Reactive Lymph Nodes and Castleman Disease

Clinical Features

The diagnosis of symptomatic Epstein-Barr virus (EBV) infection, infectious mononucleosis (IM), is usually established on clinical grounds, but when involved lymph nodes or tonsils are biopsied, they frequently cause problems in differential diagnosis. IM most often affects adolescents and young adults, although cases of IM in young children and in adults as old as 80 years have been reported. Manifestations include fever, pharyngitis, cervical lymphadenopathy, splenomegaly, rash, atypical peripheral blood lymphocytosis, and a positive heterophile antibody (Monospot) test. However, the heterophile antibody test may not be positive throughout the illness, sometimes requiring repeated monospots or serologic studies to establish a diagnosis. In some cases, particularly among young children, a positive heterophile antibody test may never be obtained. Evaluating plasma EBV viral load by molecular methods may also be useful in establishing a diagnosis. In more severe cases, there may be generalized lymphadenopathy, upper airway obstruction related to lymphoid hyperplasia, hepatomegaly with hepatic dysfunction, peripheral blood cytopenias, neurologic complications, such as aseptic meningitis and meningoencephalitis, and even a hemophagocytic syndrome/hemophagocytic lymphohistiocytosis. Most patients with infectious mononucleosis who receive a beta-lactam antibiotic develop a morbilliform rash. In most cases, the illness is self-limited, but rarely intercurrent infection, Guillain-Barré syndrome, or splenic rupture with hemorrhage results in death. Young children with genetic defects, such as perforin deficiency, are at increased risk for hemophagocytic syndrome/hemophagocytic lymphohistiocytosis. Boys with the X-linked lymphoproliferative disorder are at risk for severe infectious mononucleosis; those who survive the acute infection often develop lymphoma and/or have persistent immunologic abnormalities.

Pathologic Features

The lymph nodal architecture is typically distorted but not effaced by an expanded paracortex containing a polymorphous population of lymphoid cells, including small lymphocytes, intermediate-sized lymphoid cells, immunoblasts, tingible body macrophages, and mature and immature plasma cells. The EBV-infected immunoblasts may form aggregates and may be atypical, with pleomorphic or lobated nuclei; binucleated cells resembling Reed-Sternberg cells may be identified. Mitotic figures may be numerous. Apoptosis is common, and zonal necrosis may be present. EBV+ cells may be most numerous surrounding the foci of necrosis. Reactive follicles may be present, but follicular hyperplasia is usually inconspicuous. Sinuses are patent in at least some areas, and frequently they are dilated. Sinuses contain histiocytes and a polymorphous population of lymphoid cells, including immunoblasts. Lymphoid cells sometimes infiltrate the capsule and extend into perinodal fat. Similar histologic features are found in the tonsils of patients with IM. In tonsils, crypts are usually present, although the epithelium lining them may be necrotic ( Fig. 4.2A through C ).

The small and intermediate-sized cells in the paracortex are predominantly T cells, including many that are activated in response to the presence of the virus. The CD4-to-CD8 ratio is typically decreased. The EBV+ immunoblasts are B cells, typically CD20+, with a non-germinal center immunophenotype (CD10-, BCL6-/weakly positive, MUM1+). They are in addition CD30+/-, CD15-, Oct2+, Bob1+. Polytypic light chain expression by plasma cells and sometimes by immunoblasts is seen. Using in situ hybridization with probes for EBV-encoded RNA (EBER), EBV can be detected in the immunoblasts and in some smaller cells (see Fig. 4.2D and E ).

Differential Diagnosis

The differential diagnosis of IM includes a variety of reactive and neoplastic conditions. Obtaining adequate clinical information is helpful in making the correct diagnosis, whether the differential is with lymphoma or other types of reactive hyperplasias. Since the early years of the twentieth century the tendency of IM to mimic lymphoid malignancies has been recognized. If a patient is known to have clinical or laboratory evidence of IM, a diagnosis of Hodgkin lymphoma or non-Hodgkin lymphoma should be made with great caution.

