Normal Lymph Node
Histopathology
- •
A lymph node contains a cortex, a paracortex, a medulla, sinuses, a hilum, and a fibrous capsule
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The cortex is a B-cell area, which contains primary (nonstimulated) lymphoid follicles composed of small mature lymphocytes and secondary (activated) follicles with germinal centers composed of a mixture of small cleaved lymphocytes (centrocytes) and large noncleaved lymphoid cells (centroblasts), as well as numerous tingible-body macrophages
- •
The paracortex is a T-cell area with a mixture of lymphocytes, antigen-presenting cells, and immunoblasts
- •
The medulla contains predominantly plasma cells, admixed with small lymphocytes and immunoblasts
- •
Sinuses contain histiocytes admixed with small lymphocytes
Special Stains and Immunohistochemistry
- •
B lymphocytes express CD20, Pax-5, and CD79a, whereas T lymphocytes are positive for CD3, CD2, CD5, and CD7
- •
B lymphocytes of the primary follicles and mantle zones are naïve and memory cells that express Bcl-2 and are negative for CD10 and Bcl-6
- •
B lymphocytes in the germinal centers express CD10 and Bcl-6 and are negative for Bcl-2
- •
Follicular dendritic cells form a scaffold of the lymphoid follicle and express CD21 and CD23
- •
T lymphocytes in the paracortex are predominantly CD4 positive with a smaller number of admixed CD8-positive cells
- •
The antigen-presenting interdigitating dendritic cells of the paracortex express S-100 protein; Langerhans cells are positive for S-100, CD1a, and langerin
Reactive Follicular Hyperplasia
Autoimmune Disease
Clinical Features
- •
Autoimmune diseases are chronic systemic illnesses that are frequently characterized by lymphadenopathy
- •
They usually occur in middle-aged women
- •
Lymphadenopathy is a common finding, especially during periods of active disease
Histopathology
See Figure 14.1 .
- •
Florid reactive follicular hyperplasia with sinus histiocytosis and neutrophilia
- •
Marked plasmacytic proliferation in the paracortex and medulla
- •
Rheumatoid arthritis patients who were treated with gold can have scattered nonbirefringent crystal structures associated with foreign body giant cell reaction
- •
Sjögren syndrome patients may have aggregates of pale-staining monocytoid B-cells
Special Stains and Immunohistochemistry
- •
B lymphocytes in the reactive germinal centers express CD10 and Bcl-6 and are negative for Bcl-2
- •
Proliferation rate with Ki67 immunostain is >90% in the reactive germinal centers and approximately 5% in the interfollicular areas
- •
Plasma cells are polytypic with staining for kappa and lambda immunoglobulin light chains
Other Techniques for Diagnosis
- •
Flow cytometry shows evidence of polytypic B-cells and T-cells that express all the pan-T-cell antigens
- •
Immunoglobulin heavy chain gene (IgH) rearrangement analysis is typically negative
- •
A subset of the patients with active autoimmune disease may have evidence of B-cell clonality by polymerase chain reaction (PCR), but this finding by itself does not indicate malignancy
- •
Cytogenetic analysis shows a normal karyotype
Differential Diagnosis
Nonspecific Follicular Hyperplasia
- •
A patient without an established clinical diagnosis of autoimmune disease may show identical morphology and immunophenotype
Syphilis
- •
Usually presents with inguinal lymphadenopathy
- •
Prominent perilymphadenitis with thickening of the capsule, marked plasmacytic infiltration, and vasculitis
- •
Warthin-Starry stain demonstrates evidence of spirochetes in endothelial cells, within blood vessels, and occasionally in germinal centers
Early Viral Infection
- •
HIV: frequent follicle lysis
- •
Mononucleosis: expanded paracortex with numerous immunoblasts
- •
Cytomegalovirus (CMV): monocytoid B-cell hyperplasia and large intranuclear inclusions
- •
Clinical history and serology confirm the diagnosis
Toxoplasma Lymphadenitis
- •
Triad of follicular hyperplasia, monocytoid B-cell hyperplasia, and aggregates of epithelioid histiocytes in the lymphoid follicles
- •
Clinical history and serology confirm the diagnosis
I gG 4- Related Lymphadenopathy
- •
Type II is characterized by follicular hyperplasia
- •
Intrafollicular and paracortical plasmacytosis and scattered eosinophils
- •
Immunohistochemical stains for IgG and IgG4 quantify the number of plasma cells
- •
>100 IgG4-positive plasma cells per high-power field
- •
IgG4/IgG ratio >40%
- •
Follicular Lymphoma
- •
Usually in older patients with generalized lymphadenopathy
- •
Increased number of follicles, which appear monotonous in size and shape
- •
Neoplastic follicles present throughout the lymph node and may extend outside into the perinodal fat
- •
Lymph node capsule is thickened and frequently appears split due to the follicular proliferation
- •
Mantle zone is attenuated or absent
- •
The cellular composition within the follicles is monomorphic
- •
Tingible-body macrophages are rare to absent
- •
Lymphoid cells in the follicles coexpress Bcl-2
- •
Proliferation rate within the follicles with Ki67 immunostain is <90% (usually around 10% to 50%)
- •
Flow cytometry: monotypic B lymphocytes
- •
PCR for IgH gene rearrangement is monoclonal
- •
Cytogenetic analysis and fluorescence in situ hybridization (FISH): evidence of t(14;18) translocation and other genetic abnormalities
Marginal Zone Lymphoma
- •
Rare lymphoma that typically presents in middle-aged patients
- •
Patients may have a history of autoimmune disease, especially Sjögren syndrome and Hashimoto thyroiditis
- •
Typically, tumor cells are composed of monocytoid B-cells, plasma cells, and immunoblasts that surround reactive follicles
- •
Follicular colonization may be present
- •
Tumor cells may aberrantly coexpress CD43 and Bcl-2
- •
Plasma cells frequently show evidence of clonality with immunostains for kappa and lambda light chains
- •
Flow cytometry: monotypic B lymphocytes
- •
PCR for IgH gene rearrangement is monoclonal
- •
Cytogenetic analysis: abnormal karyotype
Plasma Cell Neoplasm in Lymph Node
- •
Very rare
- •
Suspect in patients with a clinical history of plasma cell myeloma
- •
Plasma cells always show evidence of clonality with immunostains for kappa and lambda light chains
- •
Flow cytometry: polyclonal B lymphocytes and monoclonal plasma cells
- •
PCR for IgH gene rearrangement is monoclonal
- •
Cytogenetic analysis may show an abnormal karyotype
- •
Autoimmune disease is a risk factor for lymphoma; thus, lymphoma has to be ruled out in all cases with immunohistochemistry, flow cytometry, and, if indicated, cytogenetics and PCR
- •
Rheumatoid arthritis usually manifests with axillary lymphadenopathy
- •
Correlation with clinical presentation is recommended to rule out infection
Selected References
Bagg A.: Malleable immunoglobulin genes and hematopathology—the good, the bad, and the ugly: a paper from the 2007 William Beaumont Hospital Symposium on Molecular Pathology. J Mol Diagn 2008; 10: pp. 396-410.
Engels K., Oeschger S., Hansmann M.L., et. al.: Bone marrow trephines containing lymphoid aggregates from patients with rheumatoid and other autoimmune disorders frequently show clonal B-cell infiltrates. Hum Pathol 2007; 38: pp. 1402-1411.
Cytomegalovirus Lymphadenitis
Clinical Features
- •
Can be seen in immunocompetent and immunosuppressed individuals
- •
Only ∼10% of acquired CMV infections produce symptoms
- •
The most common presentation in symptomatic patients is with infectious mononucleosis (IM)-like illness (fever, fatigue, atypical lymphocytosis)
Histopathology
- •
Early CMV is characterized by reactive follicular hyperplasia and monocytoid B-cell hyperplasia ( Figure 14.2A )
Figure 14.2
Cytomegalovirus lymphadenitis.
A, Marked reactive follicular hyperplasia and monocytoid B-cell hyperplasia. B, Cytomegaly and large intranuclear viral inclusion.
