|Year : 2012 | Volume
| Issue : 1 | Page : 11-17
Clinical approach to Lymphadenopathy
Abdullah A Abba1, Mohamed Z Khalil2
1 Department of Medicine, Division of Pulmonology, Ahmadu Bello University, Zaria, Nigeria
2 Department of Medicine, King Khalid University, Hospital & College of Medicine, King Saud University, Riyadh, Saudi Arabia
|Date of Web Publication||28-Aug-2012|
Abdullah A Abba
Department of Medicine, Ahmadu Bello University Teaching Hospital, Shika, Zaria, Kaduna State
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Lymphadenopathy (LAP) is a common clinical finding that may be localized, limited or generalized. The enlargement of a lymph node, due to primary disease or secondary cause, is of concern to both patients and clinicians, particularly, if the underlying pathology is a malignant disease. Lymph node aspiration or biopsy for histopathological evaluation may not reveal the diagnosis due to several factors. However, a methodological approach to LAP can disclose the accurate diagnosis with minimal discomfort to the patient and in a short time. In this review article, we provide evidence-based clinical evaluation of LAP, guided by the probability of the underlying disease to assist clinicians in establishing the proper cause and hence offer appropriate management.
Keywords: Approach, diagnosis, enlarged lymph nodes, lymphadenopathy
|How to cite this article:|
Abba AA, Khalil MZ. Clinical approach to Lymphadenopathy. Ann Nigerian Med 2012;6:11-7
| Introduction|| |
Lymph nodes (LNs) are group of specialized cells that represent a division of the defense system in the human body. The body has approximately 600 LNs, and their locations are scattered around ports of entry as well as major vessels.  The peripheral groups are those readily palpable by clinical examination, and routinely looked for, but only those in the submandibular, axillary or inguinal regions may normally be palpable in healthy individuals. Studies have shown that as many as 56% of patients examined for other reasons may be found to have lymphadenopathy (LAP). 
Lymphadenopathy can be defined as LNs that are abnormal in size, consistency or number. Fortunately, the majority of patients presenting with peripheral LAP have easily identifiable causes that are benign or self-limiting.
Lymphadenopathy is considered to be localized if only one group of LN is involved, limited if 2-3 groups of LN are involved and generalized if more than three noncontiguous groups are involved.  Localized LAP is more common and it has been reported to affect nearly 75 percent of patients presenting with LAP, whereas 25 percent of those patients had generalized LAP. , In our study of 258 adults who presented with LAP as a presenting feature, localized LAP occurred in 54.7%, limited in 11.6% and generalized in 33.7%.  Distinguishing between the extensions of LAP is important in formulating a differential diagnosis. Generalized LAP is almost always due to a significant systemic illness.
The cause of LAP is essentially due to either an immune response to infective agents, or inflammatory cells in infections involving the LN. Moreover, it may be due to infiltration of neoplastic cells carried to the node by lymphatic or blood circulation. Alternatively, primary neoplastic proliferation of lymphocytes may be the underlying pathology of LAP. [Table 1] gives the list of causes of LAP. It is not exhaustive but considering the causes as classified may be helpful in arriving at a diagnosis in a timely manner. Furthermore, the epidemiological pattern in a particular locality may also determine which causes to put uppermost in the differential diagnosis.
The prevalence of malignancy, the most serious of the causes of LAP, is quite low among the general population with LAP being as low as 1.1 percent or even lower. ,, This, however, is not true among patients seen in referral centers where LN biopsies have revealed malignancy in as many as 40-60% of cases.  Lyimphatic metastasis of tumor cells represents a series of extremely complex and sequential processes that include dissemination and invasion into surrounding stromal tissues from primary tumors, penetration into lymphatic walls and implantation in regional LNs. Recent developments in lymphatic biology and research, especially the application of unique molecular markers specific for lymphatic endothelial cells have provided exciting new insights into the tumor microenvironment. ,,,
Non-malignant causes of LAP are numerous and diverse, ranging from infections such as tuberculosis (TB), Brucellosis More Details, mononucleosis syndromes, and cat-scratch disease; extending to connective tissue disease such as systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA); or it may be iatrogenic as a result of certain drug intake such as phenytoin, carbamazepine, captopril, allopurinol, and atenolol.
