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ABSTRACT
Background and Objective. How to reach the correct ther investigation; second, deciding whether it would
diagnosis of a lymph node enlargement is still a prob- be advisable to perform a nodal biopsy when tests
lem which strongly challenges the knowledge and and other clinical findings have not provided suffi-
experience of the clinician. Organized and specifi- cient diagnostic elements to categorize the LAM with
cally oriented literature on the right sequential steps certainty.
and the logical criteria that should guide this diag- It should, however, be noted that all the findings,
nostic approach is still lacking.
observations and testing that make up the rational
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Methods. The authors have tried to exploit available approach to LAM offer no predetermined relation-
knowledge and their personal experience by corre- ships, but only merely probable ones, and that
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lating a large body of information regarding size, together they constitute a set of norms in which dif-
physical characteristics, anatomical location of ferent factors play significant roles: e.g. the variabil-
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enlarged lymph nodes, and the possible epidemio-
logical, environmental, occupational and clinical cat-
ity of expression of the different possible disorders,
egorization of this condition. individual patient variability, and a hard-to-quanti-
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fy amount of clinical experience and specific obser-
Results and Conclusions. It was intended that such vational expertise on the part of the physicians work-
material would have constituted the basis of a hypo-
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ing on the case. The entire subject matter of this
thetic decision-making tree, but this was impossible
because of the lack of epidemiological investigation study could be used to outline a decision-making
and registry data. Nevertheless, we present this tree that would be extremely complex and quite dif-
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est of concerned readers and because of its possible The definition of what constitutes a normal lymph
direct usefulness in hematologic practice. node may in itself frequently be difficult. It is well
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©1999, Ferrata Storti Foundation known that the lymph nodes, together with the
spleen, are the peripheral organs of the immune sys-
Key words: diagnosis, lymph node enlargement, tem within which the anatomical and functional
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patient presents with lymphadenomegaly (LAM) of which consists of a cellular component composed
has no immediate solution. Most of the time the of fibroblasts (whose function is mainly structural),
family doctor only participates in the early stages of macrophages, dendritic and Langerhans’ cells
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the diagnostic process, then a specialist is called in (whose function is to recognize and present an anti-
– usually a hematologist – whose goal is not only to gen and to activate lymphocytes), T and B lympho-
do his best to reach a diagnosis but to do so in the cytes (which are the effector cells of cellular and
shortest, most reasonable, least expensive and, humoral immunity, respectively). All these elements
above all, least uncomfortable way for the patient. are contained within connective stroma and encased
The clinical approach to LAM follows two main in a capsular shell.
logical steps:1 first, making a diagnostic distinction During an immune response the flow of blood and
between a true lymphadenopathy, with a patholog-
lymph through a lymph node can increase by as
ical significance that deserves more detailed diag-
much as twenty-five times with a resulting accumu-
nostic attention, and a state of exaggerated palpa-
lation of activated proliferating cells, and the entire
bility of normal lymph nodes, due to causes such as
lymph node may swell up to fifteen times its normal
a very thin patient or flaccid connective tissue, or a
volume. When this occurs it is capsular edema and
simple LAM – mainly stromal – that is the result of a
the tension this causes, along with the consequent
previous adenopathy and does not require any fur-
process of perilymphadenitis, that is responsibile for
the characteristic pain of inflammatory adenopathy.