- •
Subsequently there is predominantly paracortical hyperplasia with many immunoblasts and hypervascularity
- •
Immunocompromised patients may have necrosis
- •
Large intranuclear inclusions and cytomegaly are found most often within monocytoid B-cell areas (see Figure 14.2B )
Special Stains and Immunohistochemistry
- •
CMV immunostain confirms the diagnosis
- •
Cells containing inclusions may express CD15
Other Techniques for Diagnosis
- •
Viral culture
- •
CMV serology
- •
Molecular amplification
Differential Diagnosis
Nonspecific Follicular Hyperplasia
- •
No staining with CMV antibody
- •
No clinical evidence of CMV infection
Toxoplasma Lymphadenitis
- •
Has numerous aggregates of epithelioid histiocytes in the lymphoid follicles in addition to follicular hyperplasia and monocytoid B-cell hyperplasia
- •
No staining with CMV antibody
Classical Hodgkin Lymphoma
- •
Cells with viral inclusions may resemble Reed-Sternberg cells and variants
- •
Reed-Sternberg cells express CD15 and CD30, whereas CMV-infected cells are CD30 negative
- •
No staining with CMV antibody
Small B-Cell Lymphoma
- •
Viral inclusions are not present
- •
No staining with CMV antibody
- •
Flow cytometry: monotypic B lymphocytes
- •
PCR for IgH gene rearrangement is monoclonal
- •
Cytogenetic analysis: abnormal karyotype
- •
Only a few cells with viral inclusions may be found
- •
CMV immunostain is paramount in making the diagnosis
Selected References
Navalpotro D., Gimeno C., Navarro D.: PCR detection of viral DNA in serum as an ancillary analysis for the diagnosis of acute mononucleosis-like syndrome due to human cytomegalovirus (HCMV) in immunocompetent patients. J Clin Virol 2006; 35: pp. 193.
Orasch C., Conen A.: Severe primary cytomegalovirus infection in the immunocompetent adult patient: a case series. Scand J Infect Dis 2012; 44: pp. 987-991.
Toxoplasmosis
Clinical Features
- •
Caused by the intracellular protozoan parasite, Toxoplasma gondii
- •
Immunocompetent persons with primary infection are usually asymptomatic
- •
There is a lifelong risk of reactivation should the individual become immunocompromised
- •
The most common clinical manifestation is bilateral, symmetrical, nontender cervical adenopathy
Histopathology
See Figure 14.3A .
- •
Triad of reactive follicular hyperplasia, monocytoid B-cell hyperplasia, and aggregates of epithelioid histiocytes
- •
The histiocytes may be present as single cells or small clusters, typically encroaching on germinal centers
- •
The organism itself is identified in <1% of cases
- •
No evidence of significant necrosis or granuloma formation
Special Stains and Immunohistochemistry
- •
Toxoplasma immunostain is usually negative due to absence of the parasites but occasionally may be useful (see Figure 14.3B )
Other Techniques for Diagnosis
- •
Serology testing is the most common diagnostic tool
- •
Toxoplasma DNA identification by PCR in the tissue or blood has been reported
Differential Diagnosis
Nonspecific Follicular Hyperplasia
- •
Does not have epithelioid histiocytes encroaching on germinal centers
HIV Lymphadenitis
- •
Does not have epithelioid histiocytes encroaching on germinal centers
Leishmaniasis
- •
Can have similar morphology
- •
Necrotizing or non-necrotizing granulomas with giant cells
- •
Intracellular organisms can be seen in the histiocytes with hematoxylin and eosin (H&E) stain, Giemsa, and other special stains
Cat Scratch Disease
- •
Does not have epithelioid histiocytes encroaching on germinal centers
- •
Typically has multifocal necrosis with clusters of neutrophils
- •
Intracellular organisms are detected by Warthin-Starry stain
Sarcoidosis
- •
Granulomas are larger, more numerous, and well circumscribed
- •
Frequently the lymph node is partially or wholly replaced by granulomas
- •
No evidence of follicular hyperplasia or monocytoid B-cell hyperplasia
- •
The classic triad is strongly associated with serologic confirmation of infection
- •
In AIDS patients, toxoplasmosis reactivates as toxoplasma encephalitis; lymph node involvement is rare
- •
When toxoplasma infection is acquired for the first time during pregnancy, infection can be transmitted to the fetus, resulting in severe damage
Selected References
Eapen M., Mathew C.F., Aravindan K.P.: Evidence based criteria for the histopathological diagnosis of toxoplasma lymphadenopathy. J Clin Pathol 2005; 58: pp. 1143-1146.
Lin M.H., Kuo T.T.: Specificity of the histopathological triad for the diagnosis of toxoplasmic lymphadenitis: polymerase chain reaction study. Pathol Int 2001; 51: pp. 619-623.
HIV-Related Lymphadenopathy
Clinical Features
- •
Acute symptomatic HIV infection is characterized by fever, lymphadenopathy, sore throat, rash, myalgia/arthralgia, and headache
- •
The axillary, cervical, and occipital nodes are primarily enlarged
- •
Lymph nodes decrease in size following the acute presentation, but some degree of adenopathy tends to persist
- •
- •
Persistent generalized lymphadenopathy is defined as lymphadenopathy of >3-month duration involving at least two noncontiguous lymph node areas in the absence of other illness
Histopathology
- •
Morphologic features depend on evidence of disease progression
- •
Early HIV is characterized by florid follicular hyperplasia:
- •
Numerous large, irregular germinal centers
- •
Germinal centers have high mitotic rate, numerous centroblasts, and tingible-body macrophages
- •
Follicle lysis is characteristic (fragmented follicles with hemorrhage and invagination by small lymphocytes)
- •
Mantle zones are attenuated
- •
Monocytoid B-cells are frequently prominent
- •
Paracortex contains plasma cells, immunoblasts, histiocytes, eosinophils, neutrophils, and prominent vasculature
- •
Sinus histiocytosis with occasional erythrophagocytosis and polykaryocytes
- •
Well-formed granulomas or scattered epithelioid histiocytes may be seen
- •
- •
Advanced stages of disease are associated with lymphoid depletion ( Figure 14.4 ):
- •
Follicles become small, atrophic, and hyalinized
- •
Paracortex is expanded with increased histiocytes and plasma cells and decreased lymphocytes
- •
Numerous blood vessels and fibrosis or deposition of amorphous eosinophilic material
Figure 14.4
HIV-related lymphadenopathy, advanced stage disease.
Atrophic germinal center with expanded paracortex and hypervascularity.
- •
Special Stains and Immunohistochemistry
- •
Reactive germinal centers contain numerous CD8-positive T lymphocytes
- •
Interfollicular area contains a decreased number of CD4-positive T lymphocytes and an increased number of S-100–positive interdigitating dendritic cells
- •
Scattered Epstein-Barr virus (EBV)-positive cells are frequently found
- •
Advanced cases show no evidence of CD21+, CD23+ follicular dendritic cell meshworks
Other Techniques for Diagnosis
- •
HIV serology
- •
HIV RNA detection (viral load)
- •
Flow cytometry for CD4 and CD8 T-cell subsets
Differential Diagnosis
Nonspecific Follicular Hyperplasia
- •
May be morphologically indistinguishable from early HIV
- •
Follicles are typically not as large and less irregular
- •
Well-defined mantle zones
Infectious Mononucleosis
- •
May be morphologically indistinguishable from early HIV
- •
EBV-positive lymphocytes are much more numerous
Follicular Lymphoma
- •
Follicles tend to be uniform in size and shape and uniformly distributed throughout the node
- •
No evidence of tingible-body macrophages in the germinal centers
- •
Germinal center cells express Bcl-2
- •
Flow cytometry and PCR: evidence of a monoclonal B-cell population
- •
Cytogenetics and FISH: t(14;18) translocation and other cytogenetic abnormalities
Angioimmunoblastic T-Cell Lymphoma
- •
May resemble late-stage HIV due to presence of regressed germinal centers, scattered EBV-positive immunoblasts, lymphoid depletion, and marked proliferation of high endothelial venules
- •
Morphologic evidence of atypical small to medium-sized lymphocytes with clear cytoplasm
- •
Tumor cells are CD4-positive T-cells that coexpress CD10, Bcl-6, PD-1, and CXCL13 (T-helper cells)
- •
Follicular dendritic cell meshworks are numerous and expanded
Castleman Disease
- •
May resemble late-stage HIV due to presence of atrophic follicles and paracortical vascularity and hyalinization
- •
The follicles are distinctive, with onion-skinning of mantle zones and lollipop appearance
- •
May express human herpesvirus 8 (HHV-8)
Kaposi Sarcoma
- •
Common in HIV patients
- •
Neoplastic proliferation of lymphatic endothelial cells with evidence of red blood cell extravasation and hyaline globules
- •
Extensive expression of HHV-8 by the endothelial cells
Mycobacterium Avium Intracellulare Infection
- •
Atypical mycobacterial infection in HIV patients may show a histiocytic proliferation with foamy or spindle histiocytes (mycobacterial pseudotumors)
- •
HIV-positive patients do not develop well-formed granulomas
- •
Acid-fast stain reveals numerous intracellular organisms
- •
Lymph node excision due to acute HIV is uncommon nowadays due to extensive accumulated clinical experience with HIV
- •
Lymph node excision in patients with known advanced HIV is usually performed to rule out AIDS-associated lymphoma
- •
Histologic features of HIV are highly suggestive but are not pathognomonic
- •
HIV may be detected in follicular dendritic cells even in patients treated with antiretroviral therapy
Selected References
Alos L., Naverrete P., Morente V., et. al.: Immunoarchitecture of lymphoid tissue in HIV-infection during antiretroviral therapy correlates with viral persistence. Mod Pathol 2005; 18: pp. 127-136.
