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can lead to dysphagia. Hoarseness caused by compression of or traction on the recurrent
laryngeal nerve is rare in simple goiter and suggests a malignancy. Goiter with compressive
or cosmetic symptoms usually requires surgical consultation, but referral for radioiodine
therapy could be considered, especially in older patients. The natural history of simple goi-
ter may include spontaneous resolution or no clinical change but may also involve gradual
thyroid growth, nodule formation, and the development of functional autonomy. The use
of thyroid hormone suppression in goiter is controversial. Nodules within a multinodular
goiter may become toxic in the presence of a supplemental thyroid hormone (4,5).
REFERENCES
1. Day TA, Chu A, Hoang KG. Multinodular goiter. Otolaryngol Clin North Am 2003;36:35–54.
2. Hermus AR, Huymans DA. Pathogenesis of nontoxic diffuse and nodular goiter. In: Braverman LE,
Utiger RD, eds. Werner and Inbar’s the thyroid, 9th ed. Philadelphia. PA: Lippincott Williams &
Wilkins, 2005:873–878.
3. Knudsen N, Laurberg P, Perrild H, et al. Risk factors for goiter and thyroid nodules. Thyroid
2002;12:879–888.
4. Hermus AR, Huymans DA. Clinical manifestations and treatment of nontoxic diffuse and nodular
goiter. In: Braverman LE, Utiger RD, eds. Werner and Inbar’s The Thyroid, 9th ed. Philadelphia, PA:
Lippincott Williams & Wilkins, 2005:879–885.
5. Hegedus L, Bonnema SJ, Bennedbaek FN. Management of simple nodular goiter: current status and
future perspectives. Endocr Rev 2003;24:102–132.
6. Bahn RS, Castro MR. Approach to the patient with nontoxic multinodular goiter. J Clin Endocrinol
Metabol 2011;96(5):1202–1212.
14.7
Thyroid Nodule
M. Jawad Hashim
I. BACKGROUND. A thyroid nodule is a palpable swelling in an otherwise normal thyroid gland.
Only about 5–10% of nodules are cancerous (Figure 14.7.1). The most common nodule is the
colloid nodule, which is not associated with an increased risk of cancer.
II. PATHOPHYSIOLOGY
A. Etiology.
Exposure to ionizing radiation or external beam radiation therapy (especially
before 20 years of age) increases the incidence of both benign and malignant thyroid nodules
at a rate of 2% annually and peaks 15–20 years after exposure (2). Iodine deficiency results
in increased thyroid-stimulating hormone (TSH) levels, increased thyroid cell replication,
and an increased incidence of nodules.
B. Epidemiology. Palpable nodules are present in 4–7% of adults (3). Nodules found inci-
dentally on ultrasound are estimated to occur as often as 19–67%. Age younger than 20
years or older than 65 years, male gender, exposure to radiation, and previous history of
thyroid cancer are risk factors for thyroid cancer. Benign thyroid nodules are present four to
five times more often in women, but are more likely to be cancerous in men.
III. EVALUATION. The evaluation of nodular thyroid disease focuses on the functional status of
the gland and detection of thyroid cancer. Hypothyroidism or hyperthyroidism may be sug-
gested by the history and physical examination.
A. History. Rapid growth of a nodule or symptoms of local invasion (hoarseness, neck pain,
dysphagia, stridor, or dyspnea) increase the suspicion of cancer. Sudden onset of localized
swelling, pain, or tenderness suggests hemorrhage into a preexisting nodule or cyst.
328
Taylor’s DifferenTial Diagnosis Manual
B. Physical examination. The neck is inspected below the thyroid cartilage from the front
and side, using cross-lighting to accentuate shadows and masses. Full extension of the neck
enhances the visibility of the gland. The patient is approached from either the front or
behind during palpation, which is accomplished using the fingers or thumbs. Having the
patient swallow during both inspection and palpation causes the thyroid to move and aids
in developing a three-dimensional impression of the gland. The location, size, consistency,
mobility, and tenderness of all nodules should be documented. A nodule that is hard,
irregular, nontender, >4 cm, fixed to surrounding structures, associated with local lymph-
adenopathy or vocal cord immobility suggests malignancy (3).
