Benign and Malignant Hematopoietic Diseases of the Head and Neck

Clinical Features

Patients are usually 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. The paracortical regions are markedly expanded by a polymorphous population of cells, including small lymphocytes, plasmacytoid lymphocytes, immunoblasts, Reed-Sternberg–like cells, histiocytes, and plasma cells. Foci of coagulative necrosis may occur ( Fig. 13.1B ). As the paracortical expansion becomes more marked, it overruns lymphoid follicles. In the late stages of infection, the architecture can appear completely replaced, although usually residual follicles or patent sinuses can be identified.

Differential Diagnosis

Of all types of reactive lymphadenopathy, IM may be most likely to be misdiagnosed as lymphoma. 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 and Hodgkin lymphoma. Although non-Hodgkin lymphomas and particularly T-cell lymphomas can be heterogeneous, these tumors are usually composed of a relatively more homogeneous population of cells than observed in IM. In Hodgkin 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-encoded small RNA (EBER) can be very helpful in establishing the diagnosis ( Fig. 13.1C ). Immunohistochemical analysis for EBV latent membrane protein can be helpful but is less sensitive than assessment of EBER. Furthermore, additional immunohistochemical studies can be helpful if the differential diagnosis includes Hodgkin 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 lymphoma (HL) are positive for CD15 and negative for CD45. Reactive immunoblasts in IM and Reed-Sternberg and Hodgkin cells in HL express the CD30 antigen.

In the differential diagnosis of IM and B-cell non-Hodgkin lymphoma, immunohistochemical studies are also helpful, since 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 downregulation of CD7 and CD5, simulating a T-cell lymphoproliferative disease.

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. 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 or γ-interferon, have been used but their benefit is not well established.

Pathologic Features

Lymph node changes in benign HIV-infected lymph nodes may be arbitrarily divided into general stages. 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 tangible body macrophages. Evidence of follicle lysis may be found. In follicle lysis, small lymphocytes infiltrate into 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 ( Fig. 13.2 ). Similarly, the likelihood of malignant neoplasms is increased.

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 many T cells, both CD4 ⁺ and CD8 ⁺ T cells, with the latter predominating. Over time, lymphoid cells are decreased and eventually become absent. Plasma cells express polytypic immunoglobulin (Ig) light chains.

Treatment and Prognosis

In patients with lymph node biopsy specimens without evidence of specific infection or neoplasm, prognosis is determined by the stage of HIV infection.

Clinical Features

The lymphadenopathy of cat scratch disease is usually unilateral and most commonly involves axillary or cervical lymph nodes. Cat scratch disease usually affects children or young adults, resulting in a single enlarged, 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 prior to the development of lymphadenopathy. The organism is fastidious and difficult to culture but can be identified by PCR-based methods in most cases. Serologic studies for high titers of IgG antibodies are sensitive, but are not specific.

Pathologic Features

Morphologically, the lymph node shows follicular hyperplasia, a mild paracortical immunoblastic proliferation, and foci of monocytoid B cells in sinuses. In the paracortex, variable foci of necrosis-containing neutrophils are present, ranging from granulomas with central necrosis to large areas of stellate abscesses with surrounding histiocytes and fibroblasts (see Fig. 13.2 ). The organisms are rod-shaped bacilli that are often identifiable within the areas of necrosis by using the Warthin-Starry or Dieterle stains ( Fig. 13.2D ). However, as has been described by Jabcuga and colleagues, histologic findings may not be specific in about 40% of cases and can resemble mycobacterial or fungal infection, Toxoplasma lymphadenitis, or Kikuchi-Fujimoto disease. In addition, organisms are not identified in a substantial subset of cases of cat scratch disease.

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 following exposure to rabbits. Although microabscesses can be seen in Hodgkin 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.

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, a subset of patients develop fever and generalized lymphadenopathy.

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 ). If all three findings are present, serologic studies are usually positive for Toxoplasma antibodies. Toxoplasma cysts or intracellular trophozoites can rarely be found in lymph node biopsy specimens.

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. 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. 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 or PCR analysis 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.

Clinical Features

Affected patients are most often young women, and cervical lymph nodes (often posterior cervical) are the most common site of involvement. Patients usually present with a tender (∼50%) painless mass. KFD is often associated with fever and a subset of patients may have skin rash, weight loss, upper respiratory symptoms, or hepatomegaly. A subset of patients have laboratory studies including elevated erythrocyte sedimentation rate, high serum lactate dehydrogenase, abnormal liver enzymes, anemia, or thrombocytopenia. Atypical lymphocytes can be observed in the peripheral blood smear.