Chadburn A., Abdul-Nabi A.M., Teruya B.S., et. al.: Lymphoid proliferations associated with human immunodeficiency virus infection. Arch Pathol Lab Med 2013; 137: pp. 360-370.
Kimura Disease
Clinical Features
- •
Kimura disease presents as large, painless subcutaneous masses and lymphadenopathy of the head or neck
- •
East Asian males are classically affected
- •
Up to 40% of the patients have salivary gland involvement
- •
Patients have eosinophilia and elevated serum IgE level
Histopathology
- •
Reactive follicular hyperplasia
- •
Highly vascular germinal centers and paracortex
- •
Germinal centers have deposition of eosinophilic proteinaceous material (IgE)
- •
Germinal centers and paracortex contain numerous eosinophils with eosinophilic microabscesses and polykaryocytes ( Figure 14.5 )
Figure 14.5
Kimura disease.
A germinal center with deposition of eosinophilic material and numerous eosinophils.
Courtesy Dr. Dennis O’Malley, Clarient, Inc., Aliso Viejo, CA.
- •
Prominent fibrosis may be seen
Special Stains and Immunohistochemistry
- •
IgE stains the dendritic meshwork of the germinal centers
Other Techniques for Diagnosis
- •
Laboratory workup reveals eosinophilia and elevated serum IgE levels in virtually all patients
Differential Diagnosis
Angiofollicular Hyperplasia With Eosinophilia
- •
Typically presents in middle-aged Caucasian women
- •
Smaller, more superficial, and better defined lesions
- •
Has prominent epithelioid endothelial cell proliferation (may represent a benign vascular neoplasm)
- •
Eosinophilic abscesses are unusual
Classical Hodgkin Lymphoma
- •
Diagnostic Reed-Sternberg cells are present
- •
The inflammatory infiltrate contains eosinophils, but also numerous small lymphocytes, plasma cells, neutrophils, and histiocytes
- •
Reed-Sternberg cells express CD15 and CD30
Langerhans Cell Histiocytosis
- •
Sinusoidal dilation and infiltration
- •
May have prominent eosinophilia associated with neutrophils, histiocytes, and aggregates of Langerhans cells
- •
Langerhans cells express CD1a, S-100 protein, and langerin
Parasitic Infection
- •
Clinical history of active parasitosis
Drug-Related Lymphadenopathy
- •
Part of a systemic hypersensitivity reaction to medication
- •
Paracortical proliferation of immunoblasts, with or without follicular hyperplasia
- •
May have increased number of eosinophils in the paracortex
Nonspecific Follicular Hyperplasia
- •
Diagnosis of exclusion
- •
Kimura disease and angiofollicular hyperplasia with eosinophilia used to be grouped together in the older literature; however, now they are recognized as distinct entities
- •
The triad of florid follicular hyperplasia, eosinophilia, and hypervascularity is considered characteristic of Kimura disease
Selected References
Chen H., Thompson L.D., Aguilera N.S., et. al.: Kimura disease: a clinicopathologic study of 21 cases. Am J Surg Pathol 2004; 28: pp. 505-513.
Don D.M., Ishiyama A., Johnstone A.K., et. al.: Angiolymphoid hyperplasia with eosinophilia and vascular tumors of the head and neck. Am J Otolaryngol 1996; 17: pp. 240-245.
Mejia R., Nutman T.B.: Evaluation and differential diagnosis of marked, persistent eosinophilia. Semin Hematol 2012; 49: pp. 149-159.
IgG4-Related Lymphadenopathy
Clinical Features
- •
IgG4-related disease is a systemic inflammatory condition characterized by tumefactive sclerosing lesions in multiple organs
- •
Classic disease presents as autoimmune pancreatitis
- •
Other frequently involved organs include ocular adnexa, salivary glands, kidney, lung, liver, and gallbladder
- •
Up to 80% of patients have systemic lymphadenopathy on imaging
Histopathology
- •
Broad morphologic spectrum
- •
Type I (multicentric Castleman disease–like) has hyperplastic follicles and atrophic follicles with interfollicular vascular proliferation and eosinophilia
- •
Type II (follicular hyperplasia) has intrafollicular and paracortical plasmacytosis and scattered eosinophils
- •
Type III (paracortical expansion) has prominent high endothelial venules, small lymphocytes, immunoblasts, plasmablasts, and eosinophils
- •
Type IV (progressive transformation of germinal centers [PTGC]) has enlarged follicles with expanded mantle zones and scattered intrafollicular plasma cells
- •
Type V (inflammatory pseudotumor-like) is extremely rare and has focal node replacement by fibrous tissue with embedded plasma cells and lymphocytes
- •
Perifollicular granulomas may be identified
Special Stains and Immunohistochemistry
- •
Staining for kappa and lambda light chains demonstrates polytypic plasma cells
- •
IgG and IgG4 quantify the number of plasma cells ( Figure 14.6 )
- •
>100 IgG4-positive plasma cells per high power field in at least three high-power fields
- •
IgG4/IgG ratio >40%
Figure 14.6
IgG4-related lymphadenopathy.
A, Immunohistochemical stain for IgG4 highlights numerous positive plasma cells. B, Immunohistochemical stain for IgG from the same area.
- •
Other Techniques for Diagnosis
- •
Elevated serum level of IgG4 in approximately two-thirds of the patients
- •
Imaging to rule out involvement of other organs
Differential Diagnosis
Castleman Disease
- •
Elevated IL-6 and C-reactive protein (normal levels in IgG4-related disease)
- •
No significant increase in IgG4-positive plasma cells
- •
May express HHV-8
- •
May show light-chain restriction in the plasma cells
Nonspecific Follicular Hyperplasia
- •
No significant increase in IgG4-positive plasma cells
- •
Diagnosis of exclusion
Progressive Transformation of Germinal Centers
- •
No significant increase in IgG4-positive plasma cells
Inflammatory Pseudotumor
- •
Spindle cell proliferation with a mixed infiltrate of small lymphocytes, immunoblasts, histiocytes, eosinophils, and many plasma cells
- •
Infectious etiology can be proven in some of these cases (atypical mycobacteria, Treponema pallidum, EBV, and others)
- •
Immunohistochemical staining to rule out increase in IgG4 plasma cells should be done in all cases of suspected inflammatory pseudotumor
Small B-Cell Lymphoma with Plasmacytic Differentiation
- •
Immunohistochemical staining for kappa and lambda light chains shows light chain restriction in the plasma cells
- •
Flow cytometry and PCR: evidence of a monoclonal B-cell population
- •
Cytogenetics and FISH: evidence of cytogenetic abnormalities
Angioimmunoblastic T-Cell Lymphoma
- •
Characteristic morphology with a polymorphous paracortical infiltrate composed of small to medium-sized atypical lymphocytes with moderate pale cytoplasm admixed with numerous reactive small lymphocytes, immunoblasts, eosinophils, plasma cells, and histiocytes
- •
Paracortical vascular proliferation
- •
T-cells have a follicular T-helper immunophenotype CD10+, BCL6+, PD-1+, and CXCL13+
- •
CD21 and CD23 highlight expanded follicular dendritic cell meshworks
- •
No significant increase in IgG4-positive plasma cells
- •
There is growing evidence that the disease is CD4 positive cytotoxic and T-follicular helper cell driven autoimmune process, and that the IgG4 antibodies are not pathogenic
- •
The diagnosis cannot be rendered based on the increased number of IgG4-positive plasma cells alone, because a large number of other entities can have such cells (carcinoma, lymphoma, etc.)
