Lymphadenopathy and malignancy

Author: Andrew W. Bazemore, Douglas R. Smucker
Date: Dec 1, 2002

Lymphadenopathy, which is defined as an abnormality in the size or character of lymph nodes, is caused by the invasion or propagation of either inflammatory cells or neoplastic cells into the node. It results from a vast array of disease processes (Table 1), (1) whose broad categories are easily recalled using the mnemonic acronym "MIAMI," representing Malignancies, Infections, Autoimmune disorders, Miscellaneous and unusual conditions, and latrogenic causes. A common finding in the primary care outpatient setting, lymphadenopathy is typically explained by identifiable regional injury or infection. Among the serious illnesses that can present with lymphadenopathy, perhaps the most concerning to the patient and physician alike is the possibility of underlying malignancy.

The prevalence of malignancy is thought to be quite low among all patients with lymphadenopathy. Few studies define the prospective risk of malignancy with adenopathy, but three case series support the suggestion that the risk is very low. In two studies, (2,3) three of 238 and zero of 80 patients presenting with unexplained lymphadenopathy were determined to have malignancies, while a third study (4) retrospectively found a 1.1 percent prevalence of malignancy in primary care patients presenting to the office with unexplained lymphadenopathy.

Essential to identifying the infrequent but serious causes of peripheral lymphadenopathy are the following: an awareness of lymphatic anatomy, drainage patterns, and regional differential diagnosis; a thorough history including key factors such as age, location, duration, and patient exposures; and a focused physical examination according to the location of lymphadenopathy.

Historical Clues

AGE AND DURATION

The rate of malignant etiologies of lymphadenopathy is very low in childhood, but increases with age. Lymph nodes are palpable as early as the neonatal period, and a majority of healthy children have palpable cervical, inguinal, and axillary adenopathy. (5) The vast majority of cases of lymphadenopathy in children is infectious or benign in etiology. (6) In one series (7) of 628 patients undergoing nodal biopsy, benign or self-limited causes were found in 79 percent of patients younger than 30 years of age, versus 59 percent in patients 31 to 50 years of age and 39 percent in those older than 50 years. Lymphadenopathy that lasts less than two weeks or more than one year with no progressive size increase has a very low likelihood of being neoplastic. (8) The rare exceptions to the latter include low-grade Hodgkin's and non-Hodgkin's lymphomas and, occasionally, chronic lymphocytic leukemia.

EXPOSURES

A complete exposure history is essential to determining the etiology of lymphadenopathy. Exposure to animals and biting insects, chronic use of medications, infectious contacts, and a history of recurrent infections are essential in the evaluation of persistent lymphadenopathy. Travel-related exposures and immunization status should be noted, because many tropical or nonendemic diseases may be associated with persistent lymphadenopathy, including tuberculosis, trypanosomiasis, scrub typhus, leishmaniasis, tularemia, brucellosis, plague, and anthrax.

Environmental exposures such as tobacco, alcohol, and ultraviolet radiation may raise suspicion for metastatic carcinoma of the internal organs, cancers of the head and neck, and skin malignancies, respectively. Occupational exposures to silicon or beryllium may also lead to lymphadenopathy. Sexual history and orientation are important in determining potentially sexually transmitted causes of inguinal and cervical lymphadenopathy. Patients with acquired immunodeficiency syndrome (AIDS) have a broad differential of causes of lymphadenopathy, and rates of malignancies such as Kaposi's sarcoma and non-Hodgkin's lymphoma are increased in this group. (9,10) Family history may raise suspicion for certain neoplastic causes of lymphadenopathy, such as carcinomas of the breast or familial dysplastic nevus syndrome and melanoma.

ASSOCIATED SYMPTOMS

A thorough review of systems is important in the evaluation of peripheral lymphadenopathy. Constitutional symptoms such as fatigue, malaise, and fever, often associated with impressive cervical lymphadenopathy and atypical lymphocytosis, are seen most commonly with mononucleosis syndromes. Significant fever, night sweats, and unexplained weight loss of more than 10 percent of a patient's normal body weight are the "B" symptoms of Hodgkin's lymphoma, increasing in frequency from 8 percent of patients with Stage I disease to 68 percent of those with Stage IV disease. (11) These symptoms are also seen in 10 percent of patients with non-Hodgkin's lymphoma. (8)

Symptoms such as arthralgias, muscle weakness, or unusual rash may indicate the possibility of autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, or dermatomyositis. More specific review questions, such as whether pain occurs in the area of lymphadenopathy after even limited alcohol ingestion, may bring out a rare but fairly specific finding of a neoplasm such as Hodgkin's lymphoma.

Physical Examination

The physical examination should be regionally directed by knowledge of the lymphatic drainage patterns (Figures 1 through 3) and should include a complete lymphatic examination looking for generalized lymphadenopathy. Skin should be examined for unusual lesions that suggest malignancy and for traumatic lesions, which can be sites of infectious inoculation. Splenomegaly, while rarely associated with lymphadenopathy, focuses the differential on a limited number of disorders, most commonly infectious mononucleosis, (8) but also the lymphomas, the lymphocytic leukemias, and sarcoidosis.

