by Mario Brown Arnold

Lymphadenopathy is an abnormal increase in size or alteration in the consistency of one or more lymph nodes. Its presence should be considered a manifestation of a regional disease or part of a systemic disease.

Massive infiltration is frequently found due to a neoplasm in lymph nodes that are scarcely enlarged, as usually occurs in axillary metastases of breast cancer, or, in contrast, large adenomegalies in benign, viral diseases, such as infectious mononucleosis.

Lymphadenopathy is an important element for diagnosis.

Anatomy and physiology

They are located in the path of the lymphatic vessels and most of them follow the great arterial vessels (aorta and main branches) and are found in natural cavities such as the axillary and mediastinal cavities and at the entrance of visceral hilies (lungs , liver, spleen).

Not all lymph node groups are accessible by physical examination, as is the case with the mediastinal nodes and the abdominal para-aortic nodes. Although large abdominal lymphadenopathy can sometimes be palpated, it is often manifested through symptoms and signs determined by compression of neighboring structures, such as the superior vena cava and the source bronchi in the case of the mediastinum, and the lymphatic vessels and intestinal loops in paraaortic lymphadenopathy.

Nodal groups of greater semiological importance

1. Peripheral nodes
   1. Cervical: receive lymph from cephalic organs (scalp, facial skin, orbit, nose, ear, mouth).
   2. Supraclavicular: collect lymph from the mammary region and from abdominal and pelvic visceral regions through the thoracic duct.
   3. Axillary: lymph from most of the mammary region and upper limbs.
2. Deep nodes
   1. Mediastinal: lymph from the lung and bronchi.
   2. Paraaortic: they are the major tributaries of the lymphatic drainage of the abdominal and pelvic viscera.
   3. Inguinal (superficial and deep): lymph of the lower limbs and external genitalia.

A cut that passes through the hilum of a lymph node will allow the observation of three histologically well defined areas: the capsule, the cortical area and the medullary area.

1. The capsule, made up of connective tissue, scarce in its own cells and rich in collagen fibers, completely envelops the organ, penetrates it through the hilum and sends fibrous septa into the ganglion. On the way from the periphery to the interior, these partitions divide the ganglion into multiple incomplete locules and communicate with each other;
   
   
2. below the capsule is the cortical area. It consists of an area of ​​loose lymphatic tissue that surrounds the entire node (subcapsular sinus) and then nodular-looking formations rich in small lymphocytes on the periphery and with an abundance of large lymphocytes in the internal area. These nodules are the lymph follicles, almost completely surrounded by a prolongation of the subcapsular sinus called the peripheral sinus;
   
   
3. the medullary zone includes the medullary cords, which originate from the lymphatic follicles and anastomosing each other to form a reticule between whose meshes the medullary lymphatic sinuses pass, the site where the lymph circulates. This arrives through the afferent vessels, flows into the subcapsular sinus, runs through the peripheral sinuses, reaches the medullary sinuses, and penetrates the efferent vessels that transport it out of the ganglion. In its intraganglionic path, new cellular elements, coming from the follicles and spinal cords, are incorporated into the circulating lymph, while the fixed and free macrophages in the lymphatic tissue purify said lymph from foreign elements. The existence of valves favors that this circulation can only be done in the indicated direction.

The lymph node fundamentally fulfills functions of cellular formation (lymphocytes, monocytes in part and plasmacytes) and defense, through the production of circulating antibodies (globulins) and phagocytosis by means of reticular cells of the stroma itself.

Causes of lymphadenopathy

The mechanism through which the lymph node alteration occurs basically recognizes two causes, depending on whether reactivity (hyperplasia) or infiltration of cellular elements predominates. In turn, lymphadenopathies of reactive origin include infectious causes and non-infectious causes, such as collagen diseases, sarcoidosis and drugs.

Neoplastic diseases are the main causes of infiltration adenopathies, although other non-neoplastic conditions - such as systemic mast cell diseases and Gaucher disease - share the characteristic of infiltrating lymph nodes with cells that are pathological but not malignant due to their biological behavior.

Interrogation. As a reason for consultation, alone or associated with other symptoms such as fever, pain, anorexia.