Correspondence: Paolo G. Gobbi, M.D., Medicina Interna e Oncologia Moreover, if the etiologic agent is bacterial and
Medica, Università di Pavia, IRCCS Policlinico S. Matteo, p.le Golgi,
27100 Pavia, Italy. reaches the lymph node in large numbers, this can
Diagnosis of lymph node enlargement 243
cause follicular necrosis with suppuration, trans- ous enlargements and current adenomegalies with
forming the lymph node into a soft, more or less taut, clinical significance, the different physical character-
floating mass that is extremely painful and extremely istics of the lymph node, as determined by physical
sensitive to the slightest touch. While in time, after examination, are also fundamental to making such a
every episode of functional hyperplasia, the cellular distinction. There are four main types of physical
component returns to its original normal propor- characteristics: 1) enlarged nodes that are the result
tions, the same is not always true for the stroma. It of a previous inflammatory process are firm, elastic,
is difficult for stromal hyperplasia to return to its orig- very mobile, hard to hold in one place and absolute-
inal dimensions, especially if there has been conspic- ly painless and insensitive to handling; 2) in acute
uous necrosis or suppuration, and this creates an infections lymph nodes are often tender, softly elas-
anatomical basis for greater palpability of the node tic and sometimes asymmetrically enlarged if they are
even under conditions of functional rest. The more isolated; other times, however, they are confluent,
times these functional stimuli are repeated, the more painful and sensitive to touch, and covered by flushed
pronounced this condition becomes. skin. If the infection is localized, a painful red streak
A lymph node may be enlarged a) in an immune (lymphangitis) may connect the site of the infection
response to infective agents (bacterial, viral); b) as a to the involved lymph node; 3) the lymph nodes of
result of inflammatory cells in infections involving the lymphomas are firmer, rigidly elastic with superficial
lymph node (lymphadenitis); c) by the infiltration of and deep mobility that is less than normal but not
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neoplastic cells carried to the node by lymphatic or completely absent. Often these lymph nodes aggre-
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blood circulation (metastasis); d) due to localized gate to form small packets without modifying their
neoplastic proliferation of lymphocytes or macro- integument; they are only slightly or not at all painful,
phages (lymphomas), and e) as a result of an infiltra- only slightly or not at all sensitive to handling (ten-
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tion of macrophages filled with metabolite deposits derness and sensitivity to touch are possible in sites
(lipid storage diseases).2 that are readily exposed to repeated infections, such
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as the tonsils and inguinal lymph nodes); 4) metasta-
Evaluation of lymphadenomegaly
tic lymph nodes from solid tumors are typically hard,
It is known that most of the information necessary
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at times with an irregular surface, not mobile, espe-
for formulating a diagnosis of LAM comes from the
cially at the deeper levels, painless and insensitive to
patient’s medical history and a physical examination.
touch; in extreme cases the overlying skin can take
In fact, in most cases these two tools are able to pro-
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tion);
lymph nodes showing inflammatory characteristics
c. its anatomical location;
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are associated with infections of superficial tissue of of systemic granulomatoses (tuberculosis, sarcoido-
the orbit, the middle ear and the parotid glands. They sis), as well as in lymphomatous processes. Among
may also be related to oculo-parotid syndromes (e.g. possible immune reactions we would like to men-
Sjøgren’s or Heerfordt’s syndrome). Submental LAM tion the axillary adenopathy caused by silicon mam-
require a search for disorders in the anterior portion mary prostheses.3
of the mouth and the lower lip, in the submandibu- Inguinal LAM can be caused by a variety of venere-
lar portion of the face, in the nose, the maxillary al diseases such as lymphogranuloma venereum,
sinus, the mucosa of the oral cavity, the floor of the syphilis and herpes genitalis, disorders whose initial
mouth, as well as in the submental salivary gland. local lesions may not be detectable objectively but
Retromandibular LAM, besides being involved by the can be suggested from a personal medical history.
same disorders as the previous two types, can also Other possible causes of inguinal LAM include infec-
more directly mirror infectious or neoplastic process- tious and neoplastic disorders of the perineum and
es of the rhinopharynx, the supraglottic larynx, the small pelvis (rectum, vagina).
