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Home , Adenitis, Branchial cleft cyst, Cervical lymphadenopathy, Cervical lymph nodes, Diphtheria, Leukocytosis

ORIGINAL ARTICLE Childhood Cervical P

H Alexander K.C. Leung, MBBS, FRCPC, FRCP (UK & Irel), FRCPCH, & C W. Lane M. Robson, MD, FRCPC, FAAP, FRCP (Glasg)

ABSTRACT Enlarged are common in children (Leung & Rob- son, 1991). About 38% to 45% of otherwise normal children have palpable is a common problem in children. The cervical lymph nodes (Larsson et al., 1994). Cervical lymphadenopathy is condition most commonly repre- usually defined as cervical lymph nodal tissue measuring more than 1 cm sents a transient response to a be- in diameter (Darville & Jacobs, 2002; Margileth, 1995; Schreiber & Berman, nign local or generalized , 1996). Cervical lymphadenopathy most commonly represents a transient but occasionally it might herald the response to a benign local or generalized infection, but occasionally it presence of a more serious disorder. might herald the presence of a more serious disorder such as malignancy. Acute bilateral cervical lym- This article reviews the pathophysiology, etiology, , phadenopathy usually is caused by clinical evaluation, and management of children with cervical lym- a viral upper respiratory tract infec- phadenopathy. tion or streptococcal . PATHOPHYSIOLOGY Acute unilateral cervical lym- phadenitis is caused by streptococ- The superficial cervical lymph nodes lie on top of the sternomastoid muscle cal or in and include the anterior group, which lies along the anterior jugular , 40% to 80% of cases. The most and the posterior group, which lies along the external jugular vein (Darville common causes of subacute or & Jacobs, 2002). The deep cervical lymph nodes lie deep to the sternomas- chronic lymphadenitis are cat toid along the internal jugular vein and are divided into superior and infe- scratch , mycobacterial in- rior groups. The superior deep nodes lie below the angle of the , fection, and . Supra- whereas the inferior deep nodes lie at the base of the (Malley, 2000). clavicular or posterior cervical lym- The superficial cervical lymph nodes receive afferents from the mastoid, phadenopathy carries a much tissues of the neck, and the parotid (preauricular) and submaxillary nodes higher risk for malignancies than (Darville & Jacobs, 2002). The efferent drainage terminates in the upper does anterior cervical lym- phadenopathy. Generalized lym- deep cervical lymph nodes (Darville & Jacobs). The superior deep cervical phadenopathy is often caused by a nodes drain the palatine and the submental nodes. The lower deep viral infection, and less frequently cervical nodes drain the larynx, , , and . by malignancies, collagen vascular Lymphadenopathy might be caused by proliferation of cells intrinsic to , and medications. Labora- the node, such as , plasma cells, , and histiocytes, or tory tests are not necessary in the by infiltration of cells extrinsic to the node, as with and malig- majority of children with cervical nant cells (Chesney, 1994). lymphadenopathy. Most cases of lymphadenopathy are self-limited and require no treatment. The treat- Alexander K.C. Leung is Clinical Associate Professor of Pediatrics, University of Calgary; Pediatric Consultant, ment of acute bacterial cervical Alberta Children’s Hospital; and Medical Director, Asian Medical Centre, an affiliate of the University of Cal- lymphadenitis without a known pri- gary Medical Clinic, Calgary, Alberta, Canada. mary source should provide ade- W. Lane M. Robson is Professor of Pediatrics, University of Oklahoma. quate coverage for both Staphylo- Reprint requests: Dr Alexander K.C. Leung, #200, 233-16th Ave NW, Calgary, Alberta, Canada T2M 0H5; coccus aureus and group A beta e-mail: [email protected]. hemolytic streptococci. 0891-5245/$30.00 J Pediatr Health Care. (2004). 18, Copyright © 2004 by the National Association of Pediatric Nurse Practitioners. 3-7. doi:10.1016/j.pedhc.2003.08.008