Generalized LAP is more likely to occur in patients with malignancy. It is frequently seen in patients with leukemias and lymphomas, or metastatic solid tumors. Lymphomas and most metastatic carcinomas characteristically progress through nodes in anatomic sequence. Patients who are immunocompromised and those with human immunodeficiency virus (HIV) have a wide differential for generalized LAP, including early infection with HIV, activated TB, cryptococcosis, cytomegalovirus, toxoplasmosis, and Kaposi's sarcoma, which can present with LAP before visible skin lesions appear.
| Clinical Evaluation|| |
Reaching an accurate diagnosis for a patient presenting with LAP may not be an easy task for clinicians with the background of massive number of differential diagnosis. A methodological approach guided by educated evidence-based evaluation is therefore necessary from the outset. [Table 2] gives the salient points in the history and physical examination of patients presenting with LAP that may aid in the process of reaching a correct diagnosis.
Most patients can be diagnosed on the basis of a careful history and physical examination. Thorough history and meticulous physical examination will identify a readily diagnosable cause of the LAP, such as upper respiratory tract infection, pharyngitis, periodontal disease, conjunctivitis, insect bites, recent immunization, cat-scratch disease or dermatitis. Where the cause and course of LAP is obvious, no further assessment is necessary.
|Table 2: Salient points in the clinical assessment of a patient with lymphadenopathy|
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Furthermore, getting a clear history of exposure to certain risk factors may suggest the cause of LAP, such as history of animal contact or raw milk ingestion may suggest brucellosis, or intravenous drug abuse and high risk sexual practices may suggest HIV. Environmental exposures such as tobacco, alcohol, and ultraviolet radiation as well as occupational exposures to silicon or beryllium may raise suspicion for metastatic carcinoma of the internal organs, the head and neck, and skin. Family history may raise suspicion for certain neoplastic causes of LAP, such as carcinomas of the breast or familial dysplastic nevus syndrome and melanoma. Moreover, associated symptoms such as mouth ulcers, photosensitivity, arthralgias, early morning stiffness, muscle weakness, or butterfly rash may indicate the possibility of autoimmune diseases such as systemic lupus erythematosus (SLE), or rheumatoid arthritis (RA).
History of painful LAP is commonly reassuring; as it is indicative of underlying benign pathology such as an inflammatory process or suppuration. Pain or tenderness is explained by stretching of the LN capsule as a result of rapid increase in size; nonetheless, pain may also result from bleeding into a necrotic center of a malignant node and therefore does not always necessarily suggest a benign cause.
Lymphadenopathy that lasts less than two weeks or more than one year with no progressive size increase has a very low likelihood of being neoplastic. The precise timing of the onset of LAP is however elusive as most patients are unable to say with certainty as to when the enlargement started. Normal nodes are generally less than 1 cm in diameter. In one series, no patient with a LN smaller than 1 cm had cancer, compared with 8 and 38 percent of those with nodes 1 to 2.25 cm and greater than 2.25 cm, respectively.  Some authors have however suggested that epitrochlear nodes of size 0.5 cm or more and inguinal nodes of size 1.5 cm or more should be considered abnormal. , It has been shown that benign or self-limited causes were found in 79 percent of patients younger than 30 years of age, versus 59 percent in patients 31 to 50 years of age and 39 percent in those older than 50 years. In primary care settings, patients 40 years of age and older with unexplained LAP have about a4 percent risk of cancer versus a 0.4 percent risk in patients younger than age 40. 
In our study of 258 adults who presented with LAP, multivariate logistic regression model revealed that age over 40 years, male gender, generalized LAP, presence of other physical signs, abnormal liver function tests and negative Mantoux test to be statistically significantly associated with nodal malignancy. 
Other studies have also demonstrated that an increased likelihood of malignancy was associated with age over 40 years, male gender, white ethnicity, supraclavicular and epitrochlear locations, fixed nodal character, duration of greater than two weeks, and larger size. ,,,,,,,, The clinical features highlighted in [Table 3] are helpful in determining the possibility of malignancy and hence the speed, nature and extent of further investigations.
|Table 3: Clinical features to differentiate benign from malignant lymphadenopathy|
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When LAP is localized, the clinician should examine the region drained by the nodes for evidence of infection, skin lesions or tumors. The anatomic location of localized LAP may be helpful in suggesting the diagnosis; cervical LAP may be secondary to infectious mononucleosis, axillary LAP are seen in patients with cat-scratch disease, whereas inguinal LAP may point towards sexually transmitted diseases. Supraclavicular LAP has the highest risk of malignancy, estimated as90 percent in patients older than 40 years and25 percent in those younger than age 40.  Having the patient perform a Valsalva's maneuver during palpation of the supraclavicular fossae increases the chance of detecting a node. Right supraclavicular LAP is associated with cancer in the mediastinum, lungs or esophagus while left supraclavicular (Virchow's) node may indicate pathology in the testes, ovaries, kidneys, pancreas, prostate, stomach or gallbladder. Although rarely present, a paraumbilical (Sister Joseph's) node may be a sign of an abdominal or pelvic neoplasm.  [Table 1] and [Table 2] detail the common causes of localized LAP according to region involved and drugs known to cause LAP, respectively.
