Inflammatory/Hyperplastic Diseases PDF

Inflammatory/Hyperplastic Diseases 37 Figure 37.6 Pa...

Inflammatory/Hyperplastic Diseases 37 Figure 37.6 Paracortical hyperplasia, identified by the prominence of postcapillary venules. Figure 37.8 Monocytoid B-Cell Hyperplasia in a Case of Toxoplasmic Lymphadenitis. Clusters of small to medium-sized cells are present with clear cytoplasm. Note the presence of admixed neutrophils and nuclear remnants, a feature of reactive monocytoid B-cells. Figure 37.7 Sinus Hyperplasia. The cells present in the sinus represent an admixture of histiocytes and sinus lining cells. A They measure 25–150 µm in diameter and have as many as 60 nuclei arranged in grapevine clusters.92 Their cytoplasm is very scanty (Fig. 37.10). Although some early studies suggested a T-cell phenotype, more recent evaluations are in keeping with the hypothesis that these cells are multinucleated forms of follicular dendritic cells, a possibility that fits much better their morphologic appearance.93 Inflammatory/Hyperplastic Diseases Acute Nonspecific Lymphadenitis The typical case of acute nonspecific lymphadenitis is rarely biopsied. Microscopically, the earliest change is sinus dilation resulting from increased flow of lymph, followed by accumulation of neutrophils, vascular dilation, and edema of the capsule. Suppurative lymphadenitis is a feature of staphylococcal infection, mesenteric lymphadenitis, lymphogranuloma venereum, and cat-scratch disease. Necrotizing B features may be seen in bubonic plague, tularemia, anthrax, typhoid fever, melioidosis, and the entity known as Kikuchi necrotizing Figure 37.9 Plasmacytoid monocytes as seen on low (A) and high lymphadenitis (see next section). power (B). 1543 37 Lymph Nodes with malignant lymphoma with secondary necrosis and the admixed T-cell component with large crescentic histiocytes may be overinter- preted as a peripheral T-cell lymphoma. Lupus lymphadenitis may demonstrate features identical to Kikuchi lymphadenitis, and the possibility of lupus should be investigated in all cases.112 The hematoxylin bodies of lupus, which are not always present, should not be seen with Kikuchi disease. Chronic Nonspecific Lymphadenitis The morphologic features and the very concept of chronic lymph- adenitis merge with those of hyperplasia. The general features of chronic lymphadenitis are follicular hyperplasia; prominence of postcapillary venules; increased number of immunoblasts, plasma cells, and histiocytes; and fibrosis. The capsule may appear inflamed and/or fibrotic, and the process may extend into the immediate perinodal tissues. In some cases, one may find an undue predomi- nance in the number of eosinophils, foamy macrophages, and/or mast cells. Terms such as eosinophilic or xanthogranulomatous lymph- adenitis have been sometimes used, depending on the type of the infiltrate.113 The presence of numerous eosinophils in a lymph node should raise the possibility of Langerhans cell histiocytosis, parasitic infections, Hodgkin lymphoma, autoimmune disorders, and Kimura disease. Eosinophils can also be numerous in epithelioid hemangioma/ Figure 37.10 So-Called Polykaryocytes. These cells are characterized angiolymphoid hyperplasia with eosinophilia (which may rarely by numerous clustered nuclei. involve lymph nodes), Churg–Strauss disease, T-cell lymphomas, and various chronic eosinophilic neoplasms. Kikuchi Necrotizing Lymphadenitis Tuberculosis Kikuchi necrotizing lymphadenitis (Kikuchi lymphadenitis; Kikuchi– Lymph nodes involved by tuberculosis may become adherent to Fujimoto disease) is seen most commonly in Japan and other Asian each other and form a large multinodular mass that can be confused countries,94 but it also occurs elsewhere, including the United States clinically with metastatic carcinoma (Fig. 37.12). The most common and Western Europe. Most patients are young women with persistent, location of clinically apparent lymphadenopathy is the cervical region painless cervical lymphadenopathy of modest dimensions that may (“scrofula”), where a draining sinus that communicates with the be accompanied by fever.95 Microscopically, the affected nodes show skin (“scrofuloderma”) may form.114 Microscopically, the appearance focal, well-circumscribed, paracortical necrotizing lesions. There are ranges from multiple small epithelioid granulomas reminiscent of abundant karyorrhectic debris, scattered fibrin deposits, and collec- sarcoidosis to huge caseous masses surrounded by Langhans giant tions of mononuclear cells96 with cellular debris but an absence of cells, epithelioid cells, and lymphocytes. Demonstration of the intact neutrophils (Fig. 37.11). Special studies have shown that the organisms by special stains, cultures, or PCR is necessary to establish