When B immunoblasts and intermediate-sized reactive T cells are numerous, the possibility of B-cell or T-cell lymphoma may be a consideration. In favor of IM are lack of architectural effacement, presence of areas readily recognizable as reactive hyperplasia, a polymorphous background of lymphoid cells, patent sinuses containing lymphoid cells including immunoblasts, and lack of monotypic immunoglobulin (Ig) expression on immunophenotyping. The reactive T cells are usually predominantly CD8+, whereas most lymph nodal peripheral T-cell lymphomas (PTCLs) are CD4+. PTCLs are uncommon in the young patients who most often develop IM. Of note, IM can be associated with oligoclonal and rarely clonal T-cell populations directed against the virus, further potentially mimicking a PTCL.

Hodgkin lymphoma is often included in the differential diagnosis because Reed-Sternberg–like cells are often seen in IM; however, most of the large, EBV-infected cells resemble immunoblasts rather than Reed-Sternberg cells and variants. Hodgkin lymphoma is more often associated with obliteration of the lymph nodal architecture. The polymorphous background of lymphoid cells ranging from small to intermediate and large in the paracortex and sinuses seen in IM is very helpful in excluding Hodgkin lymphoma, in which the reactive background population includes small lymphocytes and, usually, granulocytes. Eosinophils are uncommon in IM. Immunoblasts in IM are CD15−, in contrast to the CD15 expression by Reed-Sternberg cells found in most cases of Hodgkin lymphoma.

Other viral infections, vaccination, certain drugs, and acute reaction to severe necrotizing processes can produce lym­phadenopathy with histologic features similar to or indistinguishable from those of IM. Clinical information can be helpful in investigating the etiology of the lymphadenopathy. In addition, in IM, EBER-positive immunoblasts are typically present in large numbers, whereas in other conditions, EBER-positive cells are absent or rare.

Clinical Features

Cytomegalovirus (CMV) can cause localized or generalized lymphadenopathy. Lymph node enlargement due to CMV infection may be found in patients who are otherwise asymptomatic. It may also be seen in the setting of a heterophile-negative, IM-like illness. CMV can infect lymphoid tissues in patients who have or have had Hodgkin lymphoma, non-Hodgkin lymphoma, or acquired or inherited immunodeficiency syndromes or in patients with a normal immune system. CMV infection is common in patients with common variable immunodeficiency.

Pathologic Features

On microscopic examination, involved lymph nodes most often show florid follicular hyperplasia and monocytoid B-cell hyperplasia. Paracortical hyperplasia may also be prominent. Infected cells contain a large eosinophilic intranuclear inclusion (mean size, 9 µm) and often also contain multiple tiny eosinophilic to amphophilic cytoplasmic inclusions. Cells with inclusions are usually present focally in relatively small numbers, but occasionally they are numerous. Neutrophils and histiocytes are often scattered around the infected cells. Inclusions are typically found among monocytoid B cells, but the infected cells are most likely endothelial cells or histiocytes rather than lymphocytes; finding inclusions in the paracortex has also been described. Immunoperoxidase stains for CMV-associated antigens can be used to confirm the diagnosis when inclusions are found on routine sections and can help identify CMV-infected cells when inclusions are difficult to find. Cells containing inclusions may express CD15, usually with a Golgi region or diffuse cytoplasmic pattern of staining, but membrane staining is uncommon ( Fig. 4.3 ).