Another clinical feature that is of diagnostic importance is the consistency. Fluctuant nodes usually indicate suppuration while rubbery, firm nodes suggest lymphoma. Metastatic nodes are usually stony hard while softer nodes indicate inflammatory or infective conditions. Small shotty nodes are felt in childhood viral infections. LNs that are matted (feels connected to each other without ability to palpate separate boundaries to each node, and seems to move as a unit) are highly suggestive of TB. This finding may however be seen in other benign conditions (e.g. sarcoidosis) or malignancy (e.g. metastasis or lymphoma).
In patients with generalized LAP, the emphasis is on finding clues to a systemic illness in the history and physical examination. The presence of joint symptoms and rash or mouth ulcers may suggest connective disease as a cause.
Splenomegaly or hepatosplenomegaly and LAP may occur concomitantly, that may suggest mononucleosis syndromes, adult onset Stills disease, chronic lymphocytic leukemia, lymphoma and sarcoidosis.
Moreover, certain clues detected by clinical examination may direct the next step such as the presence of erythema nodosum may suggest the presence of sarcoidosis consequently; a chest X ray may reveal mediastinal LAP.
Fine-needle aspiration (FNA) biopsy is a safe, simple and cost-effective technique that provides rapid information directing further approach to a patient presenting with LAP. Its findings are especially beneficial for verification of lymphoid origin of the enlarged growth and in differentiating between metastatic, infectious, reactive and lymphomatous causes of LAP. It also helps in the determination of the extent of tumor; detection of recurrence; monitoring of the course of disease; obtaining of material for special studies such as microbiological cultures, immunological or genetic studies as well as electron microscopy. Furthermore, FNA is a rapid way of allaying the fears of a patient in the event of identifying a benign cause of the growth.
The diagnostic value of FNA cytology in the assessment of palpable supraclavicular LNs as a first line of investigation has been shown by one study, to be cost-effective procedure and the overall sensitivity was 92.7%, specificity 98.5%, positive predictive value 97.3% and the negative predictive value was 94.8%.  Another study of 627 FNA of LNs of which 218 were available for cytohistological correlation, revealed that there were three (1.88%) false-negative and two (1.25%) false-positive cases. Accuracy tests revealed 97.41% sensitivity, 95.45% specificity, and 96.88% efficacy, with cytohistological agreement being almost perfect (kappa = 0.92). The high accuracy of this study based only on cytomorphological criteria demonstrates its relevance in patient care, especially in areas of limited financial resources.  Similarly, in a study of 135 patients who had FNA, O'Donnell et al. demonstrated that FNA provided sufficient pathological diagnosis to avoid day case surgery in 57 patients (42.2%), and inpatient surgery in 65 patients (48.1%).  If the LN are not palpable, endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has been shown to accurately diagnose mediastinal LN pathology with diagnostic accuracy of 84%.  This method and the more recently introduced endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) have been shown to be highly sensitive and specific in the diagnosis of mediastinal and hilar lesions. ,, Fine-needle aspiration of a representative node in either the abdominal or thoracic cavity or peripherally by any of these techniques in patients with TB, malignancy, or HIV infection may allow prompt diagnosis of LAP as shown by many studies. ,,,,,,,,,,, Open thoracic surgery, laparotomy, and other invasive diagnostic procedures such as mediastinoscopy and laparoscopy can now be avoided.
Transesophageal and transbronchial, ultrasound-guided, FNA of enlarged mediastinal LNs have become popular and provide accurate results. One study reported that in experienced hands, the transbronchial or transesophageal approach are nonsurgical approaches and have similar diagnostic yields, although the transbronchial approach is superior for right-sided LNs; however, both approaches provides results similar to those of mediastinoscopy.  The use of contrast-enhanced EUS has been shown to improve the specificity in diagnosing benign LNs as compared to B-mode EUS. It does not improve the correct identification of malignant LNs and cannot replace EUS-guided FNA. 
FNA is simple, rapid and does not require a general anesthetic. The procedure of FNA can be performed in the outpatient department. Most patients who have a benign diagnosis on FNA do not require further evaluation.
The limitations of FNA remain in the lack of proper tissue sample to run special studies including cytogenetics, flow cytometry, electron microscopy, and special stains. Additionally, the potential risk of seeding a tract with malignancy as a result of FNA procedure is always a consideration.