necrosis is the expression of cytotoxic lymphocyte-mediated apoptotic the diagnosis.115 cell death.97,98 Plasma cells are very scanty, and intact neutrophils are absent, a feature of diagnostic importance.99,100 Instead, plasma- cytoid dendritic cells, macrophages, and activated T cells are often Atypical Mycobacteriosis numerous.89,101 When these cells are abundant, the appearance may Atypical mycobacteria are a common cause of granulomatous simulate that of malignant lymphoma.102–104 The main lesional cells lymphadenitis. In the United States, caseating granulomatous disease include histiocytes (CD68 and CD163+) that contain cytoplasmic in a cervical lymph node of a child unaccompanied by pulmonary myeloperoxidase and are associated with aggregates of plasmacytoid involvement is more likely to be caused by an atypical mycobacterium. dendritic cells (TCL1 and CD123+).87,105 On occasion, a prominent The process typically involves lateral nodes in the midportion of the secondary xanthomatous reaction is seen and may be prominent.106 neck. Drainage may continue for months or years in the absence Such cases may lack areas of necrosis, but the apoptotic debris without of specific therapy, and healing may result in scarring and contrac- neutrophils remains in association with the xanthomatous change. tures. Microscopically, the host reaction may be indistinguishable Ultrastructurally, tubuloreticular structures and intracytoplasmic from that of tuberculosis, but often the granulomatous response rodlets similar to those described in lupus erythematosus are often is overshadowed by suppurative changes.116–118 A nontuberculous found.107 mycobacterial etiology should also be suspected if the granulomas The diagnosis can be made or at least suspected in material from are ill-defined (nonpalisading), irregularly shaped, or serpiginous.50,117 fine-needle aspiration because of the prominence of phagocytic An acid-fast stain should be performed in every granulomatous histiocytes with peripherally placed (“crescentic”) nuclei and medium- and suppurative lymphadenitis of unknown etiology, especially if sized cells with eccentrically placed nuclei consistent with plasma- the patient is a child or an HIV-infected individual.119 The final cytoid dendritic cells.108 identification of the organism rests on the culture or molecular The evolution is generally benign and self-limited. However, cases characteristics. have been described with recurrent lymphadenopathy or accompanied In immunosuppressed patients, mycobacterial infections may by skin lesions.109,110 Isolated fatal cases are also on record.111 The result in a florid spindle cell proliferation that can simulate a etiology is unknown. The most important differential diagnosis is neoplastic process (mycobacterial spindle cell pseudotumor).120 1544  Inflammatory/Hyperplastic Diseases 37 B A D C Figure 37.11 Necrotizing Lymphadenitis (Kikuchi-Fujimoto Disease). A, The most common pattern shows necrosis with karyorrhexis/pyknosis with nuclear debris but no neutrophils. B, Other cases show a more mononuclear infiltrate with debris without zonal necrosis. C, Increased numbers of CD123-positive cells, and D, myeloperoxidase positive histiocytes, support the diagnosis. Sarcoidosis The enigmatic clinicopathologic entity known as sarcoidosis has a worldwide distribution.121 Scandinavian countries are particularly affected.122 In the United States, the disease is 10–15 times more common in blacks than in whites. Practically every organ can be involved, but the ones most commonly affected are lung, lymph nodes, eyes, skin, and liver.123–125 Erythema nodosum often precedes or accompanies the disease. Functional hypoparathyroidism is the rule, although a few cases of sarcoidosis coexisting with primary hyperparathyroidism have also been reported.126,127 This seems to be due to the secretion of a parathyroid hormone (PTH)-related protein by the cells in the granuloma.128 Microscopically, the basic lesion is a small granuloma mainly composed of epithelioid cells, with scattered Langhans giant cells and lymphocytes (Fig. 37.13).129 As a general rule, the Langhans giant cells are smaller and have fewer nuclei than those typically Figure 37.12 Large adherent tuberculous lymph nodes containing seen in tuberculosis. Necrosis is either absent or limited to a small extensive foci of caseation necrosis. central fibrinoid focus (“hard” granulomas); a “necrotizing” variant of sarcoidosis exists, but this is usually extranodal. Schaumann bodies, asteroid bodies, and calcium oxalate crystals are sometimes found 1545 37 Lymph Nodes Figure 37.13 Numerous confluent non-necrotizing granulomas mainly Figure 37.14 Asteroid body in the cytoplasm of a multinucleated giant composed of epithelioid cells in a