Pathologic Features

Microscopically, the lymph node architecture is partially to completely replaced by KFD. In partially involved lymph nodes, the disease has a paracortical distribution ( Figs. 13.4 and 13.5 ). KFD is composed of a proliferation of histiocytes with C-shaped nuclei, plasmacytoid dendriti cells (type 2 dendritic cells [DC2]), and lymphocytes including immunoblasts. Focal to extensive necrosis is usually present, containing karyorrhectic debris without associated neutrophils. The lack of a neutrophilic infiltrate within the necrotic area is a helpful diagnostic feature. The surrounding, uninvolved lymphoid tissue generally shows evidence of reactive follicular hyperplasia. Three histologic subtypes, most likely phases of the disease evolution, occur: proliferative (see Fig. 13.4 ), necrotic (see Fig. 13.5 ), and xanthomatous. In the proliferative phase, necrosis is absent or not prominent, and the lesion is composed of crescentic histiocytes, DC2 cells, and immunoblasts with scattered karyorrhectic debris. In the necrotic phase, necrosis is abundant or predominant. In the xanthomatous phases, numerous lipid-laden (foamy) histiocytes are present. In both the necrotic and xanthomatous phases, crescentic histiocytes and immunoblasts are also identified.

Immunohistochemical studies show that the histiocytes are usually diffusely positive for CD68 and other histiocytic associated antigens. The immunoblasts are CD30+. DC2 cells are CD123+. The large majority of the intermixed lymphoid cells are CD3 ⁺ CD8 ⁺ T cells.

Differential Diagnosis

The lymphadenopathy of systemic lupus erythematosus (SLE) is morphologically similar to that of KFD, except that the hematoxylin bodies can be seen in SLE ( Fig. 13.6 ). Because of the morphologic similarities between the two processes, as well as the similarity in age of presentation and female predominance, the possibility of SLE should be suggested and clinically excluded in patients with morphologic features of KFD. However, not all lymph node biopsy specimens obtained from SLE resemble KFD. In some SLE patients, lymph nodes show nonspecific reactive changes. KFD has been rarely described in association with SLE, and KFD may precede, coincide with, or occur subsequently to the diagnosis of SLE.

Other reactive lymphadenopathies, such as cat scratch disease, lymphogranuloma venereum, and Yersinia enterocolitica infection, can be excluded by the neutrophilic component of the necrosis in these diseases. Neutrophils are not seen in KFD. The histiocytic population in KFD is helpful in excluding most malignant lymphomas. Molecular studies for T-cell receptor gene rearrangement in KFD may show an oligoclonal pattern that regresses over time.

Treatment and Prognosis

KFD is usually a self-limited condition that requires no specific therapy. The process most often resolves in 2 to 4 months, but the disease can persist for up to a year in some patients.

Clinical Features

RDD most often occurs in children, but can occur in patients at any age. Cervical lymph nodes are involved in 87% of cases. Multiple lymph nodes may be involved, and the enlarged lymph nodes are frequently matted, causing large masses. There are also rare congenital syndromes associated with RDD, but in most patients the disease is sporadic. Rarely, small foci of RDD can be detected in lymph nodes involved with malignant lymphoma. The finding of RDD in these patients is usually incidental, is not associated with other sites of involvement, and does not have clinical importance.

Pathologic Features

Grossly, involved lymph nodes may have either a nodular or diffuse yellow-white cut surface with capsular or pericapsular fibrosis. Histologically, the lymph node sinuses are massively expanded by plasma cells and histiocytes with abundant eosinophilic cytoplasm and round to oval shape, and a single, central nucleolus ( Fig. 13.7 ). Occasional multilobated nuclei may be present, and the mitotic rate is usually low. Viable lymphocytes are present within the cytoplasm of many histiocytes, so-called emperipolesis, a characteristic finding of RDD. These lymphocytes often form wreath-like rings within the cytoplasm. Less commonly, the histiocytes may contain intracytoplasmic plasma cells, neutrophils, or red blood cells. In addition to cervical lymph node involvement, SHML may involve extranodal sites of the head and neck that include the tonsils, larynx, oral cavity, orbit, and nasal cavity ( Fig. 13.8 ). Although distended lymphoid sinuses are not present in these sites, the cytologic features of the histiocytes are similar to those in lymph nodes. In some extranodal cases, however, the cellular infiltrate may have a more spindled appearance and emperipolesis can be difficult to identify.

