 |
|||||||||
|
|||||||||
| CECIL |
| TEXT BOOK of MEDICINE |
Section XIV Hematologic Diseases
| 174 APPROACH TO THE PATIENT WITH LYMPHADENOPATHY AND SPLENOMEGALY James O. Armitage • |
|
|
LYMPHADENOPATHY
Physiology and Anatomy
Lymph nodes are found throughout the body along the course of lymphatics, strategically located to allow filtering of lymphatic fluid and interdiction of microorganisms and abnormal proteins. Lymphatic fluid enters the node in afferent lymphatic vessels that empty into the subcapsular sinus. The fluid then transverses the node and exits in a single efferent lymphatic vessel. In doing so, the lymph and its contents are exposed to immunologically active cells throughout the node. Lymph nodes are populated predominantly by macrophages, dendritic cells, B lymphocytes, and T lymphocytes. B lymphocytes are located primarily in the follicles and perifollicular areas, whereas T lymphocytes are found principally in the interfollicular or paracortical areas of the lymph node. These cells function together to provide antigen processing, antigen presentation, antigen recognition, and proliferation of effector B and T lymphocytes as part of the normal immune response to microorganisms or foreign proteins.
Because the normal immune response leads to proliferation and expansion of one or more of the cellular components of lymph nodes, it also often leads to significant lymph node enlargement. In young children, who are continuously undergoing exposure to new antigens, palpable lymphadenopathy is the rule. In fact, the absence of palpable lymphadenopathy would be considered abnormal. In adults, lymph nodes larger than 1 to 2 cm in diameter are generally considered abnormal. However, lymph nodes 1 to 2 cm in diameter in the groin are sufficiently common to often be considered “normal.”
Lymphoid proliferation is a normal response to exposure to foreign antigens. The location of the enlarged lymph nodes will often reflect the site of invasion. For example, cervical lymphadenopathy would be typical in a patient with pharyngitis. Generalized immune proliferation and lymphadenopathy can occur with a systemic disorder of the immune system, disseminated infection, or disseminated neoplasia. Malignancies of the immune system might be manifested as localized or disseminated lymphadenopathy.
Differential Diagnosis
The differential diagnosis of lymphadenopathy (Table 174-1) is vast, with the underlying causes responsible for either proliferation of immunologically active cells or infiltration of the lymph node by foreign cells or substances. In practice, the cause of enlarged lymph nodes is often not certain even in retrospect; in such cases, unrecognized infectious processes are generally blamed.
Click here to view this table....
Infections by bacteria, mycobacteria, fungi, chlamydiae, parasites, and viruses are the major causes of lymph node enlargement. Lymph nodes in the drainage area of essentially all pyogenic infections can enlarge. In certain infections such as bubonic plague caused by Yersinia pestis, dramatic regional lymph node enlargement with fluctuant lymph nodes (i.e., buboes) can be a hallmark of the disease (Chapter 333). Other bacterial infections have lymph node enlargement as a prominent feature (e.g., cat-scratch disease, Chapter 336) and can mimic lymphoproliferative disorders. Mediastinal lymphadenopathy is seen in inhalational anthrax (Chapter 317). In some parts of the world, cervical lymphadenopathy is a sufficiently frequent manifestation of tuberculosis to lead to the institution of antituberculous therapy rather than biopsy. Disseminated lymphadenopathy can be seen in cases of infection by a variety of organisms, such as Toxoplasma, Epstein-Barr virus (i.e., infectious mononucleosis), cytomegalovirus, and human immunodeficiency virus.