palatine tonsils, the hypopharynx, the base of the Enlargement of the popliteal lymph nodes is gen-
tongue and the parotid gland. Laterocervical LAM in erally associated with infectious disorders of the foot
the upper portions of the neck can be associated with and leg and is rarely caused by neoplasms in these
inflammatory or neoplastic disorders of the hypo- areas or by lymphomatous localization (in which case
pharynx, the larynx or the thyroid gland, while those it is almost always non-Hodgkin's). Adenomegaly of
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in the lower part of the neck are related to disorders the femoral nodes, besides being associated with the
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of the hypoglottic larynx, the thyroid and the upper same causes as popliteal LAM, may also be due to
portion of the esophagus. Due to the close anatom- Pasteurella pestis infection.
ical and functional relationships between the lymph Lymphadenomegalies in deep sites (mediastinum,
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node stations and the numerous structures present in retroperitoneum, mesentery) are usually not detect-
the head and neck, it is clear that practically every able at physical examination but they may sometimes
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one of the above mentioned LAM can be associated be suspected through assessment of indirect signs.
with almost all of the bacterial, viral, fungal and neo- Hilar-mediastinal LAM can be suspected upon the
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plastic disorders of the upper respiratory tract and appearance of syndromes that involve compression of
the beginning of the digestive tract. Among possible mediastinal structures: a) compression of the vena
bacterial disorders we should keep in mind the sup- cava (headache, congestion of the head and neck, tur-
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purative ones caused by mycobacteria, such as scro- gor of the jugular veins, congestion of the upper part
or
fula, which at one time was frequent but has not yet of the thorax and the arms, small mantle edema); b)
completely disappeared. compression of the bronchial branches (harsh dry
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Supraclavicular LAM, together with prescalenic cough, mixed or prevalently expiratory dyspnea) or of
node enlargement, is often indicative of granuloma- the mediastinal nerve trunks (dysphonia, bitonal voice,
tous (sarcoidosis), neoplastic, intrathoracic, gas- hiccoughs). Mediastinal LAM is associated with tuber-
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trointestinal or retroperitoneal disorders. In particu- culosis, sarcoidosis, pulmonary mycoses and may be
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lar, left supraclavicular LAM, when it shows the char- the site of metastases of bronchial, pleural, mamma-
acteristics of a metastatic type (Troisier's or Virchow's ry, digestive, retroperitoneal and genital neoplasms.
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lymph node), is a sign of the metastasis of a neo- Back pains that are more pronounced when lying
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plasm, almost always gastrointestinal, that is no down, often with sciatic irradiation to one or both
longer surgically operable. In cases of lymphoma, left lower limbs, muscular weakness of varying degree
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supraclavicular LAM is often associated with involve- – from mild all the way to paralysis, dysesthesia and
ment of the lumbo-aortic stations and the spleen, paresthesia – can accompany conspicuous retroperi-
while on the right side it is associated, although less toneal LAM, in which there is initial compression of
closely, with intrathoracic lymphomatous localiza- the spinal cord or the spinal nerve roots (nevertheless,
tions. retroperitoneal LAM is seldom the only finding; if it
Epitrochlear LAM is often caused by infections in is not associated with LAM in other sites, as usually
the area of the hand and the forearm or due to bru- occurs, it is at least associated with splenomegaly).
cellosis; however, it can also be the result of non- Steatorrhea with intact pancreatic function, or ane-
Hodgkin’s lymphoma (Hodgkin’s disease is rare in mia that is resistant to oral iron or vitamin therapy,
this location). Bilateral epitrochlear LAM raises the or even a late case of sprue may be caused by mesen-
suspicion of sarcoidosis, tularemia or even secondary teric LAM associated with hyperplasia of the lym-
syphilis. This LAM site may also be involved by cat phoid component of the lamina propria of various
scratch disease, although the localizations of choice segments of the small intestine. These conditions are
for this pathology are laterocervical (40%), axillary manifest long before mesenteric LAM and intestinal
(25%) and submandibular (18%). infiltration can provoke direct or zonal symptoms or
Axillary LAM is seen in cases of infection or neo- can be documented by other types of investigation.