Lymphadenopathy causes

1. Reactive
   1. Infectious:
      • Bacterial (tuberculosis, syphilis, gram-positive and gram-negative germ infections)
      • Viral (mononucleosis, AIDS and related syndromes, herpes zoster, adenovirus)
      • Fungal (histoplasmosis, coccidioidomycosis)
      • Parasitic (toxoplasmosis)
   2. Non-infectious
      • Sarcoidosis
      • Collagen diseases (lupus, rheumatoid arthritis)
      • By drugs (diphenylhydantoin, gold salts)
2. Infiltrative
   1. Non-neoplastic:
      • Histiocytosis
      • Systemic mast cell disease
   2. Neoplastic:
      • Chronic and acute lymphatic leukemia
      • Hodgkin's disease
      • Lymphomas
      • Metastatic tumors

Pain. It is very frequent in adenitis of bacterial or viral origin, especially in angina, dental phlegmons, otitis, furuncles of the skin, rubella, but it also occurs as a consequence of compression of nerve plexuses or visceral structures by masses of neoplastic tumor adenopathies, such as It is usually seen in lymphomas or advanced carcinomas. It is common to have joint pain in collagen diseases such as systemic lupus erythematosus and rheumatoid arthritis, conditions that can present, concomitantly, multiple lymphadenopathy.

Fever. Many diseases that cause lymphadenopathy also occur with fever, it is a fact that lacks specificity. An evening fever that ranges from 37.5ºC to 38.5ºC for more than twenty-five days and that occurs daily can be a manifestation of Hodgkin's disease or another lymphoma. Prolonged fever symptoms frequently accompany systemic lupus erythematosus and also tuberculosis. The majority of upper respiratory tract infections caused by lymphadenopathy can cause fever, which is generally acute in origin, peaks that can easily exceed 39ºC, and of short evolution (from hours to a few days).

Decay. It accompanies neoplastic diseases such as lymphomas, carcinomas, and leukemias; it is usually referred to as long-standing (weeks to months) and sometimes preceding the overt development of the disease.

Among infectious diseases, tuberculosis occurs with marked decline, and almost always with anorexia and weight loss. Systemic lupus erythematosus and rheumatoid arthritis present this symptom as one of the most common and persistent throughout its evolution. A retrovirus called HIV (human immunodeficiency virus), a virus that attacks human T lymphocytes, is accepted as being responsible for acquired immunodeficiency syndrome (AIDS) and its precursor states. The latter are called AIDS-related complex and feature a marked decline syndrome, fever, lymphadenopathy and unexplained weight loss that can persist for months or longer.

Dyspnoea. Compression of the lower respiratory tract due to cervical or mediastinal lymphadenopathy, almost always due to malignancies (thyroid, lung carcinoma, lymphomas), is a very frequent cause of dyspnea. If there is compression of the cervical trachea, there may be stridor similar to that of "false croup").

When the superior vena cava is compressed, dyspnea can be associated with "slavic edema," that is, cyanosis located in the face, neck, and upper regions of the chest, collateral circulation, and venous engorgement (superior vena cava syndrome).

Dyspnea is rarely caused by a parenchymal lung, as occurs in sarcoidosis. Certain types of lung cancer, bronchiolo-alveolar variety, are bilateral, and can present mediastinal lymphadenopathy and severe dyspnea.

Pruritus. It is usually seen in Hodgkin's disease with systemic manifestations. In this case, fever, weight loss and night sweats may also be detected. Rash, such as rubella, can be accompanied by itching, although it is rarely severe in such cases.

Patient history. It is interesting to know if there is or was close and frequent contact with tuberculosis patients, a history of venereal diseases (syphilis, contact with prostitutes or promiscuous homosexual relationships) given the possibility, in these circumstances, of the transmission of the AIDS-causing retrovirus. However, it must be remembered that hemophiliacs and drug addicts are also threatened by this disease.

Keeping cats is an important fact since these animals transmit toxoplasmosis, a parasitic disease.

Ingested medication may also play a role. An agent known as a producer of lymph node hyperplasia, and therefore lymphadenopathy, is diphenylhydantoin, used as an anticonvulsant; gold salts can also cause adenomegaly.

Sex and age are linked to different diseases. Rheumatoid arthritis and systemic lupus erythematosus predominate in young women relative to the opposite sex. Acute lymphoblastic leukemia is a disease that prevails in children and adolescents, while chronic lymphatic leukemia is clearly in the elderly and the elderly. Hodgkin's disease, in turn, has two incidence peaks, one located in adolescence (15-20 years) and another between 45 and 60 years.

Physical exam

Cervical and supraclavicular lymphadenopathies. Common causes include acute, bacterial, or viral infectious diseases. These agents produce angina, tonsil phlegmon, sinusitis, colds, otitis, and dental infections. Lymphadenopathy is often painful, mobile, and variable in size. In extreme cases they can suppurate and produce an external (cutaneous) fistula. They remit with the definitive cure of the septic focus, although sometimes it may persist, as a consequence of some enlarged and indurated node.