C. Testing
1. Laboratory tests. Serum TSH should be assessed in every patient. It is the best screening
test for both hypothyroidism (elevated TSH; Chapter 14.4) and thyrotoxicosis (sup-
pressed TSH; Chapter 14.8). A family history of medullary thyroid cancer or multiple
endocrine neoplasia type II warrants a basal serum calcitonin.
2. Fine needle aspiration biopsy. In euthyroid patients with a nodule, a fine needle aspi-
ration biopsy (FNAB) should be performed. FNAB has demonstrated a sensitivity of
68–98% and a specificity of 72–100% (2). After applying local anesthetic, a 25-G needle,
guided by palpation (or ultrasound if the nodule is smaller than 1 cm) is used to obtain
two to five specimens (4). Even in experienced hands, biopsies are often unsatisfactory and
need to be repeated. A thyroid lobectomy with frozen section analysis may be required if
FNAB is repeatedly nondiagnostic and the clinical pretest probability of cancer is high.
3. Imaging studies. Ultrasound cannot reliably differentiate benign from malignant nod-
ules, although features such as microcalcifications and irregular margins are suggestive
of cancer (3). Although less frequently used, radioisotope scanning with radioiodine can
differentiate between active (“hot nodules”) and non-functional (“cold”) nodules (3).
About 5% of nodules are active and are less likely to be malignant. Similarly, computed
tomography and magnetic resonance imaging have limited value in the initial diagnostic
workup except in cases of local compression.
Negative for cancer
0
100
200
300
400
500
600
700
800
900
1,000
Non diagnostic Suspicious for cancer
Cytologic report
Positive for cancer
Initial diagnosis based on FNAB
Final cancer diagnosis (after
surgical excision)
Figure 14.7.1. Risk of cancer in thyroid nodules
FNAB, fine needle aspiration biopsy. Modeled data based on experience at one center.
Source: reference (1)
Chapter 14 • Endocrine and Metabolic Problems
329
D. Genetic biomarkers. The presence of certain genetic mutations has been correlated with
thyroid cancers, proving to be clinically useful when FNAB is indeterminate (3). These muta-
tions occur in the genes for tyrosine kinase receptors (RET/PTC, NTRK), nuclear proteins
(PAX-8-PPARγ), and signaling proteins (RAS, BRAF). The latter alterations along with RET/
PTC mutations are frequent in papillary carcinomas while follicular cancers bear RAS proto-
oncogenes and PAX-8-PPARγ defects. These genetic markers are expected to be incorporated
into diagnostic algorithms as more data are accumulated and the assays become more wide-
spread in availability (3). Approximately 4–8% of cases of papillary cancer are familial, and
a high incidence has been reported in patients with adenomatous polyposis coli (Gardner’s
syndrome) and multiple hamartoma syndromes (Cowden disease). Medullary cancer, usually
as part of multiple endocrine neoplasia type II, often occurs in a hereditary pattern.
IV. DIAGNOSIS
A. Differential diagnosis.
If the results of FNAB demonstrate a malignancy or are suspicious,
indeterminate, or repeatedly unsatisfactory, then an immediate surgical referral is warranted.
Sometimes, radionuclide scanning is used to evaluate a suspicious biopsy result, and hyper-
functioning nodules are observed rather than removed. If the biopsy is clearly benign, a careful
examination of the nodule and surrounding structures, an ultrasound, and a TSH measure-
ment should be performed every 12 months (3). While nodules that are more than 4 cm have
a 19% risk of cancer, the decision for surgery should not be based on nodule size alone.
B. Clinical manifestations. The presence of hyperthyroidism or hypothyroidism lowers the
suspicion of cancer but does not exclude it. Any nodule that enlarges or becomes clinically
suspicious should be rebiopsied.