- •
Capsular and septal-based fibrosis with inflammatory pseudotumor-like pattern is the most specific morphologic pattern for IgG4-related disease
- •
If the patient is not known to have systemic IgG4-related disease, the suggested diagnosis is “reactive lymphoid hyperplasia with increased IgG4+ cells”
- •
Clinician should be encouraged to rule out IgG4-related disease clinically
- •
IgG4-related disease is clinically important because the patients have an excellent response to steroids
- •
IgG4-related lymphadenopathy differs from IgG4-related involvement of other sites in that sclerosis is exceptionally rare
Selected References
Bledsoe J.R., Della-Torre E., Rovati L., et. al.: IgG4-related disease: review of the histopathologic features, differential diagnosis, and therapeutic approach. APMIS 2018; 126: pp. 459-476.
Cheuk W., Chan J.K.: Lymphadenopathy of IgG4-related disease: an underdiagnosed and overdiagnosed entity. Semin Diagn Pathol 2012; 29: pp. 226-234.
Deshpande V., Zen Y., Chan J.K., et. al.: Consensus statement on the pathology of IgG4-related disease. Mod Pathol 2012; 25: pp. 1181-1192.
Grimm K.E., Barry T.S., Chizhevsky V., et. al.: Histopathological findings in 29 lymph node biopsies with increased IgG4 plasma cells. Mod Pathol 2012; 25: pp. 480-491.
Rollins-Raval M.A., Felgar R.E., Krasinskas A.M., et. al.: Increased numbers of IgG4-positive plasma cells may rarely be seen in lymph nodes of patients without IgG4-related sclerosing disease. Int J Surg Pathol 2012; 20: pp. 47-53.
Sato Y., Inoue D., Asano N., et. al.: Association between IgG4-related disease and progressively transformed germinal centers of lymph nodes. Mod Pathol 2012; 25: pp. 956-967.
Stone J.H., Zen Y., Deshpande V.: IgG4-related disease. N Engl J Med 2012; 366: pp. 539-551.
Progressive Transformation of Germinal Centers
Clinical Features
- •
Typically an incidental finding of an isolated enlarged lymph node
- •
Most common in children and young adults
- •
Male predominance
Histopathology
- •
One to several well-defined nodules (transformed germinal centers) with expanded mantle zone ( Figure 14.7 )
Figure 14.7
Progressive transformation of germinal centers.
A large well-defined nodule with expanded mantle zone and a fragmented germinal center.
- •
Residual germinal centers are fragmented or not evident
- •
No evidence of large atypical lymphoid cells in the nodules
- •
Background of typical follicular hyperplasia
Special Stains and Immunohistochemistry
- •
Nodules are composed of CD20+, Pax-5+ B lymphocytes with features of mantle cells (Bcl-2+, IgD+)
- •
No evidence of large atypical B lymphocytes inside or outside the nodules
- •
Increased number of CD57+ cells in the germinal centers
Other Techniques for Diagnosis
- •
Flow cytometry may demonstrate a population of CD4+/CD8+ T lymphocytes
- •
Cytogenetics and PCR: no evidence of B-cell clonality
Differential Diagnosis
Nodular Lymphocyte-Predominant Hodgkin Lymphoma
- •
Generally the entire lymph node is involved by lymphoma
- •
Characterized by presence of scattered large atypical lymphoid cells with a folded or multilobated nucleus and scant cytoplasm (“popcorn” cell or lymphocyte predominant (LP) cell)
- •
LP cells are ringed by CD3+, CD57+, PD-1+ T lymphocytes
- •
Rarely, may coexist with or have a history of PTGC
Follicular Lymphoma
- •
Generally the entire lymph node is involved by lymphoma
- •
The B-cells coexpress Bcl-6, CD10, and Bcl-2
- •
Flow cytometry: B lymphocytes show light chain restriction
- •
Conventional karyotype and FISH: t(14;18); BCL2/IGH gene rearrangement
Mantle Cell Lymphoma
- •
Generally the entire lymph node is involved by lymphoma
- •
B lymphocytes coexpress CD5 and Cyclin D1
- •
Flow cytometry: B lymphocytes show light chain restriction
- •
Conventional karyotype and FISH: t(11;14); IGH/CCND1 gene rearrangement
IgG4-Related Lymphadenopathy
- •
Increased number of plasma cells in the interfollicular area
- •
>100 IgG4-positive plasma cells per high power field
- •
IgG4/IgG ratio >40%
- •
The differential diagnosis with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) can be challenging and requires careful examination of morphology
- •
Rarely, PTGC can precede, coexist with, or follow the diagnosis of NLPHL
Selected References
Chang C.C., Osipov V., Wheaton S., et. al.: Follicular hyperplasia, follicular lysis, and progressive transformation of germinal centers: a sequential spectrum of morphologic evolution in lymphoid hyperplasia. Am J Clin Pathol 2003; 120: pp. 322-326.
Hicks J., Flaitz C.: Progressive transformation of germinal centers: review of histopathologic and clinical features. Int J Pediatr Otorhinolaryngol 2002; 265: pp. 195-202.
Nguyen P.L., Ferry J.A., Harris N.L.: Progressive transformation of germinal centers and nodular lymphocyte predominance Hodgkin’s disease: a comparative immunohistochemical study. Am J Surg Pathol 1999; 23: pp. 27-33.
Rahemtullah A., Harris N.L., Dorn M.E., et. al.: Beyond the lymphocyte predominant cell: CD4 + CD8 + T cells in nodular lymphocyte predominant Hodgkin lymphoma. Leuk Lymphoma 2008; 49: pp. 1870-1878.
Shaikh F., Ngan B.Y., Alexander S., et. al.: Progressive transformation of germinal centers in children and adolescents: an intriguing cause of lymphadenopathy. Pediatr Blood Cancer 2013; 60: pp. 26-30.
Reactive Paracortical Hyperplasia
Infectious Mononucleosis
Clinical Features
- •
Most patients are adolescents and young adults
- •
Patients typically present with fever, pharyngitis, and cervical lymphadenopathy
- •
Caused by EBV
Histopathology
- •
Lymph node architecture is distorted
- •
Expanded paracortex with a polymorphous proliferation of small, medium-sized, and numerous large lymphoid cells (immunoblasts) ( Figure 14.8 )
Figure 14.8
Infectious mononucleosis.
Expanded paracortex with numerous large immunoblasts.
- •
Immunoblasts may be morphologically atypical, sometimes resemble Reed-Sternberg cells, and may form large aggregates
- •
Increased mitotic activity
- •
Necrosis may be present
Special Stains and Immunohistochemistry
- •
Most immunoblasts are CD20+, Mum-1+, CD10− B-cells
- •
Some immunoblasts express CD30, but are always CD15 negative
- •
The majority of the small and medium-sized lymphocytes are T-cells
- •
In situ hybridization for Epstein-Barr virus (EBV)-encoded RNA (EBER) highlights numerous positive small and large lymphocytes
Other Techniques for Diagnosis
- •
Monospot (heterophile antibody)
- •
Serology
- •
EBV viral load
Differential Diagnosis
Diffuse Large B-Cell Lymphoma
- •
Occurs in older individuals
- •
The neoplastic B-cell population is more homogeneous with sheets of large transformed lymphocytes
- •
EBV-encoded RNA (EBER) may be positive, but only in the large neoplastic cells
Peripheral T-Cell Lymphoma
- •
There is evidence of T-cell antigen loss or aberrant antigen expression
- •
EBER may be positive, but in a much smaller number of cells and only in the large immunoblasts
Classical Hodgkin Lymphoma
- •
Even though immunoblasts in IM may appear atypical, most do not resemble Reed-Sternberg cells
- •
Reed-Sternberg cells express CD30 and CD15
- •
EBER may be positive, but in a smaller number of cells and only in the large neoplastic cells
CMV Lymphadenitis
- •
Immunohistochemistry for CMV is positive
- •
EBER is negative
HIV-Associated Lymphadenopathy (Early Phase)
- •
Florid follicular hyperplasia without significant paracortical expansion
- •
EBER may be positive, but only in rare scattered cells
- •
Lymph node biopsy is not indicated in IM; thus, the diagnosis is not suspected clinically in the majority of the patients
- •
The combination of immunoblastic proliferation and necrosis frequently raises the possibility of lymphoma
- •
The possibility of IM has to be ruled out in every young patient with suspicion for aggressive high-grade lymphoma or classical Hodgkin lymphoma (CHL)
- •
IM is a frequent cause of misdiagnosis and second opinion send-out
Selected References
Kojima M., Nakamura S., Itoh H., et. al.: Acute viral lymphadenitis mimicking low-grade peripheral T-cell lymphoma: a clinicopathological study of nine cases. APMIS 2001; 109: pp. 419-427.