January/February 2004 3 PH ORIGINAL ARTICLE Leung & Robson C

cervical lymphadenopathy, followed by BOX 1 Causes of cervical BOX 2 Differential diagnosis and non-Hodgkin’s lymphadenopathy of cervical lymphadenopathy (Leung & Robson, 1991). After 6 years, Hodgkin’s lymphoma is A. Infection • Mumps the most common tumor associated with 1. Viral • Thyroglossal cervical lymphadenopathy, followed by a. Viral upper respiratory infection • non-Hodgkin’s lymphoma and rhab- b. Epstein-Barr • Sternomastoid tumor domyosarcoma. c. • Cervical rib The presence of cervical lym- d. • phadenopathy is one of five diagnostic e. Rubeola • Hemangioma criteria for ; the other f. Varicella-zoster virus • Laryngocele four are bilateral bulbar conjunctival in- g. Herpes simplex • jection, changes in the mucosa of the h. Coxsackievirus Data from Leung & Robson (1991). oropharynx, erythema or of the I. Human peripheral extremities, and polymorph- virus ous rash. Generalized lymphadenopa- 2. Bacterial thy might be a feature of systemic onset a. Staphylococcus aureus (HIV). Bacterial cervical lymphadenitis juvenile rheumatoid , systemic β b. Group A β-hemolytic is usually caused by group A -he- erythematosus, or serum sick- streptococci molytic streptococci or Staphylococcus ness. Certain drugs, notably phenytoin c. Anaerobes aureus. Anaerobic can cause and isoniazid, might cause generalized d. cervical lymphadenitis, usually in asso- lymphadenopathy (Malley, 2000). Cervi- e. Cat-scratch disease ciation with dental caries and peri- cal lymphadenopathy has been reported f. odontal disease. Group B streptococci following immunization with diphthe- 3. Protozoal and type b are ria-pertussis-, poliomyelitis, or a. Toxoplasmosis less frequent causal organisms. Diphthe- typhoid (Leung & Rob- B. Malignancies ria is a rare cause. Bartonella henselae son, 1991). Rosai-Dorfman disease is 1. (cat scratch disease), atypical mycobac- a benign form of charac- 2. teria, and mycobacteria are important terized by generalized proliferation of 3. Lymphoma causes of subacute or chronic cervical sinusoidal histiocytes. The disease usu- 4. Rhabdomyosarcoma ally manifests in the first decade of life C. Miscellaneous with massive and painless cervical lym- 1. Kawasaki disease phadenopathy and is often accompa- 2. Collagen vascular diseases nied by fever, neutrophilic , 3. Cervical masses are and polyclonal hypergammaglobuline- 4. Drugs mia (Swartz, 2000). Kikuchi-Fujimoto 5. Postvaccination common in children and disease (necrotizing lymphadenitis) is a 6. Rosai-Dorfman disease benign cause of lymphadenopathy that 7. Kikuchi-Fujimoto disease might be mistaken for primarily affects young Japanese fe- Data from Leung & Robson (1991). males. Fever, nausea, weight loss, night sweats, arthralgia, or hepatosplenomeg- enlarged cervical lymph aly might be present. ETIOLOGY nodes. DIFFERENTIAL DIAGNOSIS Common or important causes of cervi- Cervical masses are common in children cal lymphadenopathy are listed in Box and might be mistaken for enlarged cer- 1. The most common cause is reactive vical lymph nodes. The differential diag- hyperplasia resulting from an infec- lymphadenopathy (Spyridis, Malte- nosis of cervical lymphadenopathy is tious process, most commonly a viral zou, & Hantzakos, 2001). Chronic pos- listed in Box 2. In general, congenital le- upper respiratory tract infection (Peters terior cervical lymphadenitis is the sions are painless and are present at & Edwards, 2000). Upper respiratory most common form of acquired toxo- birth or identified soon thereafter tract infection might be caused by rhi- plasmosis and is the sole presenting (Twist & Link, 2002). Clinical features novirus, parainfluenza virus, influenza symptom in 50% of cases (Leung & that may help distinguish the various virus, respiratory syncytial virus, coro- Robson, 1991). conditions from cervical lymphadeno- navirus, adenovirus, or reovirus. Other More than 25% of malignant tumors pathy are discussed next in this article. associated with cervical lym- in children occur in the head and neck, phadenopathy include Epstein-Barr and the cervical lymph nodes are the Mumps. The swelling of mumps virus (EBV), cytomegalovirus, rubella, most common site (Leung & Robson, crosses the angle of the . rubeola, varicella-zoster virus, herpes 1991). During the first 6 years of life, On the other hand, cervical lymph simplex virus (HSV), coxsackievirus, neuroblastoma and leukemia are the nodes are usually below the mandible and human immunodeficiency virus most common tumors associated with (Leung & Robson, 1991).