Differential Diagnosis

The differential diagnosis of CMV lymphadenitis includes reactive hyperplasia due to some cause other than CMV, Hodgkin lymphoma, and certain non-Hodgkin lymphomas. The overall appearance of the lymph node in CMV lymphadenitis is very similar to that of toxoplasma lymphadenitis, although in most cases, the characteristic epithelioid cell aggregates of toxoplasmosis are not seen. Cells with nuclear viral inclusions may resemble Reed-Sternberg cells and variants on routinely stained sections, raising the question of Hodgkin lymphoma. In addition, CD15 expression by the virally infected cells heightens the resemblance to Hodgkin lymphoma. However, CMV lymphadenitis is much less likely to cause obliteration of the nodal architecture. Cells harboring virus may contain numerous granular cytoplasmic inclusions, in contrast to the agranular cytoplasm of Reed-Sternberg cells. Membrane staining by CD15 is more common in Reed-Sternberg cells than in CMV-infected cells. On occasion, the follicular and monocytoid B-cell hyperplasia of CMV lym­phadenitis can be so florid as to distort the nodal architecture, potentially suggesting follicular lymphoma or nodal marginal zone lymphoma. Immunostaining with CMV-specific antibodies provides a definitive diagnosis of CMV lymphadenitis.

Clinical Features

Infection by herpes simplex virus (type 1 or 2) can cause localized or generalized lymphadenopathy or involve lymph nodes in the setting of widespread visceral infection. When localized, the lymphadenopathy most often affects inguinal nodes, with cervical nodes next most often affected. Lym­phadenopathy is usually painful. Typical mucocutaneous herpetic lesions are found in some patients, but they may be inconspicuous or may not appear until after a lymph node biopsy has been performed. Many patients who present with herpes simplex lymphadenitis have an associated hematologic malignancy or an underlying immunodeficiency. The most common associated disorder is chronic lymphocytic leukemia, but B-cell lymphomas and myeloid leukemias are also occasionally found. Although disseminated herpes simplex viral infection has a poor prognosis, isolated herpes simplex lymphadenitis is self-limited in most cases.

Pathologic Features

Lymph nodes show prominent paracortical hyperplasia with areas of necrosis often with prominent extension into perinodal soft tissue. Paracortical immunoblasts may be numerous. The necrotic areas contain neutrophils, karyorrhectic or amorphous eosinophilic debris, and a variable number of cells with nuclear viral inclusions, ranging from rare to abundant. Most of them are uninucleate, although a few multinucleated cells are seen. Intact neutrophils are most abundant in early lesions and may be absent in long-standing lymphadenitis. Histiocytes often surround the necrotic areas, but granulomas are absent. Varicella zoster virus rarely causes lymphadenitis; the histologic features are similar to those of herpes simplex lymphadenitis. The diagnosis can be confirmed using immunohistochemical stains, in situ hybridization, electron microscopy, or viral culture ( Fig. 4.4 ).

Differential Diagnosis

The differential diagnosis based on histologic features includes other types of necrotizing lymphadenitis and, in some cases, lymphoma. The lack of granulomatous inflammation with epithelioid or palisading histiocytes provides evidence against infections caused by mycobacteria, fungi, yersinia, cat-scratch bacilli, and lymphogranuloma venereum. When there is pronounced paracortical expansion with numerous immunoblasts, the differential includes lymphoma. In herpes simplex lymphadenitis, the nodal architecture may be distorted, although it is not obliterated, in contrast to most nodes involved by lymphoma. Discrete foci of necrosis are less common in lymphoma, and herpes viral inclusions are absent in lymphoma, except in cases in which both herpes simplex virus and lymphoma involve the same lymph node. In instances in which patients have an established diagnosis of lymphoma and then develop rapidly enlarging lymphadenopathy related to viral infection, the clinical differential can include relapse or progression of the lymphoma.

Clinical Features

Acute symptomatic human immunodeficiency virus (HIV) infection presents as an IM-like illness with fever, pharyngitis, and cervical lymphadenopathy in approximately 16% of cases. Persistent generalized lymphadenopathy, defined as extrainguinal lymphadenopathy persisting for at least 3 months, involving at least two noncontiguous node groups, is common among HIV+ patients. Persistent generalized lymphadenopathy mainly affects adult males and is often accompanied by fever, weight loss, headaches, and malaise. A range of histologic and immunohistologic changes is found in lymphadenopathy associated with HIV infection; similar changes are found in organized extranodal lymphoid tissue. HIV+ patients with opportunistic infections (mycobacterial, fungal) who initiate antiretroviral therapy (ART) may develop “immune reconstitution inflammatory syndrome” (IRIS), an exaggerated inflammatory reaction to an infection that has already been diagnosed and treated (paradoxical IRIS) or to a previously unrecognized, untreated infection (unmasking IRIS). The most common manifestations of IRIS are lymphadenopathy, fever, and lung infiltrates.