Louissaint A., Ferry J.A., Soupir C.P., et. al.: Infectious mononucleosis mimicking lymphoma: distinguishing morphological and immunophenotypic features. Mod Pathol 2012; 2: pp. 1149-1159.
Pittaluga S.: Viral-associated lymphoid proliferations. Semin Diagn Pathol 2013; 30: pp. 130-136.
Herpes Simplex Lymphadenitis
Clinical Features
- •
Lymphadenopathy can be localized or generalized and is rarely biopsied
- •
Biopsy is usually performed on the inguinal lymph nodes, when there is a concurrent anogenital infection
- •
Lymphadenopathy is usually painful
- •
Many patients are immunosuppressed due to an associated malignancy or immunodeficiency
Histopathology
- •
Lymph node architecture is distorted but preserved
- •
Prominent paracortical hyperplasia with many immunoblasts
- •
Multifocal necrosis with neutrophils, debris, and cells with viral inclusions ( Figure 14.9 )
Figure 14.9
Herpes simplex virus lymphadenitis.
Necrosis and cells with large viral inclusions.
Courtesy Dr. Dennis O’Malley, Clarient, Inc., Aliso Viejo, CA.
- •
Cells with inclusions contain ground-glass nuclei or intranuclear eosinophilic inclusions with halos, chromatin margination, and multinucleation
- •
Rare cases may present with nonspecific viral-type morphologic pattern: florid follicular hyperplasia, monocytoid B-cell hyperplasia, and paracortical hyperplasia without extensive necrosis
Special Stains and Immunohistochemistry
- •
Herpes simplex virus (HSV) immunostain is positive
Other Techniques for Diagnosis
- •
Viral culture
- •
Serology
Differential Diagnosis
Histiocytic Necrotizing Lymphadenitis (Kikuchi Disease)
- •
Numerous CD123+ plasmacytoid dendritic cells are present
- •
There is extensive necrosis with admixed karyorrhectic debris but no neutrophils
- •
Viral inclusions are absent
Cat Scratch Disease
- •
Early lesions contain prominent monocytoid B-cell hyperplasia and neutrophils, but little necrosis
- •
Late lesions show granulomas
- •
Viral inclusions are absent
- •
Warthin-Starry stain shows numerous microorganisms
Diffuse Large B-Cell Lymphoma
- •
The nodal architecture is effaced with sheets of large transformed lymphoid cells
- •
Viral inclusions are absent
- •
Necrosis is not associated with granuloma formation, arguing against most other necrotizing infections
- •
Rare cases of concomitant HSV and EBV infection in the same lymph node have been described in immunosuppressed patients
- •
Rarely, initial diagnosis of genital HSV infection may be established by inguinal lymph node biopsy
Selected References
Fleming SA, Strickler JG. Unusual initial presentation of herpes simplex virus as inguinal lymphadenopathy. Case Rep Pathol . 2015;2015:573230.
Gattenlohner S, Etschmann B, Lippert BM, et al. Concomitant herpes simplex and Epstein-Barr virus lymphadenitis with simultaneous lymph node metastases of an occult squamous cell carcinoma in a patient with chronic lymphocytic leukemia. Leuk Lymphoma . 2008;49:2390–2392.
Higgins J, Warnke R. Herpes lymphadenitis in association with chronic lymphocytic leukemia. Cancer . 1999;86:1210–1215.
Joseph L, Scott MA, Schichman SA, et al. Localized herpes simplex lymphadenitis mimicking large cell (Richter) transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma. Am J Hematol . 2001;68:287–291.
Witt M, Torno M, Sun M, et al. Herpes simplex virus lymphadenitis: case report and review of the literature. Clin Infect Dis . 2002;34:1–6.
Dermatopathic Lymphadenitis
Clinical Features
- •
Found in patients with benign and malignant chronic skin conditions
- •
Lymphadenitis occurs in the lymph nodes that drain the affected area
- •
Axillary and inguinal lymph nodes are most commonly affected
Histopathology
- •
The lymph node architecture is preserved
- •
Marked diffuse or nodular expansion of the paracortex
- •
Proliferation of interdigitating dendritic cells, Langerhans cells, and histiocytes that contain melanin pigment ( Figure 14.10 )
Figure 14.10
Dermatopathic lymphadenitis.
Nodular paracortical hyperplasia with numerous admixed dendritic cells and pigment-laden macrophages.
Special Stains and Immunohistochemistry
- •
The lymphocytes are predominantly CD4+ T-cells
- •
Langerhans cells express S-100 and CD1a
- •
Interdigitating cells express S-100 and are negative for CD1a
- •
Histiocytes are highlighted by CD68 and CD163
Other Techniques for Diagnosis
- •
T-cell receptor gamma gene (TCR) rearrangement shows polyclonal T lymphocytes
Differential Diagnosis
Mycosis Fungoides
- •
Nodal architecture may be preserved or effaced depending on the degree of involvement
- •
Atypical lymphocytes are present singly, in small clusters, or in large aggregates
- •
Typical immunophenotype of neoplastic lymphocytes is CD3+, CD2+, CD5+, and CD4+, and negative for CD8 and CD7
- •
PCR: monoclonal TCR gene rearrangement
- •
Conventional cytogenetics: many cases have a complex karyotype
Adult T-Cell Leukemia/Lymphoma
- •
Lymphadenopathy is one of the most frequent manifestations of adult T-cell leukemia/lymphoma (ATLL)
- •
Diffuse architectural effacement with proliferation of medium-sized or large pleomorphic cells is usually seen
- •
Atypical lymphoid cells have an abnormal T-cell phenotype
- •
PCR: monoclonal TCR gene rearrangement
Langerhans Cell Histiocytosis
- •
Numerous Langerhans cells, present singly or in aggregates
- •
Neoplastic proliferation occurs in the sinuses and is accompanied by eosinophils, neutrophils, plasma cells, and histiocytes
Nonspecific Paracortical Hyperplasia
- •
Dendritic cells and Langerhans cells are less numerous
- •
No evidence of melanin-containing macrophages
- •
Enlarged lymph nodes from patients with cutaneous T-cell lymphoma, such as mycosis fungoides or ATLL frequently show dermatopathic changes
- •
Cutaneous T-cell lymphoma in lymph node can be subtle morphologically; thus, PCR for TCR gene rearrangement should be ordered in difficult cases
- •
Melanin pigment particles are darker, smaller, and nonrefringent as opposed to hemosiderin
Selected References
Chinen S., Miyagi T., Murakami Y., et. al.: Dermatopathic reaction of lymph nodes in HTLV-1 carriers: a spectrum of reactive and neoplastic lesions. Histopathology 2020; 77: pp. 133-143.
Garces S., Yin C.C., Miranda R.N., et. al.: Clinical, histopathologic, and immunoarchitectural features of dermatopathic lymphadenopathy: an update. Mod Pathol 2020; 33: pp. 1104-1121.
Drug-Related Lymphadenopathy
Clinical Features
- •
Lymphadenopathy usually occurs 2 to 8 weeks after exposure to the drug
- •
May be part of drug reaction with eosinophilia and systemic symptoms (DRESS)
- •
Most often associated with antiepileptic agents (carbamazepine, lamotrigine, phenytoin, phenobarbital), vancomycin and allopurinol
- •
HHV-6 reactivation is thought to contribute to the underlying pathogenesis and clinical manifestations of DRESS lymphadenitis
- •
Cervical lymph nodes are usually involved, but lymphadenopathy may be systemic
Histopathology
- •
Paracortical hyperplasia with increased immunoblasts and eosinophilia ( Figure 14.11 )
Figure 14.11
Drug-related lymphadenopathy.
Paracortical hyperplasia with numerous immunoblasts.