lymph node affected by sarcoidosis. cell in sarcoidosis. A B C Figure 37.15 Hamazaki–Wesenberg bodies in a lymph node with sarcoidosis, as shown in (A) hema- toxylin–eosin, (B) periodic acid–Schiff, and (C) Gomori methenamine-silver stains. in the cytoplasm of the giant cells (Figs. 37.14 and 37.15).130 syphilis, leishmaniasis, brucellosis, tularemia, chalazion, zirconium Schaumann bodies are round, have concentric laminations, and granuloma, berylliosis, Crohn disease, and Hodgkin lymphoma; in contain iron and calcium. Ultrastructurally, asteroid bodies are nodes draining a carcinoma; and in several other conditions.134 Only composed of radiating filamentous arms enveloped by “myelonoid” when all these possibilities have been excluded and the clinical membranes.131 Elemental analysis has shown calcium, phosphorus, picture is characteristic is there justification in labeling a case as silicon, and aluminum in these formations.129,131 Peculiar PAS-positive consistent with sarcoidosis. inclusions known as Hamazaki–Wesenberg, yellow, or ovoid bodies Most of the lymphocytes present in the sarcoidal granulomas were claimed to be specific for sarcoidosis, but subsequent histochemi- are CD4-positive T cells; both these cells and the epithelioid histiocytes cal and ultrastructural studies132 have shown that they have no etiologic exhibit features of proliferation and/or activation, as shown by their or pathogenetic significance. They probably represent large lysosomes immunocytochemical positivity with the Ki-67 antibody and for containing hemolipofuscin material and are found in a large variety interleukin-1, respectively.135,136 Pathogenetically, sarcoidosis is thought of conditions.130,133 None of these inclusions is specific for sarcoidosis. to represent a dysfunction of circulating T cells with overactivity of From a pathologic standpoint the diagnosis of sarcoidosis is always B cells.137 The association of particular human leukocyte antigens one of exclusion. A noncaseating granulomatous inflammation in (HLAs) with sarcoidosis suggests a role for HLA-linked immune the lymph nodes or skin microscopically indistinguishable from response genes and disease susceptibility.138 Specifically, it has been sarcoidosis can be seen in tuberculosis, atypical mycobacteriosis shown that certain types of genetic polymorphism are associated (including swimming pool granuloma), fungus diseases, leprosy, with increased risk of disease or affect disease presentation.139 1546  Inflammatory/Hyperplastic Diseases 37 The Kveim test for sarcoidosis is an intradermal reaction that parasite Toxoplasma gondii.142 Toxoplasmic lymphadenitis (formerly occurs following inoculation with an extract of human spleen involved known as Piringer–Kuchinka lymphadenitis), in its most typical with the disease. It is positive in 60%–85% of patients with sarcoid- form, involves the posterior cervical nodes of young women.143 osis, and the number of false-positive results is small. The test is On palpation, the nodes are firm and only moderately enlarged. regarded as positive when a biopsy of the area taken 4–6 weeks after Microscopically, the nodal architecture is rather well preserved. The inoculation shows microscopically sarcoid-type granuloma. A trial typical triad of the disease, which is not present in all cases, is employing a single test suspension among 2400 subjects in 37 constituted by: (1) marked follicular hyperplasia, associated with countries on six continents showed a similar level of reactivity and intense mitotic activity and phagocytosis of nuclear debris; (2) microscopic appearance from country to country, supporting the small, loose collections of epithelioid histiocytes, located within concept that sarcoidosis is the same disease the world over. The the hyperplastic follicles and at the periphery, encroaching on Kveim test is rarely practiced today because of lack of availability and blurring their margins; and (3) distention of marginal and of the antigen. The etiology and pathogenesis of sarcoidosis remain cortical sinuses by monocytoid B cells (Fig. 37.17). An additional elusive.140 feature is the presence of immunoblasts and plasma cells in the medullary cords.144 Variations on the theme include presence in Fungal Infections Fungal infections of lymph nodes may present as chronic suppurative lesions, as granulomatous processes, or as a combination of the two. The most important fungal lymphadenitis is histoplasmosis, which in addition to the previously mentioned patterns can also result in widespread nodal necrosis and in marked diffuse hyperplasia of sinus histiocytes (Fig. 37.16). Other fungal diseases known to result in lymphadenitis are blastomycosis, paracoccidioidomycosis, coccidioidomycosis, and sporotrichosis.141 To