REFERENCES
1. Sebo TJ. Thyroid fine needle aspiration cytology: nothing new except a re-emphasis on a back-to-
basics and cost-effective approach to interpretation in the era of ultrasound examination and molecu-
lar diagnostics. Clin Endocrinol. Available at: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-
2265.2012.04404.x/abstract. Accessed May 9, 2012.
2. Welker MJ, Orlov D. Thyroid nodules. Am Fam Physician 2003;67(3):559–566.
3. Bomeli SR, LeBeau SO, Ferris RL. Evaluation of a thyroid nodule. Otolaryngol Clin North Am
2010;43(2):229–238, vii.
4. Layfield LJ, Cibas ES, Gharib H, Mandel SJ. Thyroid aspiration cytology: current status. CA: A Cancer
J Clin 2009;59(2):99–110.
14.8
Hyperthyroidism/
Thyrotoxicosis
Rodolfo M. Sanchez
I. BACKGROUND. Hyperthyroidism is excessive thyroid hormone secretion. Thyrotoxicosis is
the state of symptomatic thyroid hormone excess.
II. PATHOPHYSIOLOGY. Causes of thyrotoxicosis are summarized in Table 14.8.1.
A. Etiology
1. Graves’ disease, an autoimmune disorder and the most common cause of hyperthy-
roidism, results when thyrotropin receptor antibodies stimulate thyroid growth, lead-
ing to the synthesis and release of the thyroid hormones T3 and T4, usually resulting
in a goiter.
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Taylor’s DifferenTial Diagnosis Manual
2. Toxic adenoma and toxic multinodular goiter are characterized by the development
of areas of focal or diffuse hyperplasia of thyroid follicular cells, which function without
regulation by thyroid-stimulating hormone (TSH). In trophoblastic tumors, TSH recep-
tors may be stimulated by the overproduction of the human chorionic gonadotropin or
other placental proteins.
3. Thyroiditis results in the release of preformed thyroid hormone from the thyroid gland.
It is of viral or postviral origin (subacute granulomatous thyroiditis) or from an autoim-
mune process (subacute lymphocytic thyroiditis). Subacute thyroiditis can also be caused
by chemical toxicity from drugs such as amiodarone, by radiation, or by drugs that
interfere with the immune system, such as interferon alfa.
B. Epidemiology. Hyperthyroidism affects up to 2% of women and 0.2% of men. The
prevalence increases with age and is highest in patients older than 80 years of age (1). Graves’
disease accounts for 60–80% of cases of thyrotoxicosis, occurs typically in patients between
20 and 50 years of age, and is less prevalent in areas of low iodine intake (2). Toxic nodular
goiter is the next most common cause of thyrotoxicosis (10–40%) and is the most com-
mon cause of thyrotoxicosis in patients older than 40 years of age. Thyroiditis accounts for
5–20% of the cases. The other causes of thyrotoxicosis are much less common.
III. EVALUATION
A. History.
Symptoms vary from dramatic to absent. In severe hyperthyroidism, anxiety,
emotional ability, commerce, weakness, heat intolerance, weight loss, and increased per-
spiration are common. Milder symptoms include unexplained weight loss, myopathy,
menstrual disorders, new onset of atrial fibrillation, and gynecomastia.
TABLE 14.8.1 Causes of Thyrotoxicosis and Associated Radioactive Iodine
Uptake Findings
Cause Radioactive iodine uptake
Graves’ disease (most common) Homogeneous increase
Toxic multinodular goiter Increased heterogeneous pattern
Toxic adenoma One area increased, rest of the gland suppressed
Exogenous Low or absent uptake
Iatrogenic (overtreatment)
Factitious (patient taking excess)
Thyroiditis
Acute suppurative (rare) Normal
Subacute (de Quervain’s)
a
Low (transient)
Silent thyroiditis
a
Low (transient)
Excess iodine Low or absent
Thyroid carcinoma Variable
Functioning bone metastases Absent
TSH-secreting pituitary tumor Increased
Struma ovarii Reduced in thyroid (increased over pelvis)
Activating mutation of TSH receptor Increased
Thyroid hormone resistance syndrome Increased
a
Transient, followed by hypothyroidism, then return to normal. TSH, thyroid-stimulating hormone.
