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Benign Lesions

Benign lesions involving lymph nodes are classified as either lymphadenitis or lymphoid hyperplasia. Lymphadenitis is usually caused by infectious agents such as bacteria, viruses, and parasites. Table 13-1 lists the most common infectious agents involving this region. Lymphadenitis caused by Epstein-Barr virus (EBV) and human immunodeficiency virus (HIV) are examples. Diseases that may cause extensive necrosis are also classified as lymphadenitis, such as systemic lupus erythematosus and Kikuchi-Fujimoto disease (KFD). By contrast, lymphoid hyperplasia is a response to antigenic stimulation without actual lymph node infection. Autoimmune disorders are common causes of lymphoid hyperplasia in the head and neck. There are three general patterns of reactive lymphoid hyperplasia, although many diseases cause a mixture of these patterns: follicular hyperplasia, paracortical hyperplasia, and sinus histiocytosis.[1] Granulomatous disorders do not readily fit within this conceptual framework.


Table 13-1   -- Cervical Lymphadenitis Caused by Specific Infectious Agents
Infectious AgentsDisease
Epstein-Barr virusInfectious mononucleosis
HIVHIV-associated lymphadenopathy
Rochalimaea henselae, Afipia felisCat-scratch disease
Toxoplasma gondiiToxoplasma lymphadenitis

HIV, human immunodeficiency virus



Infectious Causes of Lymphadenitis or Extranodal Lymphoid Hyperplasia

Infectious Mononucleosis

Infectious mononucleosis (IM) is caused by EBV infection.

Clinical Features

Patients usually are adolescents and young adults who present with generalized lymphadenopathy, splenomegaly, and peripheral blood lymphocytosis. The diagnosis is most easily established by serologic studies.

Pathologic Features

Histologically, there is marked paracortical hyperplasia (Fig. 13-1A), although a degree of follicular hyperplasia is present in the early stages of infection.[2,][3] The paracortical regions are markedly expanded by a polymorphous population of cells including small lymphocytes, plasmacytoid lymphocytes, immunoblasts (see Fig. 3-1B), Reed-Sternberg–like cells, histiocytes, and plasma cells; foci of coagulative necrosis may occur. As the paracortical expansion becomes more marked, it overruns lymphoid follicles. In the late stages of infection, the architecture can appear completely effaced, although usually residual follicles or patent sinuses can be identified.

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Figure 13-1  Infectious mononucleosis involving tonsil. A, At low power, the architecture is subtotally replaced. Two residual follicles in the field are surrounded by a paler paracortical proliferation. B, At high power, the infiltrate is composed of a range of cell types, including small lymphocytes, plasmacytoid lymphocytes, plasma cells, histiocytes, and immunoblasts. C, In situ hybridization for Epstein-Barr virus (EBV)–encoded RNA shows numerous EBV-infected cells.


Differential Diagnosis

Of all types of reactive lymphadenopathy, perhaps IM is most likely to be misdiagnosed as non-Hodgkin's lymphoma.[3] Features that help prevent this error include the presence of patent sinuses, residual normal architecture (often focal), and the marked heterogeneity of the paracortical infiltrate. The differential diagnoses of IM include both non-Hodgkin's and Hodgkin's lymphomas. Although non-Hodgkin's lymphomas and particularly T-cell lymphomas can be heterogeneous, these tumors are usually composed of a relatively more homogeneous population of cells than is observed in IM. In Hodgkin's lymphoma, the background non-neoplastic cells are a mixed population of cytologically normal, small lymphoid cells intermixed with other benign inflammatory cells, and the spectrum of lymphoid cells of various sizes observed in IM is not present.

Occasionally, a history of EBV infection is known when a lymph node or tonsil biopsy specimen is examined. In this instance, we interpret the histologic findings cautiously, unless the histologic findings are unequivocally malignant.

In situ hybridization studies for EBV small-encoded RNA can be very helpful in establishing the diagnosis (see Fig. 13-1C).[4] Immunohistochemical analysis for EBV latent membrane protein is also helpful,[3] but, in our experience, is less sensitive than assessment of EBV small-encoded RNA. Furthermore, additional immunohistochemical studies can be helpful if the differential diagnosis includes Hodgkin's lymphoma. In IM, the large lymphoid cells are immunoblasts positive for CD45 (LCA) and negative for CD15. By contrast, Reed-Sternberg and Hodgkin cells in Hodgkin's lymphoma are positive for CD15 and negative for CD45. Reactive immunoblasts in IM and Reed-Sternberg and Hodgkin cells in Hodgkin's lymphoma express the CD30 antigen.