4 Volume 18 Number 1 JOURNAL OF PEDIATRIC HEALTH CARE PH ORIGINAL ARTICLE Leung & Robson C

Thyroglossal cyst. A thyroglossal group (Box 3). The prevalence of vari- cyst is a mass that can be distinguished ous childhood changes BOX 3 Organisms with by the midline location between the with age. predilection for specific age thyoid bone and suprasternal notch groups and the upward movement of the cyst Laterality and chronicity. Acute bi- when the child swallows or sticks out lateral cervical lymphadenitis is usually A. Neonates his or her . caused by a viral upper respiratory 1. Staphylococcus aureus tract infection or streptococcal pharyn- 2. Group B streptococci Branchial cleft cyst. A branchial gitis (Malley, 2000). The cervical lym- B. Infancy cleft cyst is a smooth and fluctuant phadenopathy in Kawasaki disease is 1. Staphylococcus aureus mass located along the lower anterior usually unilateral. Acute unilateral 2. Group B streptococci border of the sternomastoid muscle. cervical lymphadenitis is caused by 3. Kawasaki disease streptococcal or staphylococcal infec- C. 1 to 4 years Sternomastoid tumor. A sternomas- tion in 40% to 80% of cases (Chesney, 1. Staphylococcus aureus toid tumor is a hard, spindle-shaped 1994; Peters & Edwards, 2000). The 2. Group A β-hemolytic mass in the sternomastoid muscle re- most common causes of subacute or streptococci sulting from perinatal hemorrhage into chronic cervical lymphadenitis are cat 3. Atypical mycobacteria the muscle with subsequent healing by scratch disease, mycobacterial infec- D. 5 to 15 years (Leung & Robson, 1991). The tion, and toxoplasmosis; less frequent 1. Anaerobic bacteria tumor can be moved from side to side causes include EBV and cytomegalo- 2. Toxoplasmosis but not upward or downward. Torti- virus infection (Malley, 2000; Margileth, 3. Cat-scratch disease collis is usually present. 1995). 4. Tuberculosis Data from Chesney (1994). Cervical ribs. Cervical ribs are ortho- pedic anomalies that are usually bilat- eral, hard, and immovable. Diagnosis is established with a radiograph of the Fever, night sweats, and organism. A history of cat scratch raises neck. the possibility of B henselae. Lympha- weight loss suggest denopathy resulting from cytomegalo- Cystic hygroma. Cystic hygroma is a virus, EBV, or HIV might follow a multiloculated, endothelial-lined cyst transfusion. Immunization-related lym- that is diffuse, soft, and compressible, lymphoma or tuberculosis. phadenopathy might follow diphthe- contains lymphatic fluid, and typically ria-pertussis-tetanus, poliomyelitis, or transilluminates brilliantly. Unexplained fever, , typhoid fever .