plasm localized in the upper arm (melanoma), in the The epidemiological, environmental, occupational and clin-
mammary gland, and in intrathoracic localizations ical categorization of each individual patient also pro-
Diagnosis of lymph node enlargement 245
vides important elements of probability with which to tant to antihistamines points toward a possible lym-
search for a LAM. phoma; deep abdominal or thoracic pain following
Age is an important factor to consider because of alcohol consumption, albeit rare, can be considered
the progressive quantitative reduction in and dimin- pathognomonic for Hodgkin's lymphoma. The asso-
ished reactivity of lymphatic tissue which occurs dur- ciation of uveitis or erythema nodosum and LAM
ing the aging process. On biopsy specimens, 17% of suggests sarcoidosis, while that of LAM and chorio-
the LAM in subjects under 30 years old show a pic- retinitis points to toxoplasmosis or even Walden-
ture of aspecific reactive hyperplasia or complete nor- strom's macroglobulinemia. The presence of various
mality, while these findings occur in only 2% of the types of dermatological disorders can, by itself, sup-
LAM biopsied after age 30.2 Moreover, LAM with an port the diagnosis of a simple dermatopathic lym-
inflammatory etiology are much more frequent dur- phadenitis, which most of the time will resolve spon-
ing infancy, whereas those with a neoplastic cause taneously upon remission of the dermatosis; in rare
predominate in people over 40 years old. cases this association is found in mycosis fungoides.
Thus, factors such as the fact that the patient is an LAM and arthritic disorders can lead the physician to
infant and the presence of exanthematic diseases suspect SLE or rheumatoid arthritis. If LAM is asso-
among his/her playmates or school friends, especially ciated with proteinuria and renal insufficiency, this
during their most common period of diffusion (end could signal the presence of myeloma or amyloido-
of winter, spring), will make it easy for the physician sis. LAM plus hemolytic anemia may be a sign of lym-
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to orient his diagnostic suspicions in the case of an phoma, especially the low-grade malignancy form,
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occipital or nuchal LAM with or without fever. Gen- or of angioimmunoblastic lymphadenopathy. Dia-
eralized LAM with fever, accompanied by spleno- betes insipidus and LAM can be associated with
megaly, in adolescents who sleep in school dormito-
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Hand-Schuller-Christian disease.
ries or who frequent other types of young people's Except in rare cases (e.g. spleen extremely soft in
organized activities (e.g. social clubs, sports, military systemic infections, or extremely voluminous in
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service) should bring to mind infectious mononucle- chronic leukosis, lymphocytic lymphoma, hairy cell
osis. Generalized LAM in homosexuals, heroin (or leukemia and – in particular pediatric patients – lipid
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other drug) addicts, hemophiliacs or other chronic storage diseases), assessing the spleen is not very
users of blood derivatives will lead the physician to helpful in determining the nature of the LAM; natu-
run serological tests for positivity to the acquired rally, encountering splenomegaly in the course of
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immune deficiency syndrome (AIDS) virus or to evaluating a localized LAM should orient the initial
or
ans and farmers raise the possibility of infections such Instrumental investigations
as tularemia, brucellosis, tuberculosis, nocardiosis. In the majority of cases, surgical biopsy excluded,
Erythema with generalized LAM following treatment instrumental investigations can only enrich the infor-
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with heterologous sera points to serum sickness. The mation already obtained on the basis of the medical
history and physical examination or make the judge-
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phenytoin, or of carbamazepine; the same lymph The elements of evaluation offered by each inves-
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node enlargement in a chronic arthritis sufferer could tigative procedure should be integrated with one
be due to phenylbutazone, while in a tuberculosis another, beginning with those presented by the sim-
plest and most generalized procedures and then con-
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which could be the revealing element of a generalized select the best node to remove (this choice must be
lymphadenopathy. In special conditions Doppler- clinical) and to handle the specimen properly. The
ultrasonography can supply indications about the lymph node to biopsy is not simply the one most sur-
vascularization of a lymph node, thereby helping to gically accessible, but the biggest one or the one that
distinguish between an old LAM due to a condition has undergone the greatest and most recent changes
in the past and a current LAM that is still active. in volume (as a rule, retromandibular and inguinal
Needle biopsy should be considered when a LAM lymph nodes under 3 cm in diameter are not chosen).