- •
Immunoblasts may form large aggregates
Special Stains and Immunohistochemistry
- •
Immunoblasts express CD30 and are negative for CD15
- •
HHV-6 specific immunohistochemistry and in situ hybridization may highlight the large atypical T lymphocytes
Other Techniques for Diagnosis
- •
Clinical history of exposure to high-risk medication
Differential Diagnosis
Diffuse Large B-Cell Lymphoma
- •
The lymph node architecture is typically effaced
- •
Tumor cells rarely express CD30
- •
Flow cytometry, cytogenetic analysis, and PCR show evidence of B-cell clonality
- •
Not related to recent exposure to a new medication
Human Herpesvirus 6–Associated Lymphadenitis
- •
If no history of drug exposure can be documented
- •
Present with complete or partial effacement of architecture with marked paracortical hyperplasia
- •
The large atypical lymphoid cells are T-cells with vesicular chromatin, and prominent eosinophilic intranuclear viral inclusions
Nonspecific Paracortical Hyperplasia
- •
If no history of drug exposure can be documented
- •
Is a diagnosis of exclusion
- •
Complete and accurate clinical history is necessary to make the diagnosis
- •
Cases with a prominent immunoblastic reaction have been called pseudolymphoma in the older literature
- •
The relationship between drug-related lymphadenopathy and HHV6-associated lymphadenitis is for now unclear
Selected References
Balakrishna J.P., Bhavsar T., Nicolae A., et. al.: Human Herpes Virus 6 (HHV-6)-associated lymphadenitis: pitfalls in diagnosis in benign and malignant settings. Am J Surg Pathol 2018; 42: pp. 1402-1408.
Brown J.R., Skarin A.T.: Clinical mimics of lymphoma. Oncol 2004; 9: pp. 406-416.
Johnson S., Mathews S., Hudnall S.D.: Human herpesvirus 6 lymphadenitis in drug rash with eosinophilia and systemic symptoms syndrome: a lymphoma mimic. Histopathology 2017; 70: pp. 1166-1170.
Mansur A.T., Yaşar S.P., Göktay F.: Anticonvulsant hypersensitivity syndrome: clinical and laboratory features. Int J Dermatol 2008; 47: pp. 1184-1189.
Sinus Histiocytosis
Rosai-Dorfman Disease
Clinical Features
- •
Also known as sinus histiocytosis with massive lymphadenopathy
- •
Rare, usually self-limited histiocytic disorder
- •
Most common in children and young adults
- •
Believed to be a reactive, polyclonal process
- •
About 90% of patients present with bilateral cervical lymphadenopathy
- •
Axillary, inguinal, and mediastinal lymph nodes also frequently involved
- •
Patients also may have fever, weight loss, leukocytosis, anemia, elevated erythrocyte sedimentation rate (ESR)
Histopathology
- •
Lymph node architecture is preserved
- •
The capsule is thickened
- •
There is marked dilation of the sinuses and numerous intrasinusoidal histiocytes ( Figure 14.12A )
- •
Very large cells with abundant eosinophilic cytoplasm and round nuclei with a single central nucleolus
- •
A variable number of the histiocytes contain well-preserved lymphocytes and, occasionally, plasma cells, neutrophils, and erythrocytes in their cytoplasm (emperipolesis) (see Figure 14.12B )
Figure 14.12
Rosai-Dorfman disease.
A, Dilated sinuses and numerous large histiocytes. B, Emperipolesis. C, S-100 protein immunostain highlights the abnormal histiocytes.
- •
- •
The remaining intrasinusoidal infiltrate consists of small lymphocytes and abundant plasma cells
Special Stains and Immunohistochemistry
- •
The histiocytes strongly express S-100 protein and other macrophage-associated antigens (CD14, CD68, CD163) (see Figure 14.12C )
- •
Lesional histiocytes frequently have strong and diffuse nuclear Cyclin D1 expression
- •
The histiocytes are negative for CD1a and langerin
- •
Some cases have an increased number of IgG4-positive plasma cells
Other Techniques for Diagnosis
- •
Sequencing studies demonstrate presence of recurrent KRAS, NF1, and MAP2K1 mutations in select cases
- •
BRAF-V600E mutation appears to be exceptionally rare or absent
Differential Diagnosis
Nonspecific Sinus Histiocytosis
- •
Lacks distinctive large histiocytes with round nuclei and prominent nucleoli
- •
No evidence of emperipolesis
- •
Histiocytes do not express S-100
Lymph Nodes Draining Prosthetic Implants
- •
Histiocytes contain coarse refractile material
- •
Lack distinctive large histiocytes with round nuclei and prominent nucleoli
- •
No evidence of emperipolesis
- •
Histiocytes do not express S-100
Langerhans Cell Histiocytosis
- •
Langerhans cells are smaller and have irregular nuclei with grooves (coffee-bean shape)
- •
Langerhans cells express CD1a and langerin in addition to S-100 protein
- •
Sequencing demonstrates presence of BRAF-V600E mutation or MAP2K1 mutations in over 80% of cases
Metastatic Melanoma
- •
Large atypical cells with prominent macronucleoli and intracytoplasmic melanin pigment
- •
Express S-100, Melan-A, HMB-45, microphthalmia-associated transcription factor (MITF)
Metastatic Carcinoma
- •
Cohesive clusters of malignant epithelial cells
- •
Express cytokeratins and epithelial membrane antigen (EMA)
- •
Adenocarcinoma cells may rarely be positive for S-100
- •
The abnormal histiocytic cells are distinctive and are diagnostic of the entity
- •
Extranodal disease, specifically subcutaneous lesions, is more common than lymphadenopathy; the histologic features may be more subtle in these cases
- •
Nodal and extranodal disease may also represent distinct disorders, as nodal disease is more frequently self-limiting
- •
Recent studies shed light on the pathogenesis of Rosai-Dorfman disease , demonstrating that at least a subset are neoplastic in nature, driven by recurrent mutations in MAPK-related genes
Selected References
Baraban E., Sadigh S., Rosenbaum J., et. al.: Cyclin D1 expression and novel mutational findings in Rosai-Dorfman disease. Br J Haematol 2019; 186: pp. 837-844.
Garces S., Medeiros L.J., Patel K.P., et. al.: Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai‐Dorfman disease. Mod Pathol 2017; 30: pp. 1367-1377.
Zhang X., Hyjek E., Vardiman J.: A subset of Rosai-Dorfman disease exhibits features of IgG4-related disease. Am J Clin Pathol 2013; 139: pp. 622-632.
Whipple Disease
Clinical Features
- •
Caused by Tropheryma whipplei, a gram-positive bacillus related to Actinomycetes
- •
Predilection for middle-aged white males of European ancestry
- •
Typically presents with migratory arthralgias, followed by diarrhea, weight loss, and abdominal pain
- •
Uniform regional and frequent peripheral lymph node involvement
Histopathology
- •
Dilation of the sinuses ( Figure 14.13A )
Figure 14.13
Whipple disease.
A, The sinuses are distended with numerous histiocytes. B, Periodic acid–Schiff special stain is positive in the histiocytes.
Courtesy Dr. Dennis O’Malley, Clarient, Inc., Aliso Viejo, CA.
- •
Lipogranulomas
- •
Abundant histiocytes with granular periodic acid–Schiff (PAS)–positive cytoplasm (see Figure 14.13B )
- •
PAS may be negative in rare lymph nodes with low disease burden
- •
- •
Non-necrotizing granulomas can be seen, especially in early or extraintestinal disease
Special Stains and Immunohistochemistry
- •
An immunostain for T. whipplei is available
Other Techniques for Diagnosis
- •
Electron microscopy
- •
PCR on tissue or fluid (saliva, stool)
- •
Small intestinal biopsy is the gold standard for diagnosis
Differential Diagnosis
Nonspecific Sinus Histiocytosis
- •
Sinus histiocytes should not stain with PAS
Atypical Mycobacterial Infection
- •
The organisms are acid-fast bacilli (AFB) positive, whereas T. whipplei is AFB negative
Sarcoidosis
- •
PAS staining and electron microscopy are useful in this differential
- •
In early or atypical cases, the findings may be indistinguishable
Lymphadenopathy Due to Deposition of Exogenous Material
- •
Lymphangiography dye, silicone implants, prosthetic material
- •
Extracellular spaces lined by histiocytes
- •
Histiocytes contain small vacuoles, may be retractile or birefringent
- •
Lymph nodes draining prosthesis may contain PAS-positive granular material
- •
Clinical information is important in this differential diagnosis
Lymphadenopathy Due to Deposition of Endogenous Lipid Material
- •
Typically in porta hepatis and celiac lymph nodes
- •
Can be due to mineral oil, parenteral nutrition, cholesterol crystals, fat embolism, fat necrosis
- •
Vacuolated sinus histiocytes, extracellular empty spaces, and giant cells
- •
Histiocytes are PAS negative
- •
T. whipplei is frequently identified in young children with gastroenteritis
- •
T. whipplei DNA has also been detected in stool and saliva specimens from asymptomatic individuals
- •
CNS involvement with varied symptoms is common in Whipple disease
- •
Whipple disease can be fatal if not treated with antibiotics
- •
It is important to consider Whipple disease in patients with characteristic clinical presentation and sarcoidosis-like histopathologic features
- •
Small bowel biopsy should be recommended to confirm the distinction
Selected References
Alkan S., Beals T.F., Schnitzer B.: . Am J Clin Pathol 2001; 116: pp. 898-904.