HEAD AND NECK LYMPHADENOPATHY

Palpable cervical lymph nodes, which are commonly appreciable throughout childhood, were noted in 56 percent of adult physicals in one outpatient primary care study, (12) although the incidence declined with age. The most common cause of cervical lymphadenopathy is infection, which in children is typically an acute and self-limited viral infection. While most cases resolve quickly, some entities such as atypical mycobacteria, cat-scratch disease, toxoplasmosis, Kikuchi's lymphadenitis, sarcoidosis, and Kawasaki's syndrome can create persistent lymphadenopathy for many months, and may be confused with neoplasms.

Among this group, supraclavicular nodes are the most likely to be malignant, and should always be investigated, even in children. (5,13) Overall, the prevalence of malignancy in this presentation is unknown, but rates of 54 to 85 percent have been seen in biopsy series reports. (7,14-16)

AXILLARY LYMPHADENOPATHY

Because the upper extremities that axillary lymph nodes drain are commonly exposed to local infection and injury, most axillary lymphadenopathy is nonspecific or reactive in etiology. Infectious sources of prolonged lymphadenopathy such as toxoplasmosis, tuberculosis, and mononucleosis rarely manifest with lymphadenopathy alone,8 and persistent lymphadenopathy is less commonly found in the axillary nodes than in the inguinal chain.

Breast adenocarcinoma often metastasizes initially to the anterior and central axillary nodes, which may be palpable before discovery of the primary tumor. Hodgkin's and non-Hodgkin's lymphomas rarely manifest solely or initially in the axillary nodes, (17) although this can be the first region discovered by the patient. Antecubital or epitrochlear lymphadenopathy can suggest lymphoma, or melanoma of the extremity, which first metastasizes to the ipsilateral regional lymph nodes. (18,19)

INGUINAL LYMPHADENOPATHY

Inguinal lymphadenopathy is common, with nodes enlarged up to 1 to 2 cm in diameter in many healthy adults, particularly those who spend time barefoot outdoors. (19) Benign reactive lymphadenopathy and infection are the most common etiologies, and inguinal lymphadenopathy is of low suspicion for malignancy.

Infrequently, Hodgkin's lymphomas first present in this area, (11,17) as do non-Hodgkin's lymphomas. Penile and vulvar squamous cell carcinomas, the lymphomas, and melanoma also can occur with lymphadenopathy in this area. When the overlying skin is involved, testicular carcinoma may lead to inguinal lymphadenopathy, (20) which is present in 58 percent of patients diagnosed with penile or urethral carcinoma. (21) In neither case is it the typical presenting finding.

GENERALIZED LYMPHADENOPATHY

(27.) Dunphy CH, Ramos R. Combining fine-needle aspiration and flow cytometric immunophenotyping in evaluation of nodal and extranodal sites for possible lymphoma: a retrospective review. Diagn Cytopathol 1997;16:200-6.

(28.) Wakely PE Jr. Fine needle aspiration cytopathology of malignant lymphoma. Clin Lab Med 1998;18:541-59.

(29.) Wakely PE Jr. Fine-needle aspiration cytopathology in diagnosis and classification of malignant lymphoma: accurate and reliable? Diagn Cytopathol 2000;22:120-5.

(30.) Margolis IB, Matteucci D, Organ CH Jr. To improve the yield of biopsy of the lymph nodes. Surg Gynecol Obstet 1978;147:376-8.

(31.) Sinclair S, Beckman E, Ellman L. Biopsy of enlarged, superficial lymph nodes. JAMA 1974;228:602-3.

(32.) Battista AF. Complications of biopsy of the cervical lymph node. Surg Gynecol Obstet 1991;173:142-6.

ANDREW W. BAZEMORE, M.D., is currently assistant professor in the Department of Family Medicine at the University of Cincinnati College of Medicine, where he also completed a faculty development fellowship and served a residency in family medicine. Dr. Bazemore received his medical degree from the University of North Carolina at Chapel Hill School of Medicine.

DOUGLAS R. SMUCKER, M.D., M.P.H., is associate professor and director of research in the Department of Family Medicine at the University of Cincinnati College of Medicine. Dr. Smucker completed his medical degree and served a residency in family practice at the Medical College of Ohio in Toledo. He also completed a primary care research fellowship and a residency in preventive medicine at the University of North Carolina at Chapel Hill School of Medicine.

Address correspondence to Andrew W. Bazemore, M.D., University of Cincinnati Family Practice, 2446 Kipling Ave., Cincinnati, OH 45239 (e-mail: andrew.bazemore@uc.edu). Reprints are not available from the authors.

COPYRIGHT 2002 American Academy of Family PhysiciansCOPYRIGHT 2002 Gale Group

 
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