Chapter 14 • Endocrine and Metabolic Problems
331
B. Physical examination. Vital signs may reveal weight loss, tachycardia, and systolic
hypertension with a widened pulse pressure. Patients may appear nervous or restless. Sinus
tachycardia is the most frequent arrhythmia. Atrial fibrillation occurs in 5–15% and may
be the presenting problem. The risk of atrial fibrillation or flutter is higher in men than in
women (1.8:1) and increases with age (3). Despite complaints of exertional dyspnea, the
lung examination is usually normal unless there is concomitant congestive heart failure. The
skin may be warm and moist with palmar erythema. Pretibial myxedema, painless raised
swelling of subcutaneous tissues, most often found on the anterior lower leg or dorsal foot
of patients with Graves’ disease, causes a peau d’orange texture, which can be pruritic and
hyperpigmented. A fine tremor is most evident in the fingertips when the hands are extend-
ed. Hypokalemic periodic paralysis is most commonly seen in Asian men. Auscultation of a
bruit over the gland correlates with increased vascularity.
C. Testing. Measuring serum (TSH) is the most sensitive test to screen for primary hyper-
thyroidism. A normal TSH virtually excludes hyperthyroidism, serum TSH < 0.01 mIU/L
confirms hyperthyroidism, and an elevated free T
4
would further confirm the diagnosis of
hyperthyroidism. If the free T
4
is normal and suspicion is high, a serum free triiodothyro-
nine (T
3
) should also be measured to rule out T
3
toxicosis. Drugs such as glucocorticoids,
levodopa, and dopamine can cause a low TSH in patients who are euthyroid. A low TSH
with a normal free T
4
and T
3
may indicate subclinical hyperthyroidism. A thyroid scan with
radioactive iodine uptake can help differentiate the causes of thyrotoxicosis as indicated in
Table 14.8.1 (4). Ultrasonic examination of the thyroid is useful to detect the presence of
nodules or cysts.
D. Genetics. A combination of genetic factors, including HLA-DR and CTLA-4 polymor-
phisms, and environmental factors contributes to Graves’ disease. Activating mutations of
Gs-α proteins have been identified in many toxic adenomas. Activating somatic mutations
of the genes for TSH receptor have been identified in both toxic adenomas and toxic mul-
tinodular goiters.
IV. DIAGNOSIS
A. Differential diagnosis.
Thyrotoxicosis must be differentiated from other causes of unex-
plained weight loss, including malignancies, psychiatric disorders, alcohol or drug abuse,
diabetes, occult infections, gastrointestinal disorders, and chronic renal, hepatic, cardiac, or
pulmonary disease.
B. Clinical manifestations. The signs and symptoms are extremely variable.
1. Graves’ disease is suggested by widened palpebral fissures, lid lag, and visualization of
the sclera on all sides of the iris. Typically, the thyroid is increased in size and is smooth
and nontender. A bruit is present in 50% of patients.
2. Toxic nodular goiter presents with a gland that is typically enlarged and non-tender
with multiple nodules. A single toxic nodule is more common in younger people.
3. Thyroiditis, which usually refers to subacute granulomatous thyroiditis (de Quervain’s
thyroiditis), presents with an enlarged, tender thyroid. In subacute lymphocytic thyroid-
itis (painless or silent thyroiditis), the gland is enlarged but nontender.
REFERENCES
1. Flynn RWV, MacDonald TM, Morris AD, et al. The thyroid epidemiology, audit, and research study:
thyroid dysfunction in the general population. J Clin Endocrinol Metab 2004;89:3879–3884.