In the adult, the progressive and asymptomatic appearance of hard, painless and fixed cervical lymphadenopathy should lead to suspicion of the possible existence of carcinoma of the oropharynx or larynx.

Hodgkin's disease in its localized stages usually occurs, either in the adolescent or in the adult, with unilateral or bilateral cervical lymphadenopathy.

Large cervical lymphadenopathies accompanied by cryptic tonsillitis are seen in infectious mononucleosis, a viral condition that can be manifested by systemic lymphadenopathy and splenomegaly. The disease resolves after two to four weeks with remission of the lymphadenopathy.

Other systemic diseases that cause cervical lymphadenopathy as part of generalized lymph node involvement include acute lymphoblastic leukemia, chronic myeloid leukemia, and chronic lymphatic leukemia, as well as certain non-Hodgkin-type lymphomas.

In adult women, the detection of supraclavicular lymphadenopathy can lead to examination of the axillary and mammary regions for nodules that can lead to breast carcinoma. The existence of cervical lymphadenopathy may indicate metastasis from a thyroid carcinoma, just as a hard left retroclavicular node may correspond to a metastasis from gastric carcinoma.

Lymphatic and mediastinal lymphadenopathy. They are not detectable on physical examination unless, due to their size or location, they cause symptoms or signs due to understanding or invasion of neighboring organs, such as cough, dyspnea, jugular engorgement or edema in clavina. Radiology plays the necessary diagnostic role in these cases.

The radiological finding of lymphadenopathy in both pulmonary hilies, in an asymptomatic patient, should lead to suspicion of sarcoidosis, a rare systemic disease but with pulmonary manifestations in about 90% of affected individuals.

In the case of multiple mediastinal lymphadenopathies, as usually produced by lymphomas, carcinoma of the lung, testis, and other carcinomas, the mediastinum is enlarged and polylobed in appearance due to the presence of numerous pathological nodes.

Unilateral hilar lymphadenopathy is usually a sequel to primary infection tuberculosis.

Axillary lymphadenopathy. When they are unilateral and hard, or even of elastic consistency, and they appear in a young or adult woman of any age, it is necessary to examine the breasts looking for tumors. The fact of not finding suspicious nodules in one or both breasts does not rule out the possibility of breast cancer, since one of the clinical forms of onset is through lymph node metastasis in the armpit, without palpable tumor.

Axillary whitlow, furuncles and hydrosadenitis, and infectious processes of the upper limbs, are other causes of lymphadenopathy in the armpit and in these cases there are the manifestations corresponding to the inflammatory process both locally and in the axillary nodes.

Systemic diseases have multiple lymphadenopathies, among which bilateral axillary nodes can be detected.

Inguinal lymphadenopathy (superficial and deep). It is very common to find small unilateral or bilateral lymphadenopathy, either in children or adults, since multiple factors such as sports, trauma, mycosis of the nails and feet, among others, can produce lymphadenopathy that are usually discovered accidentally since they are not usually painful. In these cases, the size and presence or absence of associated symptoms and signs should be ranked.

Cancer of the penis in men and carcinoma of the vulva in women should be considered if hard, painless, poorly mobile, and bilateral lymphadenopathy are found.

Lymphomas often occur with inguinal lymphadenopathy, which is generally part of systemic lymphadenopathy, since the presentation as a localized stage in the abdomen is of low incidence.

Generalized lymphadenopathy. They are considered as an expression of a systemic disease. The causes of multiple lymphadenopathy are numerous and range from diseases such as syphilis to AIDS and its related symptom complex. The latter is characterized by presenting itself mainly in promiscuous homosexuals, evolving over months or years, and in numerous cases progressing to acquired immunodeficiency syndrome. Painless and soft multiple lymphadenopathy, fever without apparent focus, weight loss and diarrhea are the outstanding signs of this disease.

Syphilis manifests with generalized lymphadenopathy during the secondary period. The nodes are not painful, their size is small and they can be displaced on the deep planes. Extensive mucocutaneous lesions are characteristic here.

Toxoplasmosis can occur in adults with lymphadenopathy and prolonged febrile syndrome. The nodes are usually large, hard, not painful, and the cervical groups are usually affected.

Another parasitic condition is Chagas disease. In the acute form, the local symptoms and signs caused by the bite of the vinchuca are accompanied by fever, small lymphadenopathy, discrete hepatosplenomegaly and sometimes peripheral edema.