Hemangioma. Hemangioma is a con- and arthralgia raise the Drug use. The response of cervical genital vascular anomaly that often is lymphadenopathy to specific antimi- present at birth or appears shortly there- possibility of a collagen crobial therapies might help to confirm after. The mass is usually red or bluish. or exclude a diagnosis. Lymphadeno- vascular disease or serum pathy might follow the use of medica- Laryngocele. A laryngocele is a soft, tions such as phenytoin and isoniazid. cystic, compressible mass that extends sickness. out of the larynx and through the thyro- Exposure to infection. Exposure to a hyoid membrane and becomes larger person with an upper respiratory tract with the Valsalva maneuver. There infection, streptococcal pharyngitis, or might be associated or hoarse- tuberculosis suggests the correspond- ness, and a radiograph of the neck might Associated symptoms. Fever, sore ing disease. show an air fluid level in the mass. throat, and suggest an upper respiratory tract infection. Fever, night Dermoid cyst. A dermoid cyst is a sweats, and weight loss suggest lym- General. Malnutrition or poor growth midline cyst that contains solid and phoma or tuberculosis. Unexplained suggests chronic disease such as tuber- cystic components; it seldom transillu- fever, fatigue, and arthralgia raise the culosis, malignancy, or immunodefi- minates as brilliantly as a cystic hy- possibility of a collagen vascular dis- ciency. groma, and a radiograph might show ease or serum sickness. that it contains calcifications. Characteristics of the lymph tissue. Concurrent illness and past health. All accessible node-bearing areas CLINICAL EVALUATION Preceding suggests strepto- should be examined to determine coccal infection; recent facial or neck whether the lymphadenopathy is gen- History abrasion or infection suggests staphy- eralized. The nodes should be mea- Age of the child. Some organisms lococcal infection; and periodontal sured for future comparison (Leung & have a predilection for a specific age infection might indicate an anaerobic Robson, 1991). Tenderness, erythema,

JOURNAL OF PEDIATRIC HEALTH CARE January/February 2004 5 PH ORIGINAL ARTICLE Leung & Robson C

characteristic of rubeola. The presence TABLE Differentiation of atypical mycobacterial and of pallor, petechiae, bruises, sternal tuberculosis cervical lymphadenitis tenderness, and hepatosplenomegaly suggests a diagnosis of leukemia. Pro- Mycobacterium longed fever, conjunctival injection, Clinical characteristics Atypical mycobacteria tuberculosis oropharyngeal mucous membrane in- Age 1-4 y All ages (most >5 y) flammation, peripheral edema or ery- Race Predominantly White Predominantly Black thema, and a polymorphous rash are or Hispanic consistent with Kawasaki disease. Exposure to tuberculosis Absent Present LABORATORY EVALUATION Bilateral involvement Rare Not uncommon Chest radiograph Normal (97%) Abnormal (20% to 70%) Laboratory tests are not necessary in Residence Rural Urban the majority of children with cervical PPD >15 mm of induration*UncommonUsual lymphadenopathy. A complete blood Response to antimycobacterial No Yes cell count might help to diagnose a bac- drugs terial lymphadenitis, which is often Data from Darville & Jacobs (2002). accompanied by a leukocytosis with a *PPD refers to 5 units (5 TU) intracutaneous skin test. shift to the left, and toxic granulations. Atypical is prominent in (Leung & Pinto-Rojas, 2000). Pancytopenia or the warmth, mobility, fluctuance, and con- nodes are hard and often fixed to the presence of blast cells suggests