In the differential diagnosis of IM and B-cell non-Hodgkin's lymphoma, immunohistochemical studies are also helpful because most cells in the expanded paracortex are CD8+ T cells in IM. These studies are less helpful in distinguishing IM from T-cell lymphoma. If flow cytometry immunophenotypic methods are used, the CD8+ T cells of IM may display down-regulation of CD7 and CD5, simulating a T-cell lymphoproliferative disease.[5]

Although T-cell receptor gene rearrangement studies may be helpful in most cases for distinguishing a benign from a malignant T-cell process, IM can transiently give rise to clonally expanded CD8+ T cells, usually detected in an oligoclonal pattern, but appearing with a predominant clone.[6] In difficult cases, follow-up may be necessary to allow the clonally expanded T cells to regress and eventually disappear. It is essential that serologic studies be performed to confirm the diagnosis of IM.

Treatment and Prognosis

IM is usually a self-limited infection that resolves in weeks or a few months. Antiviral agents, such as acyclovir and interferon gamma, have been used but their benefit is not well established.

Human Immunodeficiency Virus Infection

Persistent generalized lymphadenopathy is common in HIV-infected patients.[7] Biopsies are most often performed in these patients to exclude treatable infections or malignant neoplasms such as Kaposi sarcoma and malignant lymphoma. Intermediate and high-grade B-cell lymphomas, such as Burkitt's lymphoma or diffuse large B-cell lymphoma (DLBCL) are most common (90%), but Hodgkin's lymphoma and T-cell lymphomas have been reported.[7–9] Primary effusion lymphoma (Kaposi sarcoma–associated herpesvirus/human herpesvirus positive) and plasmablastic lymphoma (PBL) of the oral cavity (EBV positive) may also rarely occur.[9] Major salivary glands, especially the parotid glands, can also be enlarged in HIV patients. They are usually bilateral, multiple, cystic, and associated with lymphadenopathy.[10]

Pathologic Features

Lymph node changes in benign HIV-infected lymph nodes may be arbitrarily divided into general stages.[7] Initially, there is marked reactive follicular hyperplasia. The secondary germinal centers are commonly very large with bizarre shapes, and, in some cases, the surrounding mantle zones may be minimal or absent. As in all forms of follicular hyperplasia, the germinal centers are composed of a heterogeneous mixture of cells, are polarized, and contain many tingible body macrophages. Evidence of follicle lysis may be found. In follicle lysis, small lymphocytes infiltrate the germinal centers, often associated with hemorrhage. Commonly, there is also a marked monocytoid B-cell reaction in the sinuses. The paracortical regions are not prominent.

With time, the lymph node undergoes involution, as manifested by lymphoid depletion. Initially, there is a variable mixture of reactive follicular hyperplasia and lymphoid depletion, with subsequent progression to severe lymphoid depletion. The lymphoid follicles become smaller and depleted of lymphoid cells until only follicular dendritic cells remain. Some of these follicles may resemble the hyaline-vascular lesions of Castleman disease. In the paracortical regions, lymphoid cells are also depleted, leaving plasma cells, histiocytes, and a prominent vascular network. The sinuses are widely patent.

Particularly in the later stages of HIV infection, infectious organisms are likely to be found. For example, the presence of many histiocytes in the paracortical regions suggests Mycobacterium avium-intracellulare infection. Similarly, the likelihood of malignant neoplasms is increased.[7]

Immunohistochemical studies parallel the histologic findings. In the early stages, lymphoid follicles are composed of polytypic B cells and follicular dendritic cells, and the paracortical regions are composed of both CD4++/CD8 and CD4/CD8++ cells, with the latter predominating.[8,][9] Over time, lymphoid cells are decreased and eventually become absent. Plasma cells express polytypic immunoglobulin (Ig) light chains.