A variety of nonmalignant disorders of the immune system can lead to localized or disseminated lymphadenopathy. Autoimmune diseases such as rheumatoid arthritis (Chapter 285) and systemic lupus erythematosus (Chapter 287) often have accompanying lymphadenopathy, which can pose a diagnostic challenge because of the increased incidence of lymphoma in patients with these disorders. In the lymphadenopathy that occurs as a reaction to drugs such as phenytoin, lymph node biopsy findings can sometimes be confused with those of lymphoma. Benign proliferative diseases of the immune system that can also be confused with lymphoma include Castleman's disease (Chapter 196; angiofollicular lymph node hyperplasia), sinus histiocytosis with massive lymphadenopathy, and disorders seen more frequently in Asia, such as Kawasaki syndrome (Chapter 465) and Kimura's disease.
All of the cells in the immune system can become malignant. Several of these malignancies are typically manifested as lymphadenopathy, and it can be seen in all. Lymphadenopathy as the initial manifestation is the rule for Hodgkin's disease and non-Hodgkin's lymphoma and is common in Waldenström's macroglobulinemia and B-cell chronic lymphocytic leukemia, but it is only occasionally seen in the myeloid leukemias (Chapters 194 through 198). Malignancies of all organ systems can metastasize to the lymph nodes and cause lymphadenopathy, which is usually seen in the drainage area of the primary tumor, for example, axillary lymph nodes in patients with breast cancer, hilar and mediastinal lymph nodes in patients with lung cancer, and cervical lymph nodes in patients with head and neck cancer. However, widespread lymphadenopathy can also occur with many solid tumors.
Other disorders that can have lymphadenopathy as an initial finding include storage diseases such as Gaucher's disease (Chapter 223), endocrinopathies such as hyperthyroidism (Chapter 244), sarcoidosis (Chapter 95), and dermatopathic lymphadenitis. Amyloidosis (Chapter 296) can cause lymphadenopathy in patients with multiple myeloma, hereditary amyloidosis, or amyloidosis associated with chronic inflammatory states.
Among patients with lymphadenopathy actually seen in practices in the United States, diagnoses will not be determined in a high proportion (Table 174-2). In such cases, the lymphadenopathy will usually be blamed on infection. When the lymphadenopathy is in the drainage site of a known infection (e.g., cervical lymphadenopathy in a patient with pharyngitis) or the patient has a known infection associated with lymphadenopathy (e.g., infectious mononucleosis; Chapter 400), this infectious assumption is usually correct. Alternatively, if a patient has an immunologic disorder that is known to cause lymphadenopathy, such as rheumatoid arthritis, this disorder is usually an acceptable explanation; however, progressive lymphadenopathy in such patients should trigger a biopsy because these patients are at increased risk for lymphoma. Localized, progressive lymphadenopathy, particularly when associated with fever, sweats, or weight loss, requires biopsy to exclude lymphoma.
Click here to view this table....
Lymph Node Evaluation
Evaluation of a patient with lymphadenopathy includes a careful history, a thorough physical examination, laboratory tests, and sometimes imaging studies to determine the extent and character of the lymphadenopathy. The age of the patient and any associated systemic symptoms might be important hints in the evaluation (Table 174-3). Cervical lymphadenopathy in a child would be much less worrisome than equally prominent lymphadenopathy in a 60-year-old adult. The occurrence of fever, sweats, or weight loss raises the possibility of a malignancy of the immune system. The explanation for the lymphadenopathy might become apparent by identification of a site of infection, a particular medication, a travel history, or a previous malignancy.
Click here to view this table....
Physical examination allows the identification of localized versus widespread lymphadenopathy. The particular sites of involvement can be important hints to the diagnosis inasmuch as infections and carcinomas are likely to cause lymphadenopathy in the lymphatic drainage of the site of the disorder. In general, lymph nodes that are tender are more likely to be due to an infectious process, whereas painless adenopathy raises concern for malignancy. Lymph node consistency can also aid in the diagnosis: typically, lymph nodes containing metastatic carcinoma are rock hard, lymph nodes containing lymphoma are firm and rubbery, and lymph nodes enlarged in response to an infectious process are soft.