Systemic lupus erythematosus and rheumatoid arthritis present generalized lymphadenopathy, but always in the context of other more notable symptoms and signs, such as prolonged fever, marked asthenia, and arthralgias in lupus and the infallible bilateral and symmetrical arthritis in arthritis. rheumatoid.

Malignant diseases of the lymphatic system are among the most frequent causes of systemic lymphadenopathy.

Acute lymphoblastic leukemia, lymphomas, and Hodgkin's disease usually present with similar symptoms and signs in children and young adolescents, so that the differential diagnosis will be achieved through a biopsy examination, either of a lymph node or bone marrow.

The adult is characterized by a low incidence of acute lymphoblastic leukemia, compared to that of the child and the adolescent. Chronic lymphatic leukemia and Hodgkin lymphomas are observed in those over 60 years of age.

Chronic lymphatic leukemia is a slowly evolving pathology with a variable asymptomatic period, which in the clinic is manifested by multiple, usually large and hard adenomegalies.

Certain drugs, such as diphenylhydantoin, used as an anticonvulsant, can cause a generalized lymphadenopathy syndrome similar to that of a lymphoma. Histologically, only lymph node hyperplasia is observed without evidence of malignancy at the level of the lymph reticulum and follicles.

In children younger than three years, a syndrome of polyadenopathy, hepatosplenomegaly, low-grade fever, and maculopapular erythema may be due to malignant histiocytosis, non-neoplastic infiltrative disease, of very low incidence, but which may manifest an aggressive course. Histologically, the lesions are granulomas formed by accumulations of histiocytosis and eosinophils.

Similar findings are reported in systemic mast cell disease. This disorder affects male adults and is rare. It is now accepted that both malignant histiocytosis and mast cell disease are closely related.

Rare systemic diseases are causes of lymphadenopathy that frequently require biopsy for diagnosis.

• Castleman's disease. Angiofollicular lymph node hyperplasia, characterized by massive lymphadenopathy, fever, hepatosplanomegaly, polyclonal hypergammaglobulinemia, and rarely amyloidosis. This multicenter disease can be fatal if not treated with chemotherapy.
• Kikuchi disease. Rare disease of unknown cause and benign course, more common in young women. She presents cervical lymphadenopathies (although they can be generalized) and fever. The histopathology of the lymph nodes can be confused with lymphoma.
• Kawasaki disease. Most common cause of vasculitis in children. The syndrome consists of fever, cervical lymphadenopathy, conjunctivitis, mucositis, skin rash, and coronary artery aneurysms.
• Progressive transformation of germinal centers. It usually presents as persistent or recurrent, asymptomatic and unexplained lymphadenopathy.

Diagnostic methodology

Laboratory

The rate of globular erythrosedimentation (ES) is elevated in diseases such as lymphomas and leukemias, although a limit cannot be established in these cases. Systemic lupus erythematosus and rheumatoid arthritis usually present with ES of 100 mm or more in the first hour. The treatment, when successful, produces a decrease in the SE values.

Infections, whether localized or systemic, are capable of elevating erythrocyte sedimentation, as well as any disease that produces dysproteinemia.

The blood count; In the case of white blood cells, the numerical increase may be due to infectious foci and systemic infections, but also to acute and chronic leukemias and sometimes lymphomas. Large leukocytosis, with numbers greater than 30,000, and even more than 50,000 white blood cells, are compatible with leukemias. A decrease in the number of white blood cells can be observed as an expression of medullary cytotoxicity by antineoplastic drugs. Bacteria, especially golden staphylococcus and gram-negative germs, can produce myelotoxicity through their circulating toxins. Infectious mononucleosis presents with a slight initial leukocytosis, and then presents leukopenia. The examination of the red series allows to recognize an anemia in any of its variants on the basis of the morphological description of the red cells and to suspect the probable cause. In chronic diseases, whether infectious or neoplastic, it is common to find morphologically normocytic and normochromic anemia due to the difficulty in iron uptake by the bone marrow.

As for the platelet series, it can be diminished in cases of proliferative diseases such as leukemias due to the displacement it causes on it. Peripheral thrombocytopenia can also express the action of myelosuppressive drugs.

Peripheral blood smear is a common diagnostic method for detecting malignant cells, as occurs in most leukemias and in certain cases of terminal non-Hodgkin lymphoma.

Examination of urine and urinary sediment reflect abnormalities in kidney function. Urinary density may be low (1,010 or less) if there is renal failure due to lymphomatous invasion or lupus nephritis. In the latter case, variable proteinuria is also seen, and red cells and granular casts can be seen in the sediment. Infections in general, when systemic, can favor the appearance of proteinuria and red blood cells in the urinary sediment.