2. Cooper DS. Hyperthyroidism. Lancet 2003;362:459–468.
3. Frost L, Vestergaard P, Mosekilde L. Hyperthyroidism and the risk of atrial fibrillation or flutter: a
population based study. Arch Intern Med 2004;164:1675–1678.
4. Intenzo CM, dePapp AE, Jabbour S, et al. Scintigraphic manifestations of thyrotoxicosis. Radiographics
2003;23:857–869.
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Taylor’s DifferenTial Diagnosis Manual
14.9
Vitamin D Deficiency
Amy L. McGaha
I. BACKGROUND. Vitamin D (Vit D) is a fat-soluble vitamin, the main function of which is to
regulate calcium levels in the blood. Vit D in its active form increases the absorption of calcium
from the intestine. Vit D has receptors on most cells in the body, suggesting a wide range of
functions some of which are not yet fully elucidated. Recent research findings suggest that Vit D
plays a major role in immune regulation and thus may be of critical importance in infections,
autoimmune disorders, as well as possibly playing a role in the genesis of malignant disease.
Calcium is a critical mineral in the body and is important to cellular function, especially in
muscle and neural cells.
Humans obtain 90% of their Vit D from sunlight and skin synthesis. It is difficult to
maintain adequate levels of Vit D from dietary sources alone, as Vit D is not naturally present
in a wide variety of foods. There are two kinds of Vit D: ergocalciferol (D2) from irradiation
of yeast and plant sterols and cholecalciferol (D3) from skin synthesis and also present in some
kinds of fish. Although only a small number of foods naturally have Vit D, many US foods are
fortified, usually in the form of cholecalciferol. Naturally occurring dietary sources of Vit D
(cholecalciferol) include breast milk (if the woman is not deficient), tuna, mackerel, salmon,
sardines, cod liver oil, and egg yolks (ergocalciferol).
II. PATHOPHYSIOLOGY
A. Etiology.
When intestinal absorption of calcium does not provide sufficient calcium to
maintain normocalcemia, Vit D will then suppress osteocytes and activate osteoclasts to
mobilize calcium from bones. Parathyroid hormone (PTH) is released in response to hypo-
calcemia and acts by stimulating the conversion of Vit D to its active form in both liver and
kidneys.
B. Epidemiology. More than half of the persons older than 65 years in North America and
66% of all persons internationally failed to maintain healthy bone density and tooth attach-
ment because of inadequate Vit D. Risk factors for Vit D deficiency include age >65 years,
exclusively breast-fed infants, persons with dark skin, decreased sunlight exposure, obesity,
sedentary lifestyle, and some medications (glucocorticoids, anticonvulsants). In addition,
patients with a history of gastric bypass or malabsorption, liver disease, or renal failure are
at higher risk for Vit D deficiency.
The incidence of rickets has declined in most industrialized countries (including the
United States) due primarily to fortification of food and beverages. However, there has been a
resurgence in some susceptible populations. These include exclusively breast-fed infants, espe-
cially those born to Vit D-deficient mothers, and among vegetarian and vegan populations.
III. EVALUATION
A. History.
Although most commonly Vit D deficiency is asymptomatic, and only discov-
ered after the development of a fracture or another disorder such as rickets, the clinician
should maintain a high index of suspicion, particularly among patients with darker skin,
on chronic anticonvulsants or steroids, with unexplained elevations in serum alkaline phos-
phatase, or in children presenting with irritability, or growth delay. Bone (particularly low
back pain, sternum, or tibia) and muscle pain and weakness can also be manifestations of
Vit D deficiency.
B. Physical exam. Clinical manifestations of Vit D deficiency can be classified as skeletal
and extraskeletal. They can also be classified as manifestations of negative calcium balance
or direct Vit D deficiency.
Negative calcium balance in the growing skeleton produces rickets. Manifestations
of rickets include bone deformity, as well as symptomatic hypocalcemia, manifesting as
Chapter 14 • Endocrine and Metabolic Problems
333
seizures or hypocalcemic tetany. Widening of the wrists, bowing of legs, delayed closure
of fontanels, craniotabes, and rachitic rosary (widened costochondral junctions) are classic
and advanced bone manifestations of rickets. Extraskeletal symptoms of rickets include
motor delay and dental maldevelopment. In addition, infants and children with rickets have
increased susceptibility to infections such as pneumonia.