these, one should add opportunistic infections such as cryptococcosis, aspergillosis, mucormycosis, and candidiasis. The fungal organisms can usually be demonstrated with Gomori methenamine silver (GMS) or PAS–Gridley stains, but sometimes their number is so small that they can be detected only in cultures or by molecular testing.10 Toxoplasmosis Toxoplasmosis, one of the most common parasitic infections of Figure 37.16 Numerous Histoplasma organisms in the cytoplasm of humans and other warm-blooded animals, is caused by the protozoan histiocytes. A B Figure 37.17 Toxoplasmosis of Lymph Node. A, Small noncaseating granulomas composed of epithelioid cells are located at the periphery of a hyperplastic follicle. This picture is almost pathognomonic of this disease. B, An area of massive monocytoid B-cell hyperplasia. 1547 37 Lymph Nodes Syphilis Generalized lymphadenopathy is a common finding in secondary syphilis, whereas localized node enlargement can be seen in the primary and tertiary stages of the disease. In secondary syphilis, the changes are those of a florid follicular hyperplasia. In primary syphilis, the combination of changes may result in a mistaken diagnosis of malignant lymphoma. Most of the cases have presented as solitary inguinal lymphadenopathy.150 There are capsular and pericapsular inflammation and extensive fibrosis, diffuse plasma cell infiltration with extension often into or beyond the capsule, proliferation of blood vessels with endothelium swelling and inflammatory infiltration of vessel walls (phlebitis and endarteritis), and follicular hyperplasia (Fig. 37.19).150 Rarely, noncaseating granulomas and abscesses are present. Exceptionally, the appearance is that of a nodal inflammatory A pseudotumor, the message being that spirochetes should be searched for whenever making that diagnosis in a nodal biopsy, by histochemi- cal or immunohistochemical stain.151 The morphologic features of syphilitic infection are not substan- tially different when occurring in HIV-infected patients152 and can be identified in most cases by the Warthin–Starry or Levaditi stains, by immunofluorescence techniques applied to imprint preparations, or immunohistochemical staining on paraffin section.153 The organ- isms are most frequently found in the wall of blood vessels. Detection of Treponema pallidum is now also feasible in lymph node biopsies and fine needle aspirations by PCR.154 Leprosy Lymph nodes involved by the lepromatous type of leprosy have a very characteristic microscopic appearance. The main change is the progressive accumulation of large, pale, rounded histiocytes (“lepra” or “Virchow” cells), without granuloma formation and with minimal or no necrosis (Fig. 37.20). Wade–Fite and Fite–Faraco stains (which B are modified Ziehl–Neelsen reactions) demonstrate packing of the cytoplasm by acid-fast organisms, which can also be demonstrated Figure 37.18 Toxoplasma cyst as seen in a microscopic section, by a fluorescent method,155 and by PCR.156 (A) and a touch preparation (B). This is a very unusual finding in lymph nodes affected by the disease. Mesenteric Lymphadenitis Mesenteric (Masshoff) lymphadenitis is produced by Yersinia pseu- dotuberculosis or Yersinia enterocolitica, two gram-negative polymorphic the granulomas of necrosis or more than an occasional Langhans coccoid or ovoid motile organisms.157–160 It is a benign, self-limited giant cell. disease that can clinically simulate acute appendicitis. Microscopically, It is extremely rare to find Toxoplasma organisms in the lymph there are capsular thickening and edema, increase of immunoblasts node by morphologic examination, immunohistochemistry, or PCR and plasma cells in the cortical and paracortical region, dilation of (Fig. 37.18).145,146 This finding contrasts sharply with the results sinuses with accumulation of large lymphocytes within, and germinal obtained in toxoplasmic encephalitis and myocarditis146 and suggest center hyperplasia.161,162 In the lymphadenitis produced by Y. pseu- that the lymph node findings may be an immunologic response to dotuberculosis, small granulomas and abscesses are commonly present, infection at other sites. The combination of microscopic features whereas this is unusual in infection caused by Y. enterocolitica.162 described correlates remarkably well with serologic studies. Of 31 These nodal changes are accompanied by inflammatory changes of cases studied by Dorfman and Remington147 the Sabin–Feldman the terminal ileum and cecum. Ideally, the diagnosis should be dye test was positive in all and the IgM immunofluorescent antibody confirmed with cultures. Too often, the diagnosis of mesenteric test was positive in 97% of the cases. lymphadenitis is made on normal or mildly hyperplastic nodes in If the diagnosis