Recent studies of RDD using next-generation sequencing methods have shown RAS pathway mutations in a subset of cases. Garces and colleagues showed mutations in KRAS or MAP2K1 in about a third of cases of SHML.

Differential Diagnosis

Although identification of the characteristic histiocytes with emperipolesis ( Fig. 13.2B ) is often sufficient for diagnosis, immunohistochemical studies are also useful in supporting the diagnosis and excluding other histiocytic proliferations. The histiocytes of RDD are positive for S-100 protein ( Fig. 13.7C ) and CD68. The S-100 immunostain also negatively outlines the lymphocytes in the histiocyte cytoplasm, facilitating recognition of emperipolesis. In contrast to Langerhans cell histiocytes, RDD histiocytes are negative for CD1a and CD207/langerin, and do not demonstrate Birbeck granules by electron microscopy. In addition, eosinophils are not a cellular component in RDD, as they are in most cases of Langerhans cell histiocytosis.

The sinusoidal pattern of lymph node involvement by RDD may suggest a metastatic tumor or anaplastic large-cell lymphoma. The RDD histiocytes, however, do not demonstrate cytologic atypia. S-100 protein expression may raise the possibility of metastatic melanoma, but the identification of cells with emperipolesis as well as the lack of HMB45 or other melanoma-associated markers aids in excluding melanoma. The lack of keratin staining in RDD excludes the possibility of metastatic carcinoma. Cases of RDD have been reported to be CD30 positive, but only weakly and focally in RDD histiocytes, as opposed to the strong expression seen in most cases of anaplastic large-cell lymphoma. In addition, RDD does not demonstrate evidence of B- or T-cell receptor gene rearrangement. The clinical presentation of matted lymph nodes as well as the capsular fibrosis may suggest Hodgkin lymphoma, but Reed-Sternberg and Hodgkin cells are not observed in RDD.

Treatment and Prognosis

In most cases, the lymphadenopathy of RDD eventually resolves without specific therapy. Some patients with persistent disease have been treated with various therapies; inhibitors of MEK (encoded by MAP2K1 ) have shown promising results.

Clinical Features

Kimura disease is a disease of unknown etiology that involves the head and neck region. Patients often present with large, multifocal masses that may involve subcutaneous tissue, lymph nodes, and salivary glands. The disease is most common in Asia and it most often affects young adult men. Elevated serum IgE and peripheral blood eosinophilia are usually present. In some patients, Kimura disease is associated with proteinuria.

Pathologic Features

Microscopically, the lesion shows lymphoid tissue with reactive follicular hyperplasia and eosinophilic proteinaceous deposits within germinal centers ( Fig. 13.9 ). The interfollicular areas contain numerous eosinophils with admixed small lymphocytes, plasma cells, and mast cells. In addition, postcapillary venules with low cuboidal to flat endothelium are increased in the interfollicular areas and encroach on the reactive germinal centers. Eosinophils can infiltrate the germinal centers in areas of vascular encroachment. Eosinophilic abscesses may be present. Immunohistochemical studies identify IgE deposition within the germinal centers as well as IgE-positive mast cells in the interfollicular areas. Molecular studies show no evidence of clonality.

Differential Diagnosis

Although Kimura disease and angiolymphoid hyperplasia with eosinophilia (ALHE) were once thought to be closely related, Kimura disease is a chronic inflammatory disorder and ALHE is a benign vascular neoplasm. The differential diagnosis of Kimura disease and ALHE is discussed in the next section. The mixed interfollicular cell composition of Kimura disease may suggest classical Hodgkin lymphoma or a T-cell lymphoma, but cytologically atypical neoplastic cells are not identifiable in Kimura disease.

Treatment and Prognosis

There is no specific therapy. The lymph node enlargement may persist for years, and the proliferation frequently recurs after biopsy; however, the overall prognosis is excellent.

Clinical Features

ALHE is often confused with Kimura disease but is a distinct entity. Similar to Kimura disease, the process frequently involves the head and neck region in young adult Asian men, but may also affect non-Asians of both sexes. In contrast to Kimura disease, ALHE is more often superficial, most frequently involving the dermis, and forms multiple, smaller papules or nodules. Lymph node involvement is uncommon and peripheral blood eosinophilia is less common in ALHE than in Kimura disease.