Pathologic Features

Early stages of immunodeficiency are characterized by florid follicular hyperplasia, with large, irregular germinal centers with a high mitotic rate, numerous blast cells, many tingible body macrophages, and ill defined, attenuated, or effaced mantle zones. There is often follicle lysis. The interfollicular region contains a mixture of immunoblasts, plasma cells, lymphocytes, and histiocytes. Monocytoid B cells are often prominent. Sinus histiocytosis, sometimes with erythrophagocytosis, epithelioid histiocytes, and polykaryocytes (Warthin-Finkeldey–type giant cells) may be seen.

More advanced stages of immunodeficiency are associated with lymphoid depletion. Reactive follicles are decreased in number or absent. Residual follicle centers are “burned out” or regressively transformed and contain a decreased number of B cells. Over time, follicles may become inconspicuous and difficult to identify. The interfollicular region contains scattered lymphocytes, immunoblasts, plasma cells, and many blood vessels. Amorphous eosinophilic material may be present, or there may be fibrosis, and the node may have a pale, depleted appearance. In some cases, lymph nodes show changes intermediate between florid follicular hyperplasia and lymphoid depletion. Plasmacytosis is frequent. Occasional polykaryocytes may be found. Cutaneous rashes are common among HIV+ patients; these individuals often have a component of dermatopathic lymphadenopathy. The interfollicular region contains decreased numbers of CD4+ cells, and the CD4-to-CD8 ratio is usually reversed. It is common to find scattered cells harboring Epstein-Barr virus (EBER+) consistent with poor T-cell control of EBV-infected B cells.

Most patients who have been treated with highly active antiretroviral therapy show improvement in lymphoid architecture, as well as an increase in CD4+ T cells and a decrease in CD8+ T cells, within lymphoid tissue. However, HIV often is detectable in follicular dendritic cells in lymphoid tissue, even after a prolonged course of highly active antiretroviral therapy, and even in the absence of detectable virus in the peripheral blood.

Clinical Features

Cat-scratch disease is among the most common causes of subacute or chronic benign lymphadenopathy in the United States, with about 24,000 cases occurring per year. For reasons that may be related to the breeding patterns of cats, it is more common between July and December than between January and June. The principal causal agent for cat-scratch disease is Bartonella henselae . Although cat-scratch disease can affect patients of any age, the vast majority are younger than 30. A history of exposure to a cat (typically a kitten with fleas) can be found in most cases. The infectious agent has been found within the gastrointestinal tract of fleas, and it is possible that fleas act as vectors in the transmission of the disease. Three to 10 days after exposure, a papule develops in the skin at the inoculation site; the papule typically becomes vesiculated and then crusted over the next several days. Regional lymphadenopathy is usually found 1 to 2 weeks after the papule appears.

The lymphadenopathy, which is often tender, usually involves only one node or one group of nodes. Noncontiguous lymphadenopathy is occasionally found, probably because of more than one inoculation site or because the inoculation site is midline, allowing organisms to drain to lymph nodes bilaterally. Axillary lymph nodes are most commonly involved, followed by cervical and then by inguinal lymph nodes. When the inoculation site is the eye, patients may develop the oculoglandular syndrome of Parinaud (granulomatous conjunctivitis and preauricular lymphadenopathy). As many as half of patients have fever, but it is usually low grade (lower than 39° C). Patients may also experience malaise, anorexia, or, rarely, nausea or abdominal pain. The disease is usually mild and self-limited, and some cases probably go unrecognized. Severe complications, occurring in as many as 2%, include involvement of the nervous system, bone, lung, liver, or spleen. Neurologic manifestations include encephalopathy, encephalitis, meningitis, and involvement of cranial or peripheral nerves. The liver and spleen may be the sites of abscess formation. The skeleton is rarely involved by a necrotizing granulomatous osteomyelitis, sometimes via direct extension from an affected lymph node. Patients with lung involvement may have pneumonia or pleural effusions. Immunocompromised patients are more likely to develop severe manifestation of infection, including disseminated disease.