of toxoplasmic lymphadenitis is suspected from an attempt to explain why a patient with the clinical picture of acute the microscopic pattern, it should be confirmed serologically, keeping appendicitis has a normal appendix. in mind that these tests may be normal in the early stages of the The organism can be identified by PCR. Interestingly, Yersinia disease.148 DNA has been detected in mesenteric lymph nodes in patients with The differential diagnosis of toxoplasmosis includes other infec- Crohn disease.163 tious diseases and the lymphocyte predominant form of Hodgkin lymphoma. In this regard, Miettinen and Franssila149 have made the interesting point that occurrence of collections of epithelioid cells Cat-Scratch Disease within germinal centers seems to be a nearly specific feature for Cat-scratch disease is characterized by a primary cutaneous lesion toxoplasmosis. and enlargement of regional lymph nodes, usually axillary or cervical 1548  Inflammatory/Hyperplastic Diseases 37 A B Figure 37.19 Syphilis of Lymph Node. A, Follicular hyperplasia associated with striking pericapsular inflammation and fibrosis. B, The prominent vasculitis seen in this field is an important clue to the diagnosis. A B Figure 37.20 A and B, Lymph node involvement by lepromatous leprosy. The sinuses are massively dilated as a result of the accumulation of foamy histiocytes. (Fig. 37.21).164 The changes in the nodes vary with time. Early lesions necrosis with abundant neutrophils, surrounded by a palisading of have histiocytic proliferation and follicular hyperplasia, intermediate histiocytes.166 However, similar abscesses can be seen in lympho- lesions have granulomatous changes, and late lesions have abscesses granuloma venereum. Another common feature of lymph nodes of various sizes (Fig. 37.22).165 These abscesses are very suggestive with cat-scratch disease is the packing of sinuses by monocytoid B of the diagnosis because of their pattern of central, sometimes stellate cells, which, together with the follicular hyperplasia, may simulate 1549 37 Lymph Nodes Figure 37.23 Necrotizing granuloma in a lymph node affected by lymphogranuloma venereum, showing features similar, if not identical, to cat-scratch disease. Rare complications of the disease include granulomatous con- junctivitis (“oculoglandular syndrome of Parinaud”), thrombocy- topenic purpura, and central nervous system manifestations.176 Figure 37.21 Lymph Node Involved by Cat-Scratch Disease. Lymphogranuloma Venereum This sexually transmitted disease (not to be confused with granuloma inguinale) is caused by Chlamydia trachomatis organisms corresponding to serotypes L1, L2, and L3.177 The initial lesion is a small (2–3 mm), painless genital vesicle or ulcer that often goes unnoticed and heals in a few days. This is followed by inguinal adenopathy, which can be very prominent. As mentioned, the morphologic features are similar to cat-scratch disease, although the site of disease is a helpful clue to the diagnosis. The earliest microscopic change in an affected node is represented by tiny necrotic foci infiltrated by neutrophils. These enlarge and coalesce to form the stellate abscess that represents the most characteristic feature of this disease (Fig. 37.23). In later stages, epithelioid cells, scattered Langhans giant cells, and fibroblasts are seen to line the abscess walls. Confluence of these abscesses is common, and cutaneous sinus tracts may develop. The healing stage is represented by nodules with dense fibrous walls surrounding amorphous material.178 The microscopic picture just described is not pathognomonic of this disease. Similar changes can occur in cat-scratch disease, atypical Figure 37.22 Cat-scratch disease with an area of stellate necrosis with mycobacteriosis, and tularemia. Therefore a presumptive diagnosis neutrophils surrounded by histiocytes. of lymphogranuloma venereum should be confirmed with the Frei test (a delayed hypersensitivity skin test using purified “lygranum” chlamydial antigen), complement fixation, immunofluorescence, or toxoplasmosis.81 However, clusters of perifollicular and intrafollicular molecular testing.177,179–181 epithelioid cells are absent.55 The primary lesion is a red papule in the skin at the site of inoculation, usually appearing between 7 and 12 days following Tularemia contact. It may become pustular or crusted. Microscopically, there Tularemia is a bacterial disease produced by Francisella tularensis, are foci of necrosis in the dermis surrounded by a mantle of histio- an extremely virulent pathogen,182–184 which has recently gained cytes. Multinucleated giant cells, lymphocytes, and eosinophils are notoriety as a potential biowarfare agent.185,186 In the ulcero-glandular also present.167 form of the disease, prominent