The larger the lymph node, the more likely that a serious underlying cause exists; lymph nodes greater than 3 to 4 cm in diameter in an adult are very worrisome. Physical examination to assess lymph node size is only marginally accurate and reproducible, although it is by far the most widely used method. More precise methods are available with various imaging techniques.
Imaging
Imaging studies, including routine radiographs or computed tomography (CT), ultrasonography, lymphangiography, magnetic resonance imaging, gallium scans, and positron emission tomography, are the only methods that can be used to assess the extent of lymphadenopathy in the chest and abdomen (Table 174-4). Chest radiographs provide the most economical and easiest method to assess mediastinal and hilar lymphadenopathy but are not as accurate as CT of the chest. Although the technique is no longer widely available, lymphangiography provides an extremely accurate assessment of the lower abdominal lymph nodes and, because of retained contrast material, allows repeat examinations and assessment of response to therapy. CT and ultrasonography are the most useful modalities for assessing abdominal and retroperitoneal lymphadenopathy. In most patients, CT is probably the most accurate approach, but ultrasonography has the advantage of being less expensive and not requiring radiation exposure. Magnetic resonance imaging and positron emission tomography are not first-line studies for the assessment of lymphadenopathy. Positron emission tomography is frequently positive in patients with Hodgkin's disease and aggressive non-Hodgkin's lymphomas and can be used to assess the presence of active lymphoma in patients with lymphadenopathy and a proven diagnosis; they are especially useful for re-evaluating patients after therapy because lymph nodes do not always regress to normal size after treatment, particularly those in the mediastinum and retroperitoneum.
Click here to view this table....
Interventional Evaluation
Lymph node aspiration or biopsy is often necessary for an accurate diagnosis of the cause of the lymphadenopathy. Fine-needle aspiration is currently popular and is often an accurate means of diagnosing infection or carcinoma involving a lymph node. Although lymphomas can occasionally be diagnosed with this approach, it is inappropriate as an initial diagnostic maneuver for lymphoma. Cutting needle biopsy will occasionally provide sufficient material for an unequivocal diagnosis and subtyping of the lymphoma. However, excisional biopsy, which is most likely to provide the pathologist with adequate material to perform histologic, immunologic, and genetic studies, is the approach most likely to yield the correct diagnosis.
An Approach to the Patient with Lymphadenopathy
Patients with lymphadenopathy (Table 174-5) come to medical attention in several ways. Perhaps the most common is a patient who has felt a lymph node in the neck, axilla, or groin and then seeks a physician's opinion. Lymphadenopathy might also come to medical attention as an unexpected finding on routine physical examination or as part of evaluation for another complaint. Finally, patients might be found to have unexpected lymphadenopathy on imaging studies of the chest or abdomen. When the nodes are multiple or larger than 2 to 3 cm, biopsy via mediastinoscopy, a paramediastinal incision, laparoscopy, or laparotomy is often required for diagnosis.
Click here to view this table....
The approach to a patient complaining of newly discovered lymphadenopathy in the neck, axilla, or groin depends on the size, consistency, and number of enlarged lymph nodes and the patient's general health. In most cases, very large or very firm lymph nodes in the presence of systemic symptoms such as unexplained fever, sweats, or weight loss should lead to lymph node biopsy. Patients who have enlarged lymph nodes in the drainage area of a previously treated malignancy (e.g., neck nodes in a patient with a history of head and neck cancer) might be best approached by lymph node aspiration. Carcinoma can often be diagnosed in this manner, although it is a poor approach for the diagnosis of lymphoid malignancies. For the cervical lymph nodes, excisional biopsy should be delayed in a patient who has head and neck cancer (Chapter 200) as a diagnostic consideration. These patients should initially undergo careful ear, nose, and throat examinations to avoid performing a biopsy that can complicate the patient's subsequent therapy.