Pathologic Features

The appearance of the infected lymph nodes changes over time. The earliest changes are follicular hyperplasia and a prominent proliferation of monocytoid B cells. Subsequently, within aggregates of monocytoid B cells, small foci of necrosis with a few neutrophils and scant fibrin and cellular debris appear. These foci are usually close to, or encroach on, germinal centers, or they may be adjacent to the subcapsular sinus. In some cases, they are found in the vicinity of a small blood vessel. The paracortex is hyperplastic. Sinuses contain immunoblasts, neutrophils, and histiocytes. With time, the necrotic foci enlarge, extending deeper into the node. They contain pus, fibrin, and abundant cellular debris and acquire a rim of macrophages. The foci continue to enlarge and coalesce and are surrounded by palisading histiocytes to produce the classic stellate microabscess or granuloma. At later stages, the necrosis can become amorphous and eosinophilic without recognizable neutrophils, resembling caseation necrosis. Multinucleated giant cells are occasionally seen. Plasmacytosis and extension to involve the capsule and perinodal soft tissue are common. The cat-scratch bacillus is a small, slender, pleomorphic, weakly gram-negative rod as long as 3 µm. Its small size makes it very difficult to see, but using a Warthin-Starry stain or Steiner stain, the bacilli are coated with the black reaction product, making them appear larger and more readily visualized. Bacilli are present singly, in chains, or large clumps. They may be found along the walls of blood vessels, in macrophages in necrotic areas, in sinus histiocytes, or admixed with necrotic debris. Bacilli are most numerous in the stages of early necrosis within clusters of monocytoid B cells. When well-developed stellate abscesses have formed, the organisms can be difficult to detect ( Fig. 4.6 ). Bartonella henselae is a fastidious organism that is difficult to culture.

Serologic studies may be helpful in establishing a diagnosis, although serology may yield false-negative results and also may not distinguish between recent and past infections. An antibody to B. henselae has been developed that may help to identify the microorganisms. In addition, probes for Bartonella -specific genetic sequences are available that can be used to detect cat-scratch disease using the polymerase chain reaction (PCR). However, establishing a diagnosis is often difficult because microorganisms may be present only focally and in small numbers and because prior antibiotics may decrease the sensitivity of some of these assays.

Differential Diagnosis

A variety of microorganisms cause necrotizing lymphadenitis that can be considered in the differential diagnosis of cat-scratch disease. Clinical features, including age, risk factors for different types of infections, anatomic distribution of lymphadenopathy, and severity of disease; special stains on tissue sections; serologic studies; and culture are helpful in establishing a definite diagnosis. Infection caused by certain bacteria, including Chlamydia trachomatis (lymphogranuloma venereum), Francisella tularensis (tularemia), Hemophilus ducreyi (chancroid), Yersinia enterocolitica (pseudotuberculous mesenteric lymphadenitis ), Listeria monocytogenes (listeriosis), Pseudomonas mallei (glanders), and Pseudomonas pseudomallei (melioidosis), can be associated with a necrotizing lymphadenitis with histologic features that may be indistinguishable from those of cat-scratch disease. In nearly all cases, the diseases listed here are associated with significantly greater morbidity than cat-scratch disease. Early involvement by cat-scratch disease may also resemble toxoplasma lymphadenitis (see later section on this topic).

As noted previously, infection by pyogenic cocci may be associated with an acute suppurative lymphadenitis with follicular hyperplasia that can suggest cat-scratch disease. Unlike cat-scratch disease, however, the pyogenic cocci typically do not elicit a rim of palisading histiocytes around areas of suppurative necrosis. One exception is in cases of chronic granulomatous disease of childhood, in which palisading granulomas with suppurative necrosis may be found in association with infection due to Staphylococcus aureus and a variety of gram-negative bacteria (see later section on this topic). The appearance can closely resemble that of cat-scratch disease.

