential diagnosis. Sem Diagn Pathol 1988; 5: culous mycobacterial lymphadenitis. Arch Dis Child 1986; 329-45. 61: 368-71. 19 Smith HL. Necrotising lymphadenitis (Kikuchi's disease). 12 Lake AM, Oski FA. Peripheral lymphadenopathy in child- Pediatrics 1993; 91: 152. hood. Am J7 Dis Child 1978; 132: 357-9. 20 Dhillon R, Newton L, Rudd PT, Hall SM. Management of 13 Kirshnan J, Danon AD, Frizzera G. Reactive lympha- Kawasaki disease in the British Isles. Arch Dis Child 1993; denopathies and atypical lymphoproliferative disorders. 69: 631-8. Am J Clin Pathol 1993; 99: 385-96. 21 Stamos JK, Corydon K, Donaldson J, Shulman ST. 14 Chan JKC, Tsang WYW. Uncommon syndromes of reac- Lymphadenitis as the dominant manifestation of tive lymphadenopathy. Semin Oncol 1993; 20: 648-57. Kawasali disease. Pediatrics 1994; 93: 525-7. http://adc.bmj.com/ on September 27, 2021 by guest. Protected copyright.