lymphadenopathy occurs; this The agent of cat-scratch disease is a coccobacillary pleomorphic predominates in the axillary region when mammalian vectors extracellular bacterium that can be identified with the Warthin–Starry are involved and in cervical or inguinal regions with arthropod silver stain or by immunohistochemistry, particularly in those cases vectors.187 A history of handling rabbits suggests the diagnosis in the exhibiting extensive necrosis.168–170 This organism, which has also first instance. The diagnosis is supported by a rise in hemagglutinin been detected ultrastructurally,171 was originally designated Rochalimaea titers.183,188 henselae and has been renamed Bartonella henselae. The diagnosis Microscopically, the picture in the acute phase is that of an intense can be confirmed by serology, immunohistochemistry, or PCR.172–175 lymphadenitis with widespread necrosis, sometimes associated with 1550  Inflammatory/Hyperplastic Diseases 37 irregularly shaped microabscesses and granulomas.185 In the more may be accompanied by collections of monocytoid B cells in the chronic forms, there is a granulomatous reaction that in some cases sinuses, neutrophils, and features of dermatopathic lymphadenopathy. may have a frankly tuberculosis-like appearance.189 Although the In many of the cases, the reactive germinal centers show a feature histologic and cytologic features are not specific, fine-needle aspiration termed follicle lysis, characterized by invagination of mantle lym- specimens may be useful to obtain material for molecular identifica- phocytes into the germinal centers, and this feature is often associated tion of the organism.190 with interfollicular hemorrhage. Follicle lysis is associated with disruption of these centers (“moth-eaten appearance”) and a distinc- tive clustering of large follicular center cells,200,201 resulting in an Brucellosis appearance that has been termed explosive follicular hyperplasia. Brucellosis is caused by Brucella abortus, melitensis, or suis.191 In the Ultrastructurally, a prominence of follicular dendritic cells exhibiting United States it has evolved from an occupational to a food-borne alterations of their fine processes has been described;202 it has been illness related to consumption of milk and cheese.192 The most suggested also on the basis of immunohistochemically (fascin stain) common clinical manifestations are fever, hepatomegaly, and that the AIDS virus preferentially infects these cells.203,204 It has been splenomegaly.193 Lymphadenopathy is uncommon and, when present, suggested that the polykaryocytes (Warthin–Finkeldey cells) that are usually of modest dimensions. Microscopically, there may be sometimes seen in HIV-infected nodes are a multinucleated form nonspecific follicular hyperplasia and clusters of epithelioid histiocytes of follicular dendritic cell.93 Immunohistochemically, positive stain sometimes forming large noncaseating granulomas. This is accom- for the HIV core protein P24 has been documented within the panied by a polymorphic infiltrate containing eosinophils, plasma abnormal germinal centers.205,206 cells, and immunoblasts. When the latter are numerous, the micro- This combination of follicular changes is not pathognomonic scopic picture may show a vague resemblance to Hodgkin of AIDS, but the possibility of this disease should be considered lymphoma. and investigated whenever they are found, such as by immunostaining A definitive diagnosis can only be made by recovery of the organ- for P24 or by serologic study.205 ism with bacteriologic or PCR techniques194 or the detection of a Some lymph nodes in untreated AIDS patients may also show high agglutination titer.195 advanced lymphocyte depletion, with or without abnormal (regres- sively transformed) germinal centers.200,202 Acquired Immunodeficiency Syndrome– The interfollicular tissue may show prominent vascular prolifera- tion, the resulting picture acquiring a vague resemblance to Castleman Related Lymphadenopathy disease. It is important to search in these areas and in the subcapsular The lymph node abnormalities in AIDS patients can be of various region for the earliest signs of development of Kaposi sarcoma.207 types. They include mycobacterial and other opportunistic infections These changes should be distinguished from those of vascular (some resulting in spindle cell pseudotumors),120,196 Kaposi sarcoma, transformation of the sinuses. malignant lymphomas of either Hodgkin or non-Hodgkin type, and A rough relationship has been found among the pattern of nodal florid reactive hyperplasia.197–199 The lymphomas, discussed later, and reaction, the cell suspension immunophenotypic data, and the reactive hyperplasia are the most common (Fig. 37.24). Hyperplasia patient’s HIV status.208,209 A B Figure 37.24 Low-power (A) and high-power (B) microscopic views of AIDS-related lymphadenopathy. The depicted germinal center shows disruption of its architecture by intrusion of small lymphocytes from the mantle zone. This is a common but not pathognomonic feature of this disease. 