Mycobacteria ( Mycobacterium tuberculosis and non-tuberculous mycobacteria) and fungi can produce lym­phadenitis with granulomatous microabscesses that may resemble those of cat-scratch disease. The most important differential diagnosis may be between cat-scratch disease and non-tuberculous mycobacterial infection of cervical lymph nodes in children. As noted above, in some late-stage cases of cat-scratch disease, the necrotic material acquires a pink amorphous quality closely resembling the caseation necrosis characteristic of tuberculosis. Special stains for microorganisms, culture, and other special techniques may be helpful in establishing a diagnosis. The distinction is clinically relevant, as cat-scratch disease often does not require treatment, whereas infection by M. tuberculosis should be treated with antibiotics. In immunocompromised hosts, B. henselae infection rarely takes the form of localized granulomatous lymphadenitis. Instead, it may result in widespread granulomatous inflammation, bacillary angiomatosis, bacillary peliosis, or bacteremia.

Clinical Features

Tuberculous lymphadenitis is due to infection by tuberculous mycobacteria, such as Mycobacterium tuberculosis or M. bovis . Infection by M. tuberculosis is a serious global health problem, with approximately one third of the world's population harboring M. tuberculosis . Approximately 9 × 10 ⁶ new cases of tuberculosis and approximately 2 × 10 ⁶ deaths from tuberculosis occur each year. In Central Africa, for example, tuberculous lymphadenitis is the most common finding among patients who undergo a superficial lymph node biopsy; nearly all of these African patients are human immunodeficiency virus positive (HIV+). M. tuberculosis was also the most common specific cause of cervical lymphadenopathy in children in a study from South Africa. Although tuberculosis is much less common among individuals in the United States than in other parts of the world, an increased risk of infection is found in association with poor living conditions. Also, administration of incomplete courses of antibiotics because of poor patient compliance has led to the emergence of increased numbers of drug-resistant strains.

Patients with lymphadenitis due to M. tuberculosis are usually adults who present with non-tender lymphadenopathy, constitutional symptoms (fever, fatigue, and weight loss) and have associated pulmonary tuberculosis. When peripheral lymph nodes are involved, they tend to be in the supraclavicular fossa or posterior cervical triangle. Frequently, multiple lymph nodes are involved bilaterally, and there are draining sinuses. The purified protein derivative (PPD) test is usually strongly positive ( Table 4.1 ).

Pathologic Features

Lymph nodes in immunocompetent patients show multiple well-formed granulomas composed of epithelioid histiocytes and Langhans-type giant cells; caseation necrosis is present to a variable extent in the centers of the granulomas. Dystrophic calcification may be seen. A Ziehl-Neelsen stain is used to identify these acid-fast bacilli, which are usually few in number in immunocompetent patients. Culture is needed to diagnose cases in which organisms cannot be identified in tissue sections and to distinguish definitively between infections by M. tuberculosis and non-tuberculous mycobacteria.

Clinical Features

Most immunocompetent individuals who develop nontuberculous mycobacterial lymphadenitis are children, most of whom are younger than 5 years of age. Some studies have described an equal sex ratio; others report a higher proportion of female patients. It is said to be the most common cause of chronic lymphadenitis among previously healthy children, although it should be noted that in some developing countries, tuberculous lymphadenitis is more prevalent than nontuberculous mycobacterial lymphadenitis. The annual incidence is estimated to be 1.2 to 2.1 cases per 100,000 persons. The incidence appears to have increased in recent years.

Children present with firm, nontender cervical lymphad­enopathy that is almost always unilateral. Constitutional symptoms are typically absent. Lymph nodes away from the cervical area are rarely affected. The microorganisms are believed to infect the patient via the oropharynx, skin, or conjunctiva, and involved lymph nodes correspond to those with lymphatic drainage from these sites. Over time, necrosis develops within the infected nodes, and they become fluctuant. The overlying skin may become discolored, and sinus tracts may form. The PPD test is usually weakly positive or negative. The chest x-ray is almost always normal.