Baisden B.L., Lepidi H., Raoult D., et. al.: . Am J Clin Pathol 2002; 118: pp. 742-748.
Edouard S., Fenollar F., Raoult D.: . J Clin Microbiol 2012; 50: pp. 3917-3920.
Finzi G., Franzi F., Sessa F., et. al.: . Ultrastruct Pathol 2007; 3: pp. 169-172.
Lagier J.C., Lepidi H., Raoult D., et. al.: . Medicine (Baltimore) 2010; 89: pp. 337-345.
Necrotizing Lymphadenitis
Kikuchi Disease
Clinical Features
- •
Rare, benign condition of unknown cause usually characterized by cervical lymphadenopathy and fever
- •
Typically occurs in young adults with female predominance
- •
More common in Asians
- •
Patients may also have fatigue, joint pain, rash, leukopenia, and anemia
- •
Disease is self-limited in the majority of patients
Histopathology
See Figure 14.14A and B .
- •
Proliferative phase has patchy nodal involvement
- •
Prominent paracortical expansion by immunoblasts, small lymphocytes, plasmacytoid dendritic cells, and histiocytes
- •
Single cell necrosis and eosinophilic granular debris
- •
- •
Necrotizing phase has extensive necrosis with karyorrhectic debris but no intact neutrophils
- •
Immunoblasts and histiocytes surround the necrotic areas
- •
Histiocytes often have crescentic nuclei and contain phagocytosed debris
- •
- •
Resolution phase has numerous foamy macrophages
- •
The inflammatory infiltrate may extend into the perinodal fat
Special Stains and Immunohistochemistry
- •
CD8+ cytotoxic T lymphocytes are prominent in the necrotic phase
- •
B lymphocytes are virtually absent outside reactive follicles
- •
Histiocytes express lysozyme, CD68, and myeloperoxidase
- •
Plasmacytoid dendritic cells are positive for CD123 (see Figure 14.14C )
Other Techniques for Diagnosis
- •
Noncontributory
Differential Diagnosis
Systemic Lupus Erythematosus
- •
Indistinguishable histologic features
- •
Some cases contain abundant plasma cells
- •
Hematoxylin bodies (ill-defined purple structures in necrotic foci) are rarely present; these are not seen in Kikuchi disease
- •
Azzopardi phenomenon (dark blue DNA material deposited on the basement membrane of blood vessels) is rarely present; it is also absent in Kikuchi disease
- •
Prominent follicular hyperplasia may be seen
Herpes or CMV Lymphadenitis
- •
Patients are usually immunosuppressed
- •
Necrotic areas contain neutrophils and are surrounded by granulation tissue with less pronounced histiocytic infiltration
- •
Viral inclusions are present
- •
Immunohistochemistry confirms the diagnosis
Kawasaki Disease
- •
Mainly affects children younger than 5 years
- •
Characteristic clinical presentation with conjunctivitis, rash, inflammation of the oral mucosa, and lymphadenopathy
- •
Widespread necrosis with many neutrophils
- •
Fibrin thrombi in small vessels and arteritis with fibrinoid necrosis are characteristic
Fungal Lymphadenitis
- •
Patients are usually immunosuppressed and have disseminated disease
- •
Well-formed granulomatous reaction is frequently present
- •
Special stains reveal evidence of fungal forms
Tuberculous Lymphadenitis
- •
Well-formed necrotizing granulomas with many multinucleated giant cells are seen
- •
AFB stain reveals mycobacteria
Cat Scratch Disease
- •
Early disease shows prominent follicular hyperplasia and monocytoid B-cell hyperplasia with focal necrosis
- •
Late disease has extensive necrosis with many neutrophils and granulomas
- •
Warthin-Starry and Steiner stains highlight the bacteria
Diffuse Large B-Cell Lymphoma
- •
May resemble a proliferative phase of Kikuchi disease with numerous immunoblasts
- •
Extensive necrosis with karyorrhectic debris but no intact neutrophils is rare in diffuse large B-cell lymphoma (DLBCL), but it is typical of Kikuchi disease
- •
Immunohistochemical stains reveal numerous B lymphocytes, whereas B-cells are few in number in Kikuchi disease
- •
Flow cytometry, cytogenetic analysis, and PCR demonstrate a monoclonal B-cell population
Peripheral T-Cell Lymphoma
- •
Extensive necrosis with karyorrhectic debris but no intact neutrophils is rare in peripheral T-cell lymphoma (PTCL) but is typical of Kikuchi disease
- •
Nodal T-cell lymphomas are usually CD4-positive, whereas the T lymphocytes in Kikuchi disease are CD8-positive
- •
Immunohistochemical stains usually show loss of pan–T-cell antigens CD2, CD5, CD7, CD43, or Bcl-2
- •
Flow cytometry, cytogenetic analysis, and PCR may demonstrate a monoclonal T-cell population
Classical Hodgkin Lymphoma
- •
Necrosis and a polymorphous inflammatory infiltrate are frequently noted
- •
Prominent eosinophilia is common and is not a feature in Kikuchi disease
- •
Presence of classic Reed-Sternberg cells or lacunar cells is required for diagnosis; these cells are absent in Kikuchi disease
- •
Reed-Sternberg cells express CD30 and CD15
Metastatic Carcinoma
- •
Signet-ring adenocarcinoma cells may be confused with crescentic histiocytes
- •
Signet ring cells contain mucin, whereas the histiocytes contain phagocytized debris
- •
Usually presents in elderly patients with widespread metastatic disease
- •
Immunohistochemical staining for cytokeratins establishes the diagnosis
- •
Although it is commonly thought of as a disease of young Asian women, Kikuchi disease can occur in both sexes and in all age and ethnic groups
- •
The relationship of Kikuchi disease and systemic lupus is controversial; some authors believe it is a forme fruste of lupus
- •
A subset of patients subsequently develops lupus; thus, clinical workup for lupus in all cases is recommended
Selected References
Cramer J., Schmiedel S., Alegre N.G., et. al.: Necrotizing lymphadenitis: Kikuchi-Fujimoto disease alias lupus lymphadenitis?. Lupus 2010; 19: pp. 89-92.
Kim S.K., Kang M.S., Yoon B.Y., et. al.: Histiocytic necrotizing lymphadenitis in the context of systemic lupus erythematosus (SLE): is histiocytic necrotizing lymphadenitis in SLE associated with skin lesions?. Lupus 2011; 20: pp. 809-819.
O’Malley D.P., Grimm K.E.: Reactive lymphadenopathies that mimic lymphoma: entities of unknown etiology. Semin Diagn Pathol 2013; 30: pp. 137-145.
Pileri S.A., Facchetti F., Ascani S., et. al.: Myeloperoxidase expression by histiocytes in Kikuchi’s and Kikuchi-like lymphadenopathy. Am J Pathol 2011; 159: pp. 915-924.
Rosado F.G., Tang Y.W., Hasserjian R.P., et. al.: Kikuchi-Fujimoto lymphadenitis: role of parvovirus B-19, Epstein-Barr virus, human herpesvirus 6, and human herpesvirus 8. Hum Pathol 2013; 44: pp. 255-259.
Seong G.M., Kim J.H., Lim G.C., et. al.: Clinicopathological review of immunohistochemically defined Kikuchi-Fujimoto disease-including some interesting cases. Clin Rheumatol 2012; 31: pp. 1463-1469.