Treatment and Prognosis

Highly active antiretroviral therapy, consisting of nucleoside, non-nucleoside, and protease inhibitors, has decreased the incidence of many HIV-associated malignancies. The combination of highly active antiretroviral therapy with novel and more effective chemotherapy has also dramatically improved the overall survival of patients with HIV-related neoplasms.[11,][12]

Cat-Scratch Disease

The majority of cases of cat-scratch disease are caused by Rochalimaea henselae, although some also may be caused by Afipia felis.[13,][14]

Clinical Features

The lymphadenopathy of cat-scratch disease is usually unilateral and most commonly involves axillary or cervical lymph nodes.[15–17] Cat-scratch disease usually affects children or young adults, resulting in an enlarged, slightly tender lymph node. The patient may have constitutional symptoms, including fever, malaise, and headache. Most cases are associated with a history of a cat scratch involving the area drained by the lymph node 1 to 4 weeks before the development of lymphadenopathy.

Pathologic Features

Morphologically, the lymph node is reactive with follicular hyperplasia, a variable paracortical immunoblastic proliferation, and foci of monocytoid B cells in sinuses. In the paracortex, varying degrees of neutrophil-containing necrosis are also present, which range from granulomas with central necrosis to large stellate abscesses with surrounding histiocytes and fibroblasts (Fig. 13-2). In many cases, rod-shaped bacilli are identifiable within the areas of necrosis by using the Warthin-Starry or Dieterle stain (see Fig. 13-2D).[16–18]

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Figure 13-2  Cat-scratch disease. A–C, Lymph node with foci of neutrophil-containing necrosis surrounded by histiocytes, plasma cells, and fibroblasts in paracortical areas. D, Warthin-Starry stain highlights many rod-shaped bacilli within the necrosis.


Differential Diagnosis

The lymphadenopathy of tularemia and lymphogranuloma venereum are morphologically similar to that of cat-scratch disease. Although lymphogranuloma venereum, a sexually transmitted disease caused by Chlamydia species, usually involves inguinal lymph nodes, cervical lymph node involvement may occur. Tularemia usually involves axillary lymph nodes and is seen after exposure to rabibits. The presence of neutrophils in these diseases helps eliminate Kikuchi's disease from the differential diagnosis. Although microabscesses can be seen in Hodgkin's lymphoma, Reed-Sternberg and Hodgkin cells are not observed in cat-scratch disease.

Treatment and Prognosis

Cat-scratch disease is a self-limited infection that does not require specific therapy.

Toxoplasma Lymphadenitis

Toxoplasma lymphadenitis is caused by infection with Toxoplasma species, usually Toxoplasma gondii. Humans are exposed via contact with infected animal feces.

Clinical Features

Patients with Toxoplasma lymphadenitis usually present with one or a single group of enlarged lymph nodes, most commonly in the posterior cervical region. However, fever and generalized lymphadenopathy develop in a subset of patients.[19,][20]

Pathologic Features

Histologically, Toxoplasma lymphadenitis can be reliably recognized if a triad of three histologic findings is identified: florid reactive follicular hyperplasia, clusters of epithelioid histiocytes found within the germinal centers of reactive follicles, and a monocytoid B-cell reaction in the sinuses (Fig. 13-3).[19,][20] If all three findings are present, serologic studies are usually positive for Toxoplasma antibodies.[20]Toxoplasma cysts or intracellular trophozoites are rarely found in lymph node biopsy specimens.

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Figure 13-3  Toxoplasma lymphadenitis. A, Well-preserved nodal architecture with marked follicular hyperplasia is evident at low magnification. B, In this field, monocytoid B cells expanding a sinus (right) and reactive follicular hyperplasia (left) are present. C, Clusters of epithelioid histiocytes adjacent to and encroaching on a hyperplastic lymphoid follicle.


Differential Diagnosis

A variety of other infectious disorders may cause histologic changes similar to Toxoplasma lymphadenitis. Most commonly, these disorders cause an extensive monocytoid B-cell reaction and reactive follicular hyperplasia.[21] Therefore, the presence of epithelioid histiocytes within the germinal centers of follicles is the most specific finding of the triad. Rarely, infections other than toxoplasmosis, such as HIV infection and leishmaniasis, may cause reactive follicular hyperplasia, a sinusoidal monocytoid B-cell reaction, and the presence of paracortical epithelioid granulomas that can also be found in germinal centers.[21] Usually, the granulomas are associated with necrosis and acute inflammatory cells. Granulomas and necrosis are usually not features present in Toxoplasma lymphadenitis.

Although histologic findings can be very helpful in suggesting the presence of toxoplasmosis, serologic studies should be routinely recommended to definitively establish the diagnosis.

Treatment and Prognosis

The infection is usually self-limited in immunocompetent adults and older children, and no specific therapy is required. Immunodeficient patients require antibiotic therapy directed against the parasite.