Patients do not usually respond to antibiotics. Surgical excision of the abnormal lymph nodes is the traditionally accepted optimal therapy, associated with a low rate of recurrence. If incomplete removal of the lymph nodes by incision and drainage or curettage is performed, the infection often persists, resulting in sinus tract formation, and additional surgery may be required. Recently, however, it has been suggested that diagnosis based on fine needle aspiration (FNA) with culture followed by observation only may be considered as an alternative to excision.

Pathologic Features

The children have enlarged, sometimes matted lymph nodes with necrotizing and non-necrotizing granulomas. The necrosis often forms a stellate pattern and may be caseous or suppurative. Necrotic areas may contain neutrophils and nuclear debris focally or diffusely. Langhans-type giant cells can often be found. The diagnosis can be suspected based on clinical features. It can be confirmed and the infection can be treated by complete excision of affected lymph nodes. Special stains for microorganisms and culture will demonstrate the organisms. Ziehl-Neelsen stain typically reveals small numbers of acid-fast bacilli in some cases, particularly at the periphery of the necrotic area, but in other cases, organisms cannot be identified without culture. In selected instances, PCR may be used to subclassify the organisms (see Table 4.1 ).

Differential Diagnosis

The differential diagnosis of mycobacterial lymphadenitis is broad ( Table 4.2 ). Cases with little or no necrosis resemble sarcoidosis. A Ziehl-Neelsen stain and culture are helpful in establishing a diagnosis; however, the Ziehl-Neelsen stain is often negative in cases of mycobacterial infection unless there is necrosis. A wide variety of microorganisms, including fungi, cat-scratch bacilli, Brucella species, spirochetes, and leishmania, can be associated with granulomatous lymphadenitis. Caseation necrosis is more common in mycobacterial infections, although necrosis resembling caseation may be seen in fungal infections and, less often, with other infections. In cases of primary or secondary syphilis, lymph nodes may show non-necrotizing or suppurative granulomas, but they are found in the setting of marked follicular hyperplasia and plasmacytosis. Cat-scratch disease, a common cause of necrotizing granulomatous lymphadenitis in children, is more likely to be associated with exposure to a cat, a cutaneous inoculation site, systemic symptoms, and tender lymphadenopathy compared to non-tuberculous mycobacterial lym­phadenitis in immunocompetent children. Uncommon entities that may enter the differential diagnosis include leprosy, particularly the tuberculoid form, and chronic granulomatous disease of childhood. Atypical mycobacterial infection in HIV+ patients in the form of numerous foamy histiocytes can mimic lepromatous leprosy. As intracellular mycobacteria may be PAS+, those cases with foamy histiocytes may mimic Whipple's disease, although the clinical features of Whipple's disease differ from those of mycobacterial infection, and Whipple's bacilli are not expected to be acid-fast (see separate section below). A few cases of Wegener granulomatosis have been described in which there is necrotizing lymphadenitis with granulomatous vasculitis, and such cases could potentially enter the differential diagnosis of mycobacterial lymphadenitis. Results of stains for microorganisms, culture, and clinical information can be helpful in establishing a diagnosis.

Granulomatous inflammation, often accompanied by extensive necrosis, may be found in tissues involved by Hodgkin lymphoma. Identification of Reed-Sternberg cells, which tend to be found in greatest numbers at the periphery of necrotic areas, confirms the diagnosis of Hodgkin lymphoma. The presence of a polymorphous inflammatory cell infiltrate, with eosinophils and plasma cells, is more common in Hodgkin lymphoma than in mycobacterial infection. Non-Hodgkin lymphomas may also occasionally be associated with granulomas, but this is much less common than in Hodgkin lymphoma.

Metastatic carcinoma can occasionally be associated with granulomas in lymph nodes. The granulomatous inflammation may obscure the neoplastic population, and the carcinoma may be overlooked. Granulomas can also be found in lymph nodes draining carcinoma but that are themselves free of metastases.