For the most common situation, in which a lymph node is soft and not larger than 2 to 3 cm and the patient has no obvious systemic illness, observation for a brief period is usually the best approach. Performance of a complete blood cell count and examination of a peripheral smear can be helpful in recognizing a systemic illness (e.g., infectious mononucleosis) (see Fig. 161-35). These patients are often also given antibiotics. If the lymph node does not regress over the course of a few weeks or if it grows in size, a biopsy should be performed.
Part of the care of such patients involves the art of medicine and responsiveness to the patient's particular needs. For example, biopsy might be performed more quickly in a patient who is very anxious about malignancy or who needs a definitive diagnosis expeditiously.
SPLENOMEGALY
Definition
The spleen is the largest lymphatic organ in the body and is sometimes approached clinically as though it were a very large lymph node. However, although it also participates in the primary immune response to invading microorganisms and foreign proteins, the spleen has many other functions. It functions as a filter for the blood and is responsible for removing senescent red blood cells from the circulation, as well as blood cells and other cells coated with immunoglobulins. Blood enters the spleen, filters through the splenic cords, and is exposed to immunologically active cells in the spleen.
The splenic red pulp occupies more than half the volume of the spleen and is the site where senescent red cells are identified and destroyed and red blood cell inclusions are removed by a process known as pitting. In the absence of splenic function, basophilic inclusions known as Howell-Jolly bodies are seen in circulating red blood cells. The presence of Howell-Jolly bodies (Fig. 174-1) in peripheral blood indicates that the patient has undergone splenectomy or has a process that has rendered the spleen nonfunctional (e.g., sickle cell disease with repeated splenic infarcts and chronic graft-versus-host disease).
 |
| FIGURE 174-1 A Howell-Jolly body in an erythrocyte, evidence of splenectomy or a nonfunctional spleen. |
The white pulp of the spleen contains macrophages, B lymphocytes, and T lymphocytes; participates in the recognition of microorganisms and foreign proteins; and is involved in the primary immune response. Absence of this splenic function makes individuals particularly sensitive to certain infections, including sepsis with encapsulated organisms such as Streptococcus pneumoniae. The risk for overwhelming sepsis is related to the age at the time of splenectomy or other cause of loss of splenic function. Children and young adults are at highest risk. If possible, all patients should undergo vaccination against S. pneumoniae (Chapter 16) before splenectomy. Some physicians have patients take oral penicillin (penicillin VK, 250 mg twice daily) indefinitely if splenectomy has been performed in childhood or adolescence.
Pathobiology
As with lymphadenopathy, the conditions associated with splenomegaly are extremely numerous (Table 174-6). Certain bacterial infections such as endocarditis (Chapter 76), brucellosis (Chapter 331), and typhoid fever (Chapter 329) have splenomegaly as a frequent manifestation. Disseminated tuberculosis (Chapter 345) is often associated with splenomegaly, and splenomegaly can also be seen in cases of disseminated histoplasmosis (Chapter 353) and toxoplasmosis (Chapter 370). Splenomegaly is an almost constant accompaniment of malaria (Chapter 366). Rickettsial disorders such as Rocky Mountain spotted fever are frequently associated with splenomegaly. A wide variety of viral infections typically cause splenomegaly, including infectious mononucleosis associated with Epstein-Barr virus (Chapter 400) and viral hepatitis (Chapter 151). Splenomegaly can accompany human immunodeficiency virus infection. Splenic abscesses, which are usually the result of hematogenous spread of pyogenic organisms, represent an unusual and difficult-to-diagnose cause of splenomegaly.
Click here to view this table....
Splenomegaly is also seen in a variety of benign disorders of the immune system, including rheumatoid arthritis (Chapter 285), in which some patients will have Felty's syndrome and accompanying granulocytopenia. Splenomegaly is frequently detected in patients with systemic lupus erythematosus (Chapter 287), certain drug reactions, and serum sickness.