In the mature skeleton, Vit D deficiency results in osteopenia, osteomalacia, or osteopo-
rosis. These manifest both as skeletal deformities such as “Dowager’s hump” and increased
susceptibility to fractures.
IV. DIAGNOSIS
The diagnosis of Vit D deficiency should be considered in patients presenting with complaints
of widespread bone discomfort, muscle aches, or proximal muscle weakness.
A. Testing. Serum testing for 25-OH Vit D, the major circulating form of Vit D, is used to
diagnose Vit D insufficiency or deficiency. Although there is little agreement on optimal Vit
D levels, it has been suggested that 20 ng/mL (50 nmol/L) may be appropriate as a target
to indicate sufficiency (1,2).
Parathyroid Hormone. May be measured if there is a question of insufficiency; levels of
PTH tend to be inversely proportional to the levels of 25-OH Vit D in the body.
Measurement of serum levels of alkaline phosphatase, calcium, and phosphorus may
be considered if osteomalacia or rickets are a possibility. Bone density testing may also be
helpful (3).
After treatment, repeated measurements of 25-OH Vit D levels are carried out at inter-
vals and then yearly to document continued sufficiency. Radiologic healing should also be
documented in children who are treated for rickets.
REFERENCES
1. Pazirandeh S, Burns DL. Overview of Vitamin D, from www.uptodate.com. Accessed September 27,
2012.
2. Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M. Vitamin D deficiency in children and its
management: review of current knowledge and recommendations. Pediatrics 2008;122(2):398.
3. Holick MF, Vitamin D deficiency. N Engl J Med 2007;357:266–281.
334
Taylor’s DifferenTial Diagnosis Manual
Vascular and Lymphatic
System Problems
Ashley Falk
CHAPTER 15
15.1
I. BACKGROUND. Lymphadenopathy, enlarged, tender, or inflamed lymph nodes, is a common
presenting complaint. In primary care, patients presenting with nonspecific lymphadenopathy
are mainly younger than 40 years of age, and one-fourth of the patients have generalized
lymphadenopathy. Generalized lymphadenopathy is diagnosed when abnormal lymph nodes
are identified in two or more noncontiguous areas (e.g., neck and groin). Generalized lymph-
adenopathy should prompt further investigation of systemic disease by the physician.
II. PATHOPHYSIOLOGY. Infectious, autoimmune, granulomatous, malignant diseases or medi-
cation reactions can cause generalized lymphadenopathy. The overall risk of cancer in patients
with generalized lymphadenopathy is low; however, the risk of malignancy increases with
age. There is a 4% cancer risk in those patients older than 40 years of age with generalized
lymphadenopathy (1). A good complete history and physical examination can often lead to a
diagnosis of the cause of lymphadenopathy.
III. EVALUATION
A. History.
The history should focus on the common causes of generalized lymphadenopathy.
1. History of present illness should focus on the duration, location, quality, and context
of the lymphadenopathy. Enlarged, tender lymph nodes present for <2 weeks are often
due to infectious causes. Lymphadenopathy present for more than a year is usually from
nonspecific causes. Associated signs and symptoms such as rash, fever, night sweats,
weight loss, sore throat, and arthralgias may help identify a specific cause of the general-
ized lymphadenopathy (2).
2. Past medical history should focus on known illness and medication usage. Common
chronic illnesses (e.g., lupus erythematosus, rheumatoid arthritis, and human immuno-
deficiency virus [HIV]) can also cause generalized lymphadenopathy. Drug reactions
resulting in lymphadenopathy can occur with certain antibiotics and seizure and hyper-
tension medications (1).
3. Social history may identify risk factors for hepatitis B, secondary syphilis, and early
HIV. All of these diseases can present with generalized lymphadenopathy.