leuke- sistency should be assessed. underlying tissue. mia. The erythrocyte sedimentation Acute posterior cervical lymphadeni- rate is usually significantly elevated in tis is classically seen in persons with Associated signs. A beefy red throat, persons with bacterial lymphadenitis. rubella and infectious mononucleosis on the tonsils, petechiae on the A rapid streptococcal antigen test or a (Leung & Pinto-Rojas, 2000). Supra- hard palate, and a strawberry tongue throat culture might be useful to con- clavicular or posterior cervical lym- suggest group A streptococcal infec- firm a streptococcal infection. Skin tests phadenopathy carries a much higher tion. Diphtheria is associated with for tuberculosis should be performed if risk for malignancy than does anterior edema of the soft tissues of the neck, these are suspected. Addi- cervical lymphadenopathy. Cervical tional studies that might be helpful in- lymphadenopathy associated with gen- clude chest radiography and serologic eralized lymphadenopathy is often tests for B henselae, EBV, cytomegalo- caused by a viral infection. Malignan- virus, and toxoplasmosis. An electro- cies such as leukemia or lymphoma Supraclavicular or cardiogram and echocardiogram are in- and collagen vascular diseases such as dicated if Kawasaki disease is suspected. juvenile or sys- posterior cervical Ultrasonography and computed tomo- temic lupus erythematosus, along with graphy might help to differentiate a medications, are usually associated lymphadenopathy carries solid from cystic mass and to establish with generalized lymphadenopathy. the presence and extent of suppuration In lymphadenopathy resulting from or infiltration. a viral infection, the nodes are usually a much higher risk for Fine-needle aspiration and culture of bilateral and soft and are not fixed to a is a safe and reliable pro- the underlying structure. When a bacte- malignancy than does cedure to isolate the causative organ- rial is present, the nodes are ism and to determine the appropriate usually tender, either unilateral or bilat- anterior cervical when bacterial infection is the eral, might be fluctuant, and are not cause (Buchino & Jones, 1994). All aspi- fixed. The presence of erythema and lymphadenopathy. rated material should be sent for both warmth suggests an acute pyogenic gram and acid-fast stain and cultures process and fluctuance suggests ab- for aerobic and anaerobic bacteria, my- scess formation. In patients with tuber- cobacteria, and fungi (Umapathy, De, & culosis, the nodes might be matted often described as a “bull neck” ap- Donaldson, 2003). If the gram stain is or fluctuant, and the overlying skin pearance. Sinus tract formation is positive, only bacterial cultures are might be erythematous but is not warm commonly seen in tuberculosis. The mandatory. (Spyridis, Maltezou, & Hantzakos, 2001). presence of gingivostomatitis suggests An excisional with micro- Clinical features that help differentiate infection with HSV, whereas herpang- scopic examination of the lymph node atypical mycobacterial from Mycobac- ina suggests coxsackievirus. The pres- might be necessary to establish the di- terium tuberculosis are summarized in ence of pharyngitis, maculopapular agnosis if there are symptoms or signs the Table. In lymphadenopathy result- rash, and suggest EBV of malignancy or if the lymphadenopa- ing from malignancy, signs of acute in- infection (Leung & Pinto-Rojas, 2000). thy persists or enlarges in spite of flammation are absent, and the lymph Conjunctivitis and Koplik spots are appropriate antibiotic therapy and the