Sukswai N., Jung H.R., Amr S.S., et. al.: Immunopathology of Kikuchi-Fujimoto disease: a reappraisal using novel immunohistochemistry combinations. Histopathology 2019; 77:
Systemic Lupus Erythematosus
Clinical Features
- •
Chronic inflammatory disease of unknown cause that can affect the skin, joints, kidneys, lungs, nervous system, serous membranes, and many other organs
- •
Enlargement of lymph nodes occurs in approximately 50% of patients
- •
Lymph nodes are soft, nontender, and discrete
- •
Usually detected in the cervical, axillary, and inguinal areas
- •
Lymphadenopathy is more frequently noted at the onset of disease or in association with an exacerbation
- •
- •
Numerous laboratory abnormalities include neutropenia, anemia, and positive tests for antinuclear antibodies (double-stranded DNA and Smith antigen)
Histopathology
- •
Edema, hemorrhage, and areas of necrosis surrounded by histiocytes and immunoblasts
- •
Some cases contain abundant plasma cells
- •
Hematoxylin bodies (ill-defined purple structures in necrotic foci) are typical of lupus
- •
Azzopardi phenomenon (dark blue DNA material deposited on the basement membrane of blood vessels) is typical of lupus
- •
Prominent follicular hyperplasia and capsular inflammation may be present
Special Stains and Immunohistochemistry
- •
CD8+ cytotoxic T lymphocytes are prominent
- •
B lymphocytes are virtually absent outside the reactive follicles
- •
Histiocytes express lysozyme, CD68, and myeloperoxidase
- •
Plasmacytoid dendritic cells are positive for CD123
Other Techniques for Diagnosis
- •
Noncontributory
Differential Diagnosis
- •
See section on “Differential Diagnosis” for Kikuchi disease
- •
Diagnosis requires correlation with the clinical and laboratory findings
- •
Lupus lymphadenitis may precede or follow cases of Kikuchi disease
Selected References
Cramer J., Schmiedel S., Alegre N.G., et. al.: Necrotizing lymphadenitis: Kikuchi-Fujimoto disease alias lupus lymphadenitis?. Lupus 2010; 19: pp. 89-92.
Hu S., Kuo T.T., Hong H.S.: Lupus lymphadenitis simulating Kikuchi’s lymphadenitis in patients with systemic lupus erythematosus: a clinicopathological analysis of six cases and review of the literature. Pathol Int 2003; 53: pp. 221-226.
Kim S.K., Kang M.S., Yoon B.Y., et. al.: Histiocytic necrotizing lymphadenitis in the context of systemic lupus erythematosus (SLE): is histiocytic necrotizing lymphadenitis in SLE associated with skin lesions?. Lupus 2011; 20: pp. 809-819.
Zuo Y., Foshat M., Qian Y.W., et. al.: A rare case of Kikuchi Fujimoto’s disease with subsequent development of systemic lupus erythematosus. Case Rep Rheumatol 2012; 2012: pp. 325062.
Granulomatous Lymphadenitis
Tuberculosis
Clinical Features
- •
Tuberculous lymphadenitis is among the most frequent presentations of extrapulmonary tuberculosis
- •
Cervical lymphadenitis is the most common site and is known as scrofula
- •
Tuberculosis is responsible for up to 40% of peripheral lymphadenopathy in the developing world
- •
In the United States, although the overall number of patients with tuberculosis has decreased, the proportion of tuberculous lymphadenitis has increased
- •
Isolated peripheral tuberculous lymphadenopathy is usually due to reactivation of disease
- •
Abdominal tuberculous lymphadenopathy may occur via ingestion of sputum or milk infected with Mycobacterium tuberculosis or Mycobacterium bovis
Histopathology
See Figure 14.15 .
- •
Gross examination shows areas of white-yellow, soft, crumbly cheeselike (“caseous”) material
- •
Multiple well-formed granulomas with epithelioid histiocytes and giant cells
- •
Caseous necrosis with no discernible cell membranes in the center of the granulomas
- •
AFB stain reveals the mycobacteria
Special Stains (other than acid-fast bacilli) and Immunohistochemistry
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Noncontributory
Other Techniques for Diagnosis
- •
Microbial culture
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PCR
Differential Diagnosis
Sarcoidosis
- •
Granulomas are more uniform, better defined, and compact
- •
Necrosis is rare, and when present it is focal
- •
AFB stain is negative
Fungal Lymphadenitis
- •
Fungal forms can be identified on the H&E-stained sections
- •
AFB stain is negative
- •
Gomori methenamine silver (GMS) and PAS stains highlight the fungal forms
Foreign-Body Type Granuloma
- •
Granulomas are non-necrotizing
- •
Giant cells have a different appearance (foreign-body type)
- •
Foreign material is usually easily identified in the cytoplasm of the giant cells
- •
AFB stain is negative
Kikuchi Disease
- •
No well-formed granulomas or multinucleated giant cells
- •
Necrosis is coagulative and not caseous
- •
Numerous immunoblasts, crescentic histiocytes, and plasmacytoid dendritic cells around the areas of necrosis
- •
AFB stain is negative
Aggressive B-Cell Lymphoma
- •
May have extensive necrosis
- •
Lymph node architecture is effaced
- •
No well-formed granulomas and no multinucleated giant cells
- •
Sheets of medium-sized or large atypical lymphoid cells surround areas of necrosis
Classical Hodgkin Lymphoma
- •
Frequently associated with granulomas and necrosis
- •
Lymph node architecture is effaced
- •
Mixed inflammatory infiltrate with many small lymphocytes, plasma cells, eosinophils, and neutrophils
- •
Presence of classic Reed-Sternberg cells or lacunar cells is required for diagnosis
Peripheral T-Cell Lymphoma
- •
Lennert lymphoma (lymphoepithelioid type) is characterized by clusters of epithelioid histiocytes
- •
No well-formed granulomas or multinucleated giant cells
- •
Necrosis is very unusual
Metastatic Carcinoma
- •
Can be associated with granulomas
- •
Nasopharyngeal carcinoma can cause marked necrotizing granulomatous inflammation
- •
Granulomas can also be seen in lymph nodes that drain carcinoma
- •
Immunohistochemical staining for cytokeratin highlights the epithelial cells
- •
AFB stain needs to be carefully examined under oil (100× magnification) because mycobacteria are usually few in number and are hard to find
- •
Occasionally tuberculous lymphadenitis manifests with non-necrotizing granulomas; thus, AFB stain should be performed on all such cases
Selected References
Kato T., Kimura Y., Sawabe M., et. al.: Cervical tuberculous lymphadenitis in the elderly: comparative diagnostic findings. J Laryngol Otol 2009; 123: pp. 1343-1347.
Linasmita P., Srisangkaew S., Wongsuk T., et. al.: . Clin Infect Dis 2012; 55: pp. 313-321.
Marais B.J., Wright C.A., Schaaf H.S., et. al.: Tuberculous lymphadenitis as a cause of persistent cervical lymphadenopathy in children from a tuberculosis-endemic area. Pediatr Infect Dis J 2006; 25: pp. 142-146.
Peto H.M., Pratt R.H., Harrington T.A., et. al.: Epidemiology of extrapulmonary tuberculosis in the United States, 1993-2006. Clin Infect Dis 2009; 49: pp. 1350-1357.
Atypical Mycobacterial Infection and Leprosy
Clinical Features
- •
Atypical mycobacterial infections are increasing in number and severity in developed countries
- •
Atypical mycobacteria that cause lymphadenitis include Mycobacterium avium complex (MAC), M. kansasii, M. scrofulaceum, M. malmoense, and M. haemophilum
- •
Found in the environment: water, soil, food products, and domestic and wild animals
- •
- •
Atypical mycobacterial lymphadenitis typically occurs in immunocompetent children (1 to 5 years old)
- •
Isolated cervicofacial nodes, particularly the submandibular nodes, are most frequently involved
- •
Presents as a unilateral, nontender node that slowly enlarges over several weeks
- •
- •
Atypical mycobacterial lymphadenitis may also occur in immunocompromised patients (HIV positive)
- •
Associated with disseminated infection
- •
- •
The incidence of leprosy appears to have markedly decreased since the 1990s
- •
Countries with high numbers of cases include India, Brazil, Indonesia, Bangladesh, and Nigeria
- •
- •
Leprosy primarily involves skin and peripheral nerves; if left untreated it may spread to lymph nodes
Histopathology
- •
Enlarged, matted lymph nodes
- •
Immunocompetent patients with atypical mycobacterial lymphadenitis or tuberculoid leprosy have necrotizing and non-necrotizing granulomas with Langhans-type giant cells
- •
Immunosuppressed patients with atypical mycobacterial lymphadenitis may fail to develop well-formed granulomas
- •
Small aggregates of histiocytes
- •
Rare cases of mycobacterial pseudotumors with a proliferation of foamy or spindle histiocytes, which contain numerous intracellular organisms ( Figure 14.16A )
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