4. Family history is important to identify illness with a genetic predisposition such as lipid
storage diseases and immunologic diseases (e.g., Niemann-Pick disease and rheumatoid
arthritis). Any known exposures to family members with infectious diseases (e.g., tuber-
culosis, infectious mononucleosis, or hepatitis B) can also yield important information
when trying to identify a causative etiology of lymphadenopathy.
Lymphadenopathy,
Generalized
Kristy D. Edwards
335
5. Review of systems should focus on constitutional symptoms such as weight loss, fatigue,
night sweats, malaise, arthralgias, nausea, and vomiting.
B. Physical examination
1. General. A comprehensive physical examination should be performed on all patients
with generalized lymphadenopathy. It should focus on identifying systemic diseases.
Vital signs are important, because fever may suggest infectious etiology and weight loss
may suggest systemic disease. Skin rashes or lesions, mucous membrane ulcers, and
inflammatory arthritis are important physical findings in establishing a differential diag-
nosis for the adenopathy. An abdominal examination for splenomegaly can yield useful
information. Generalized lymphadenopathy with splenomegaly implies systemic illness
(e.g., infectious mononucleosis, lymphoma, leukemia, lupus, sarcoidosis, toxoplasmosis,
or cat-scratch disease) and virtually excludes nonhematologic metastatic disease (1,2).
2. Nodal examination. In generalized lymphadenopathy, lymph node size, location, and
consistency can help in establishing a diagnosis.
a. Size. Lymph nodes >1.5 cm in diameter have a 38% risk of cancer involvement and
require further workup (2). Lymph nodes 1 cm in diameter and smaller can be normal
and can usually be observed.
b. Location. The anatomic location of lymphadenopathy is sometimes helpful in
establishing a diagnosis. However, with generalized lymphadenopathy, the anatomic
location is less helpful. Anterior cervical, submandibular, and inguinal nodes may
normally be palpable. However, lymph nodes palpated in certain areas are always
alarming. For example, supraclavicular lymphadenopathy has a 90% risk of cancer in
patients older than 40 years of age.
c. Consistency. Rock hard nodes particularly in older patients are worrying for meta-
static disease (2). Firm rubbery nodes are found with lymphomas. Soft tender nodes
tend to occur with infectious causes; however, this should not be considered diagnos-
tic. Pain is not a reliable indicator of the cause of lymphadenopathy.
C. Testing
1. Laboratory tests. Laboratory testing in patients with generalized lymphadenopathy
should be purposeful and specific. Tests should be directed by the patient’s signs and
symptoms of an underlying disease process (3). A complete blood count (CBC) with
peripheral smear is almost always indicated (4). Elevated neutrophils suggest pyogenic
etiologies, lymphocytosis suggests viral infection, and pancytopenia suggests leukemia or
HIV infection. An erythrocyte sedimentation rate is nonspecific, but if it is persistently
elevated, further investigation is indicated. Disease-specific serologic tests, including
antibody testing for Epstein-Barr virus, cytomegalovirus, HIV, rubella virus, syphilis
(FTA-ABS), and others, are useful. Antibody testing can be diagnostic and can differen-
tiate between acute and chronic illnesses. Chest X-rays are rarely positive but should be
ordered to look for mediastinal lymph node involvement in sarcoid disease, metastatic
disease, lymphomas, or granulomatous disease. Purified protein derivative (PPD) testing
is used to identify tuberculin disease (2).
2. Lymph node biopsy. If the laboratory testing is nondiagnostic, then lymph node biopsy
should be considered if the enlarged lymph node persists for more than a month. The
largest and most pathologic node should be removed. Axillary and inguinal nodes should
be avoided, because they often reveal only reactive hyperplasia. Biopsy should be avoided
in cases of suspected infectious mononucleosis and drug reaction because the histologic
picture is easily confused with malignant lymphoma (2). Experienced hematologists or
hematopathologists should handle all specimens. The value of fine needle aspiration is
controversial, with reasonable arguments both for and against this procedure (5).