has not been able to be categorized clinically or diag- Computerized axial tomography (CAT) is particu-
nostically. Many superficial LAM can be needle biop- larly useful for visualizing deep lymph nodes, espe-
sied just by using palpation as a guide; all superficial cially in those situations in which ultrasonography
and many deep nodes can be needle biopsied under presents technical limits, namely in the mediastinum
the guidance of ultrasonography, and virtually all in general and in retroperitoneal sites in heavier
deep nodes can be needle biopsied by using tomog- patients. CAT offers only an evaluation of the size of
raphy. The problem arises from the diagnostic relia- the nodes; however, deep lymph nodes in the adult
bility of the procedure itself, which, first of all, can be that exceed 1.5 cm in diameter are considered patho-
considered in direct relation to the diameter of the logic, while those between 1 and 1.5 cm are dubious.
needle employed: the bigger the needle, the more For this reason, especially in the evaluation of
abundant and the better the quality of the material retroperitoneal lymph node involvement in patients
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that will be obtained, and the less difficulty the cytol- with lymphoma or genital neoplasms, until recently a
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ogist who must evaluate the specimen (and whose procedure called abdominal lymphography was
expertise is crucial) will have.6 employed. This examination allowed assessment of
In fact, in about 20% of cases the needle-biopsied
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the parenchymal tissue structure of the lymph node,
material is not adequate for cytohistologic interpre- but it is no longer being used for various reasons: its
tation when needles with a diameter of 14-18 gauge complexity and elevated cost, unwanted side effects,
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are utilized; the percentage of unsuccessful biopsies the lack of personnel with the necessary manual and
rises when narrower needles are employed. The ben- diagnostic expertise required to carry it out and the
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efits of needle biopsy are to spare the patient from difficulty in training such personnel.
surgical biopsy, more so if the LAM is in a deep site
(mediastinum, abdomen), and to offer a possibility Laboratory investigations
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On the other hand, the disadvantages of this proce- of little help. Erythrocyte sedimentation rate, C reactive
dure, besides the above mentioned problems with protein, measurement of the individual glycoproteins
migrating into the a1 and a2 regions at electrophore-
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the lymph node. The latter can be very important if value and for all of them as a group pattern, without
offering the possibility of making even a rough distinc-
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tial diagnosis, needle biopsy is completely justified as dehydrogenase is associated with lymphoproliferative
a substitute for surgical biopsy only when the LAM is diseases: the former with myeloma in particular, and
the latter with lymphomas (more often non-Hodgkin's
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orient the doctor toward either lymphoid or non-
Funding
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lymphoid leukemia, while considerable granulocyto-
sis with thrombocytosis must cast suspicion on This work was supported in part by grants from the Uni-
versity of Pavia and the Ferrata Storti Foundation, Pavia,
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chronic myeloid leukosis. Furthermore, a finding of
myeloid alteration, with the presence of even a few Italy.
myelocytes, metamyelocytes and an occasional
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Disclosures
orthochromatic or polychromato-philic erythroblast,
Conflict of interest: none.
suggests a possible neoplastic bone marrow infiltra-
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patients will be submitted to biopsy when in fact (but Editore; 1993. p. 161-77.
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a posteriori) it will prove to have been unnecessary 2. Pangalis G A, Polliack A. Benign and malignant lym-
(19% of all cases biopsied), the biopsy will not indi- phadenopathies. Chur: Harwood Academic Publish-
cate any specific therapy and the LAM will undergo ers; 1993.
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