Obtaining a proper representative tissue for pathological diagnosis can be made by excisional surgical biopsy. Ideally, the most accessible node is selected for biopsy. The diagnostic yields are reported to be quite different based on the site of nodal biopsy obtained, as it has been shown that inguinal nodes offer the lowest yield, and supraclavicular nodes have the highest. ,
Although less commonly used because of the advent of new immunohistochemical analytic techniques that have increased the sensitivity and specificity of FNA, excisional biopsy remains the diagnostic procedure of choice in delivery of timely and appropriate medical care to patients presenting with LAP. The preservation of nodal architecture is critical to the proper diagnosis of LAP, particularly when differentiating lymphoma from benign reactive hyperplasia. ,,,, While FNA may be the initial approach for most patients, certain parameters may indicate malignancy and therefore a more aggressive approach is needed. In a study of 60 patients, Matsumoto et al. identified advanced age, large swollen LNs, high levels of serum soluble interleukin-2 receptor (sIL-2r) and high lactate dehydrogenase LDH) to be indicative of malignancy and suggested early LN biopsy in such cases.  Ultrasound or computed tomography (CT)-guided percutaneous LNs biopsy often do not supply sufficient tissue for the histopathologic diagnosis of intra-abdominal LAP compared to surgical removal of the LN. Laparoscopic LN biopsy (LLB) has the advantage of obtaining the entire LN and avoiding potential complications of a laparotomy. It was recently shown that LLB is a safe and effective procedure. Its diagnostic accuracy is superior to percutaneous techniques, and can be proposed as the procedure of choice to sample deep lymphatic tissues in patients with intra-abdominal LAP at a very low morbidity. 
Lymph node biopsy is essential in making a definitive diagnosis in certain conditions. In Kikuchi's disease, for example, where the overall accuracy of FNA diagnosis of Kikuchi's lymphadenitis was found to be only 56.25%,  an LN biopsy is necessary even in patients with typical presentations such as young women with cervical LAP, fever, neutropenia who are otherwise in excellent condition. This is because this condition can be easily confused with malignant lymphoma.
With the more widespread application of molecular techniques, and the development of improved minimally invasive procedures, percutaneous and endoscopic techniques may come to dominate and the surgeon may have a diminishing role in the management of LAP. There is however a need to know when and how quickly an excisional biopsy is indicated. A recent study has shown that there was no evidence for the use of explicit protocols for referral or management and that biopsy was often delayed.  The study suggested the introduction of coordinated problem-based referral and management pathways for the management of patients with enlarged superficial LNs supported by regular audits of practice.
| Suggested Approach|| |
Guidelines and suggested approaches in handling different medical problems are based on pooled evidence from the medical literature, aided by the expert opinions of practicing physicians. However, it is important to emphasize that patients are different; not only because of variability in their response to diseases, but they are different in the way of presenting and perceiving their illness. Therefore, it is of paramount importance to rely mainly on proper history and physical examination to reach the appropriate clinical diagnosis.
The evidence provided to us in the medical literature clearly indicates that there is a need to critically review all evidence in the evaluation of patients presenting with LAP. We need to exercise care in order not to miss a potential treatable lesion while at the same time not to subject patients to unnecessary discomfort. While the duration of LAP is extremely helpful in guiding clinicians to the aggressiveness of the underlying disease, this aspect of history is subject to individual bias. We suggest using an algorithm as depicted in [Figure 1] in such assessment after obtaining a reliable history.
|Figure 1: Clinically Oriented Approach to Lymphadenopathy. *Clinical risk: As judged by clinician based on age, history and physical examination|
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For patients presenting with short duration of LAP and low clinical risk to suggest malignancy or serious illness, probably, the diagnosis can be made based on analyzing the clinical data obtained from the patient. Simple confirmatory investigations may be reassuring to both patients and clinicians. On the other hand, if the duration of LAP is long (>2 weeks), this indicates persistent LAP but not necessary serious or malignant disease. Consequently, obtaining clinical data to differentiate between high or low clinical risk would be an imperative next step in clinical evaluation. The presence of alarming symptoms and signs of LAP warrants further investigation to establish the diagnosis and to initiate the proper treatment.
Among the investigations needed to reach the diagnosis are imaging studies such as plain chest X ray, CT scan of the chest and abdomen, magnetic resonance imaging, radioisotope scan, ultrasound scan, and echocardiography.
Obtaining a tissue from the diseased LN for diagnosis is the gold standard of establishing the pathological diagnosis. This can be done by either FNA or excisional biopsy. The obtained tissue should be processed for histological examination as well as microbiological, histochemical, immunofluorescence and polymerase chain reaction when appropriate.
Certainly, despite running all available tests, small percentage of patients with LAP remains undiagnosed. Probably, referral to more specialized centers for reviewing the histopathology may be fruitful.
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[Table 1], [Table 2], [Table 3]