IV. DIAGNOSIS. The thorough history and examination should establish a differential diagnosis
including infectious, autoimmune, granulomatous, and malignant etiologies. Investigation
should be limited to specific diseases because generalized lymphadenopathy is often a sign of a
specific systemic illness. In the event that the cause is unclear, infectious etiologies must be con-
sidered and a CBC and mononucleosis spot ordered. If these are negative, then immunologic
336
Taylor’s DifferenTial Diagnosis Manual
and granulomatous etiologies are considered with serologic testing, a chest X-ray, and PPD. A
lymph node biopsy must be considered in those cases where the node is rock hard or larger than
1.5 cm × 1.5 cm in size (1). Biopsy should be avoided in those cases in which viral causes are
clinically suggested.
REFERENCES
1. Ferrer R. Lymphadenopathy: differential diagnosis and evaluation. Am Fam Physician 1998;58:
1313–1320.
2. Pangalis GA, Vassilalopoulos TP, Boussiotis VA, et al. Clinical approach to lymphadenopathy. Semin
Oncol 1993;20:570–582.
3. Williamson HA. Lymphadenopathy in a family practice. J Fam Pract 1985;20:449–452.
4. Simon HB. Evaluation of lymphadenopathy. In: Goroll AH, Mulley AG, eds. Primary care medicine:
office evaluation and management of the adult patient, 6th ed. Philadelphia, PA: JB Lippincott Williams
& Wilkins, 2009:82-86.
5. Henry PH, Longo DL. Chapter 59. Enlargement of lymph nodes and spleen. In: Longo DL, Fauci AS,
Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of internal medicine. 18th ed.
New York, NY: McGraw-Hill; 2012. http://www.accessmedicine.com/content.aspx?aID=9113581.
15.2
I. BACKGROUND. Lymph nodes are normally palpated in children and may be normally felt in
the neck, axilla, and inguinal regions of adults. Three-fourths of primary care patients present-
ing with unexplained lymph node enlargement have regional lymphadenopathy and less than
1% will have a malignancy (1). Localized or regional lymphadenopathy occurs when enlarged
lymph nodes are identified in one anatomic location. The most common anatomic locations
for localized lymphadenopathy are the head and neck (55%) and inguinal (14%) regions, but it
may also be found in the axillary, epitrochlear, supraclavicular, and other regions. Once lymph-
adenopathy is identified, a complete lymph node examination should be performed to rule out
generalized lymphadenopathy. A thorough history and physical examination including regions
drained by the lymph nodes should be performed (2).
II. PATHOPHYSIOLOGY. The cause of localized lymphadenopathy can be separated by the age of the
patient and its location. Reactive hyperplasia and benign etiologies make up 80% of the causes of
lymphadenopathy in children and adults younger than 30 years of age. Older patients, especially
those older than 40 years of age, are at increased risk for malignancy (3). In localized lymphade-
nopathy, the location can aid in determining a causative etiology. Knowledge of the patterns of lym-
phatic drainage and region-specific conditions is essential in the investigation of localized lymph-
adenopathy (4). The context in which lymphadenopathy occurs is very important in establishing
a differential diagnosis. A detailed history including present illness, review of systems, past medical
history, social history, and thorough physical examination of the region should be performed.
III. EVALUATION
A. History.
It is important to elicit a detailed history. Lymphadenopathy that is present for
months to years suggests underlying malignancy or systemic disease, whereas lymphade-
nopathy that is present for a few weeks is usually due to infectious etiologies. History of
exposure to a cat scratch or sexually transmitted disease can explain lymphadenopathy in the
axilla or inguinal regions. History of recent cold symptoms or local signs of redness, swelling,
or discharge may suggest infection, whereas nonspecific signs of fever, chills, or night sweats
may suggest systemic illness.
Lymphadenopathy,
Localized
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Chapter 15 • Vascular and Lymphatic System Problems
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