Anti-nucleus factor (FAN) is an immunofluorescent antibody agglutination reaction that gives strongly positive results in about 45% of patients with systemic lupus erythematosus. The latex test, when it is frankly positive, suggests the possibility of rheumatoid arthritis, especially in the presence of compatible symptoms and signs.

The VDRL reaction identifies sick patients with active syphilis. The test to determine antitreponema antibodies by immunofluorescence (FTA) assesses the state of immunity to Treponema pallidum and is useful for the diagnosis of syphilis in asymptomatic people with no recognized history.

The Sabin and Feldman test is used for the diagnosis of toxoplasmosis. The indirect fluorescent antibody reaction (IFA), when positive at a dilution of 1024 or greater, indicates acute toxoplasmosis. The monotest and the Paul Bunnell Davidson reaction are positive in cases of infectious mononucleosis.

The examination of serum proteins by electrophoresis allows to assess the nutritional status of the patient and the status of the circulating antibodies by means of the gamma globulin count. The latter can be elevated due to the increase of one or more of its fractions, as it can happen in lymphomas, carcinomas, systemic lupus erythematosus, rheumatoid arthritis and several other systemic diseases. Other fractions, such as alpha-2-globulins, can be increased in the course of infections, especially in those that are not focused.

Diagnostic imaging

Radiology. Teleradiography continues to be used as the initial procedure for the evaluation of the chest, and allows detection of enlargements of the mediastinum, hilar lymphadenopathy and parenchymal images of the condensing or nodular type, as can be seen in cases of lung infections and tumors, whether primitive or metastatic.

Linear tomography . Currently deprecated in the daily clinic. It continues to be used for evaluation of dental arches. In its most frequent use of yesteryear with regard to the evaluation of pulmonary images, it has been completely replaced by chest computed tomography.

Scintigraphy on gamma camera. It allows a correct visualization of the skeleton through the deposit of a radioisotope that acts as a tracer. When this isotope is deposited in increasing amounts at a certain site, it generates an increase in uptake, which is often the expression of a pathological process. It is a useful method to detect destructive lesions at the bone level, as occurs in neoplasms; however, strictly inflammatory diseases, such as rheumatoid arthritis, can produce images that are impossible to differentiate from those of a neoplastic lesion, although similar doubts may arise with common radiographs. Scintigraphy can also be used on the brain, liver, spleen, and kidney, but it provides less information on these organs than computed axial tomography and ultrasound.

Ultrasound It has its maximum application in the study of the cardiac cavities, the abdomen and the pelvis. It is useful to visualize the head of the pancreas, liver, gallbladder, gynecological and thyroid organs.

Computed axial tomography (CAT). In the thorax, it has advantages over conventional radiology in terms of perception of small and deep parenchymal images. It shows well the nodes of the aortic window and other mediastinal areas, which are inscrutable with flat radiographs. At the abdomen and pelvis level, it allows to discriminate tumor masses of retroperitoneal location, such as lateroaortic lymphadenopathies, renal tumors and liver metastases; in addition, by using an intravenous contrast medium, it enables the functional examination of both urinary tract.

Nuclear magnetic resonance. It is a very useful imaging methodology, even superior to computed axial tomography to detect lesions in the central nervous system, being able to differentiate between areas of hemorrhage and tumor mass, it also has good definition for cerebral edema and can reveal tumor invasion of the meninges . In the case of lymphadenopathy, it does not seem to provide advantages over the information provided by the computed axial tomography.

Biopsy

With regard to adenopathy, it is preferable that the material be obtained by excision of a node rather than by puncture and aspiration, since in the first case the examination of the complete piece allows for more tissue to be studied, to gain knowledge of the state of the lymph node architecture, and obviate the risk of falling into lymph node areas that eventually do not contain pathology or that are not clearly representative of it, as can happen when performing an aspiration needle puncture.

Lymph node biopsy is required as an essential element for the diagnosis of Hodgkin's disease and lymphomas and needs its complement by immuno-histochemical techniques since in this way cell populations can be differentiated based on their dominant antigens (CD5 +, CD20 + , CD33 +, etc). This nowadays constitutes the necessary basis for the diagnosis and consequently for the correct choice of treatment.

Other times the lymph node biopsy, although it defines a neoplasm, does not allow it to be typified because it is a metastasis, and in this sense the typical case is any carcinoma that invades a lymph node.

In patients with toxoplasmosis, intracellular parasites can be observed in the extracted lymph node with the corresponding histochemical preparation.