6 Volume 18 Number 1 JOURNAL OF PEDIATRIC HEALTH CARE PH ORIGINAL ARTICLE Leung & Robson C diagnosis remains in doubt (Leung & nodes become fluctuant, incision and Darville, T., & Jacobs, R. F. (2002). Lymphadenopa- Robson, 1991). The biopsy should be drainage should be performed. The cur- thy, lymphadenitis, and . In: H. B. performed on the largest and firmest Jenson, R. S. Baltimore (Eds.), Pediatric infec- rent recommendation for treatment of tious diseases: Principles and practice, pp. 610- node that is palpable, and the node isolated cervical tuberculosis lympha- 629. Philadelphia: W. B. Saunders Company. should be removed intact with the cap- denitis is isoniazid, rifampin, pyrazi- Harza, R., Robson, C. D., Perez-Atayde, A. R., & sule (Leung & Robson, 1991; Twist & namide, and ethambutol, streptomycin, Husson, R. N. (1999). Lymphadenitis due to Link, 2002). or another aminoglycoside or ethion- nontuberculous mycobacteria in children: Pre- sentation and response to therapy. Clinical In- amide for the first 1 or 2 months, fol- fectious Disease, 28, 123-129. MANAGEMENT lowed by isoniazid and rifampin for a Larsson, L. O., Bentzon, M. W., Berg, K., Mellan- Treatment of cervical lymphadenopa- total of 9 to 12 months (American Acad- der, L., Skoogh, B. E., Stranegård, I. L., et al. thy depends on the underlying cause. emy of Pediatrics, 2003). Atypical my- (1994). Palpable lymph nodes of the neck in Most cases of lymphadenopathy are Swedish schoolchildren. Acta Paediatrica, 83, cobacterial lymphadenitis is unrespon- 1092-1094. self-limited and require no treatment sive to conventional medical therapy Leung, A. K., & Robson, W. L. (1991). Cervical lym- other than observation. Failure of re- and requires surgical excision of all visi- phadenopathy in children. Canadian Journal of gression after 4 to 6 weeks might be an bly infected nodes. When is not Pediatrics, 3, 10-17. indication for a diagnostic biopsy Leung, A. K., & Pinto-Rojas, A. (2000). Infectious feasible, a macrolide-containing antimy- mononucleosis. Consultant, 40, 134-136. (Chesney, 1994). cobacterial regimen should be consid- Malley, R. (2000). Lymphadenopathy. In: G. R. The treatment of acute bacterial cer- ered (Harza, Robson, Perez-Atayde, & Fleisher, S. Ludwig, R. M. Henretig, et al. vical lymphadenitis without a known Husson, 1999; Peters & Edwards, 2000). (Eds.), Textbook of pediatric emergency medicine, primary infectious source should pro- pp. 375-381. Philadelphia: Lippincott Williams vide adequate coverage for both S au- CONCLUSION & Wilkins. β Margileth, A. M. (1995). Sorting out the causes of reus and group A -hemolytic strepto- Cervical lymphadenopathy is a com- lymphadenopathy. Contemporary Pediatrics, 12, cocci. Appropriate oral mon and usually benign finding. Agood 23-40. include cloxacillin, cephalexin, or clin- history and thorough physical exami- Peters, T. R., & Edwards, K. M. (2000). Cervical damycin (Peters & Edwards, 2000). lymphadenopathy and . Pediatrics in nation is usually all that is necessary to Review, 21, 399-404. When a primary source of infection is establish a diagnosis. The problem is Schreiber, J. R., & Berman, B. W. (1996) Lym- identified, therapy should be directed usually self-limited, and most children phadenopathy. In: R. M. Kliegman, M. L. empirically against the with cervical lymphadenopathy do not Nieder, & D. M. Super (Eds.), Practical strate- most frequently associated with that require specific treatment. gies in pediatric diagnosis and therapy, pp. source, pending the results of the cul- 791-803. Philadelphia: W. B. Saunders Com- We are grateful to Miss Enrica Ng for her pany. ture and sensitivity tests (Leung & expert secretarial assistance and Mr Sulakhan Spyridis, P., Maltezou, H. C., & Hantzakos, A. Robson, 1991). Children with cervical Chopra of the University of Calgary Medical (2001). Mycobacterial cervical lymphadenitis lymphadenopathy and periodontal or Library for help in the preparation of the manu- in children: Clinical and laboratory factors dental disease should be treated with script. of importance for differential diagnosis. Scan- dinavian Journal of Infectious Diseases, 33, 362- V or (Peters & REFERENCES 366. Edwards, 2000). Swartz, M. N. (2000). Lymphadenitis and lym- Toxic or immunocompromised chil- American Academy of Pediatrics: Tuberculosis. phangitis: In: G. L. Mandell, J. E. Bennett, & R. dren and those who do not tolerate, will (2003). In: L. K. Pickering, (Ed.), 2003 Red Book: Dolin (Eds.), Mandell, Douglas, and Bennett’s Report of the Committee on Infectious Diseases, principles and practice of infectious diseases, pp. not take, or fail to respond to an oral 26th ed., pp. 642-660. IL: American Academy 1066-1072. Philadelphia: Churchill Living- medication should be treated with in- of Pediatrics. stone. travenous nafcillin, cefazolin, or clin- Buchino, J. J., & Jones, V. F. (1994). Fine needle as- Twist, C. J., & Link, M. P. (2000). Assessment of damycin (Peters & Edwards, 2000). piration in the evaluation of children with lymphadenopathy in children. Pediatric Clinics lymphadenopathy. Archives of Pediatrics & Oral analgesia with medications such of North America, 49, 1009-1025. Adolescent Medicine, 148, 1327-1330. Umapathy, N., De, R., & Donaldson, I. (2003). Cer- as acetaminophen might be helpful to Chesney, P. J. (1994). Cervical lymphadenopathy. vical lymphadenopathy in children. Hospital relieve associated pain. If the lymph Pediatrics in Review, 15, 276-284. Medicine, 59, 553-556.

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