Malignancies of the immune system and nonimmune organs can also lead to splenomegaly. Splenomegaly is usually seen in patients with chronic myeloid leukemia and is frequent in chronic lymphoid leukemia (Chapter 195). It can develop in patients with acute myeloid or lym-phoid leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, and Waldenström's macroglobulinemia (Chapters 196 to 198) but is rare in multiple myeloma (Chapter 198). The condition previously known as angioimmunoblastic lymphadenopathy, which is now usually thought to represent a T-cell lymphoma, often has splenomegaly as one manifestation. Isolated splenomegaly (i.e., without any enlarged lymph nodes) is characteristic of certain immune system malignancies, including hairy cell leukemia (Chapter 195), the prolymphocytic variant of chronic lymphocytic leukemia (Chapter 195), and splenic marginal zone lymphoma (Chapter 197). Metastasis of carcinomas and sarcomas to the spleen is unusual except for malignant melanoma; even with melanoma, however, palpable splenomegaly is an unusual finding.
Splenomegaly can develop as a result of increased pressure in the splenic circulation, especially in patients with portal hypertension caused by a variety of hepatic disorders, including alcoholic cirrhosis (Chapter 157). However, it also can be due to splenic or portal vein thrombosis.
Hematologic disorders that can lead to palpable splenomegaly include autoimmune hemolytic anemia, hereditary spherocytosis, and a number of other anemias (Chapters 164, 165, and 167). In cases of idiopathic myelofibrosis, the spleen is frequently a site of extramedullary hematopoiesis (Chapter 177).
A variety of less common conditions can lead to splenomegaly. The storage disorder Gaucher's disease (Chapter 223) is usually manifested as splenomegaly. Splenomegaly can be seen in endocrinopathies such as hyperthyroidism (Chapter 244). Sarcoidosis (Chapter 95) and amy-loidosis (Chapter 296) can be manifested as splenomegaly. Tropical splenomegaly is a term used to describe the palpable spleens found in patients who live in tropical areas and might have numerous causes.
Diagnosis
Evaluation of Splenic Size and Function
Physical Examination
The ability to perform an accurate physical examination and determine the presence of an enlarged spleen (Table 174-7) is an important skill, but it is not easily learned. Physical examination of the spleen can be performed with the patient supine or in the right lateral decubitus position. Inspection, percussion, auscultation, and palpation can all be important in accurate assessment. It is rare to have a spleen so large that it is visible and can be seen to move with respiration. However, in patients with such a condition, it is possible to miss the splenomegaly by failing to start palpation sufficiently low to find the edge. Occasionally, percussion of the left upper quadrant will help identify an area of dullness that moves with respiration and can lead to the identification of splenomegaly. Splenic size is generally recorded as the number of centimeters that the spleen descends below the left costal margin in the midclavicular line on inspiration. Although auscultation is not usually a regular part of splenic examination, the existence of a splenic rub on inspiration can lead to the diagnosis of splenic infarction. The left kidney is sometimes confused with the spleen on physical examination, but its failure to move with respiration in the manner typical for the spleen will usually allow distinction.
Click here to view this table....
Laboratory Evaluation
Laboratory studies are frequently valuable in assessing splenic function. In patients with an absent or nonfunctional spleen, Howell-Jolly bodies will be seen in circulating red blood cells (see Fig. 174-1). Splenic hyperfunction (a condition often referred to as hypersplenism) is associated with cytopenias: the spleen is the normal reservoir for a significant proportion of platelets, and this reservoir function can lead to thrombocytopenia in patients with splenomegaly. Patients with autoimmune hemolytic anemia usually have palpable splenomegaly, but patients with idiopathic (immune) thrombocytopenic purpura usually do not.