Pathologic Features and Differential Diagnosis

ALHE is a vascular proliferation with secondary lymphoid and eosinophilic infiltration. The predominant feature is the proliferation of small vessels lined by plump endothelial cells with abundant eosinophilic and vacuolated cytoplasm ( Fig. 13.10 ). These proliferating small vessels often can be seen surrounding a damaged artery or vein. Scattered small lymphocytes and eosinophils may be admixed within the vascular proliferation. The plump endothelial cells of ALHE differ from the flattened endothelium characteristic of Kimura disease. Germinal center formation may be present but is not essential for the diagnosis of ALHE.

In addition to Kimura disease, the differential diagnosis of ALHE includes vascular lesions of lymph nodes. The eosinophilic infiltrate as well as the lack of hyaline bodies is helpful in excluding Kaposi sarcoma, and the endothelial cell nuclear atypia of angiosarcoma is not observed in ALHE.

Treatment and Prognosis

ALHE is benign but may recur if excision is incomplete.

Clinical Features

Mikulicz syndrome is defined as diffuse and bilateral enlargement of the salivary and lacrimal glands. A number of diseases may result in Mikulicz syndrome, such as sarcoidosis, tuberculosis, and malignant lymphoma, but the most common cause is lymphoepithelial sialadenitis (LESA), formerly referred to as myoepithelial sialadenitis. LESA is usually an autoimmune phenomenon. The term Mikulicz disease has also been used as a synonym for LESA.

The most common cause of LESA is Sjögren syndrome, but there are other causes, such as HIV infection. Sjögren syndrome is a systemic autoimmune disorder that causes Mikulicz syndrome, keratoconjunctivitis, xerostomia, rheumatoid arthritis, and hypergammaglobulinemia. Some of these cases are considered part of IgG4-related disease described later in the chapter.

Pathologic Features

LESA involving the major salivary glands is histologically characterized by two components: lymphoepithelial lesions and extensive lymphoid infiltration ( Fig. 13.11 ). In the minor salivary glands, the changes are similar, although lymphoepithelial lesions may be small or absent.

Lymphoepithelial lesions (epimyoepithelial islands) are nests of epithelial cells that are extensively infiltrated by small lymphoid cells. Often abundant hyaline material accompanies the epithelial cells, which ultrastructurally has been proven to be basal lamina material. These findings indicate that lymphoepithelial lesions originate as ducts that subsequently collapse. The ductal epithelium is infiltrated by small lymphoid cells of two types: small round and unremarkable lymphocytes and slightly larger lymphoid cells with mildly irregular nuclear contours and moderate pale or clear cytoplasm. Immunohistochemical studies have shown that the slightly irregular cells with clear or pale cytoplasm are predominantly B cells and the small round cells are T cells.

The lymphoid infiltrate progressively replaces the acinar tissue, resulting in atrophy. This infiltrate is composed of large reactive lymphoid follicles with secondary germinal centers and intervening areas of small lymphocytes and histiocytes. The lymphoid follicles are composed of polytypic B cells. The small lymphocytes surrounding and between the follicles are composed of normal T cells.

Treatment and Prognosis

Patients with LESA as a result of Sjögren syndrome have an incurable disease. There is no specific treatment, and the therapies used are designed to alleviate symptoms.

Patients with LESA are at increased risk of developing non-Hodgkin lymphoma, usually of B-cell lineage. The risk of malignant lymphoma in patients with LESA and Sjögren syndrome has been estimated to be approximately 40 times that of the general population. B-cell non-Hodgkin lymphomas can be generally divided into two groups: low grade and high grade. Rare cases of Hodgkin lymphoma and T-cell lymphoma also have been described, but the risk of these tumors in LESA is significantly less than that of B-cell lymphomas.

Historically, high-grade B-cell non-Hodgkin lymphomas arising in LESA were the first to be recognized. Immunohistochemical studies, restricted at that time to polyclonal Ig light chain antibodies and fixed, paraffin-embedded sections, demonstrated monotypic Ig light chain and B-cell lineage in four tumors. The increased risk of low-grade B-cell non-Hodgkin lymphoma was recognized later, with the widespread availability of numerous antibodies, fresh frozen material, and improved immunohistochemical and molecular methods. Although the risk of low-grade B-cell lymphoma in LESA is not well quantified, the risk is in addition to that of high-grade B-cell lymphoma.

Most low-grade B-cell lymphomas that arise in the setting of LESA are examples of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) ( Fig. 13.12 ), also known as MALT lymphoma, as defined by the World Health Organization classification. Distinguishing between benign LESA and MALT lymphoma can be difficult. In general, larger infiltrates are most likely to be MALT lymphoma. However, this distinction may not possible without immunophenotypic studies. Most pathologists agree that MALT lymphoma is present if a monotypic B-cell population can be detected.