The spleen can be imaged with ultrasonography, CT, traditional radionuclide scans, and positron emission tomography (Fig. 174-2). Ultrasonography can provide accurate determination of splenic size and is easy to repeat. CT will frequently give a better view of the consistency of the spleen and can identify splenic tumors or abscesses that would otherwise be missed. Positron emission tomography can aid in evaluating focal lesions in the spleen. The technetium-labeled liver-spleen scan can be important in identifying liver disease as the cause of splenomegaly; in patients with cryptogenic cirrhosis who are found to have thrombocytopenia, a technetium liver-spleen scan that shows higher activity in the spleen than in the liver might be the initial hint of liver disease.
 |
| FIGURE 174-2 Enlarged spleen with metastatic adenocarcinoma. |
Because of the spleen's location and its propensity to bleed, needle aspiration or cutting needle biopsy of the spleen is rarely performed. In general, splenic “biopsy” involves splenectomy, which can be performed at the time of laparotomy or via laparoscopy. However, performing splenectomy laparoscopically usually leads to maceration of the organ and can reduce the diagnostic information. In very young children, in whom splenectomy causes a high risk for serious infections such as pneumococcal septicemia, partial splenectomy can sometimes be performed. Patients who undergo splenectomy at the time of splenic trauma and rupture can have seeding of splenic cells to other sites in the abdomen. Some patients have additional small or accessory spleens. Persistent, functional splenic tissue can be the explanation for recurrent immune thrombocytopenia after splenectomy and might be recognized by the absence of Howell-Jolly bodies in circulating red blood cells.
An Approach to the Patient with Splenomegaly
Patients with splenomegaly (Table 174-8) may come to medical attention for a variety of reasons. Patients may complain of left upper quadrant pain or fullness or early satiety. A splenic infarct, which is typically manifested as left upper quadrant pain that sometimes radiates to the left shoulder, can be the first clue to the existence of an enlarged spleen. Rarely, splenomegaly can initially be manifested by the catastrophic symptoms of splenic rupture. Some patients are found to have splenomegaly as a result of evaluation for unexplained cytopenia. Splenomegaly can be discovered incidentally on physical examination. In recent years, splenomegaly has been frequently discovered on imaging studies of the abdomen performed for other purposes.
Click here to view this table....
The presence of a palpable spleen on physical examination is almost always abnormal. The one exception to this rule is a palpable spleen tip in a slender, young woman. In general, the presence of a palpable spleen should be considered a serious finding, and an explanation should be sought. It is less clear whether the same rules would apply to borderline splenomegaly discovered incidentally on routine imaging studies.
The approach to a patient with an enlarged spleen should focus initially on excluding a systemic illness that could explain the splenomegaly. Infectious mononucleosis, leukemia or lymphoma, rheumatoid arthritis, sarcoidosis, cirrhosis of the liver, malaria, and a host of other illnesses would be accepted as a reasonable explanation for the splenomegaly. The systemic condition should be treated and then the spleen should be re-evaluated. If the systemic illness can be treated successfully, the spleen should regress to normal size over time.
Patients with no obvious explanation for an enlarged spleen present a difficult diagnostic problem. Careful follow-up of these patients sometimes reveals occult liver disease or an autoimmune process that initially defied diagnosis. Concerns about malignancy, particularly in patients with systemic symptoms such as fever, sweats, or weight loss or in patients in whom imaging studies show a focal abnormality, are sometimes indications for splenectomy. However, in the absence of such findings, it is generally preferable to monitor patients closely with repeated attempts to establish the diagnosis by approaches other than splenectomy. It is particularly important to avoid splenectomy in a patient with occult liver disease and portal hypertension.
Splenectomy was once performed routinely as part of the staging evaluation for Hodgkin's disease or other lymphomas (Chapters 196 and 197). Today, this procedure is rarely needed to choose the correct therapy, and it should generally be avoided. Splenectomy can be an effective therapy for immune thrombocytopenic purpura (Chapter 179) and autoimmune hemolytic anemia (Chapter 164) and can occasionally be an appropriate therapy to relieve cytopenia in other conditions such as advanced myelofibrosis (Chapter 177).
|
|