1551 37 Lymph Nodes The term chronic lymphadenopathy syndrome has been defined as nucleus with a thin nuclear membrane and one or two prominent an unexplained enlargement of nodes of at least 3 months’ duration amphophilic or basophilic nucleoli. A paranuclear “hof” is often at two or more extrainguinal sites in an individual at risk for AIDS.210 seen. When binucleated, this cell may closely resemble a Reed– The microscopic picture is similar to that described previously.211 Sternberg cell and result in a mistaken diagnosis of Hodgkin lym- Overall, up to a fourth of the patients have developed AIDS on phoma (see Fig. 37.26).220,221 A combination of immunophenotyping follow-up, cachexia and weight loss being the clinical signs of this and in situ hybridization for EBV should resolve the issue in most progression.212,213 cases (Fig. 37.27),222–224 but it should be recognized that many The HIV-associated lymphoproliferative diseases of lymph nodes enlarged, EBV-infected cells that may morphologically mimic Hodgkin are discussed later in this chapter. cells will also express CD30225 and the neoplastic cells of approxi- mately 40% of cases of classical Hodgkin lymphoma will be EBV positive. The EBV infection in Hodgkin disease, however, is largely Infectious Mononucleosis restricted to the neoplastic cells, while in infectious mononucleosis The etiologic agent of classic infectious mononucleosis is EBV,214 the EBV positive cells are more variable in size and include small but other agents may be involved in atypical cases.215 It is rare for cells. Because of the morphologic overlap between infectious the pathologist to see a lymph node from a patient with a typical mononucleosis and Hodgkin lymphoma and even DLBCL, extreme clinical picture because in most instances the presumptive clinical caution should be used before diagnosing either malignancy in diagnosis is confirmed by examination of the peripheral blood and immunocompetent adolescent or young adults in the head and neck serologic evaluation without need of a lymph node biopsy.216 It is region, especially on a tonsil biopsy. in the atypical case, presenting with lymphadenopathy without fever, sore throat, or splenomegaly, that the clinician will perform a lymph Other Viral (Including Postvaccinial) node biopsy to rule out the possibility of malignant lymphoma. Microscopically, nodes and other lymphoid organs affected by Lymphadenitides infectious mononucleosis can be confused with malignant lymphoma Lymph nodes draining an area of the skin subjected to smallpox because of the effacement of the architecture; infiltration of the vaccination can enlarge and become painful. If removed and examined trabecular, capsule, and perinodal fat; and the marked proliferation microscopically, they can be easily confused with lymphoma, of immunoblasts, immature plasma cells, and mature plasma cells especially if the history of vaccination is overlooked. Of 20 cases of (“polymorphic B-cell hyperplasia”) (Figs. 37.25 and 37.26). These postvaccinial lymphadenitis reported by Hartsock,226 13 were located features are particularly prominent when the disease develops in in the supraclavicular region on the side of the vaccination. The transplant recipients or other immunosuppressed patients.217 Necrosis largest node measured 6 cm in diameter. The interval between the may also be present; this is usually only focal, but in immunodeficient vaccination and the biopsy varied between 1 week and 3 months. children it may be massive. Microscopically, the changes are those of a diffuse or nodular Features of importance in the differential diagnosis with lymphoma paracortical expansion, with mixed cellular proliferation, consisting include the predominantly sinus distribution of the large lymphoid of eosinophils, plasma cells, and a large number of immunoblasts. cells, follicular hyperplasia with marked mitotic activity and phago- The alterations are accompanied by vascular and sinus changes and cytosis (these follicles being usually small), increase in the number focal discrete necrosis. The most important histologic feature of of plasma cells, often polymorphic in appearance, and vascular postvaccinial hyperplasia is the presence of numerous immunoblasts proliferation.218 Another important feature is the fact that, although scattered among the lymphocytes and imparting to the lymphoid the nodal architecture may appear effaced, the sinus pattern remains tissue a mottled appearance (Fig. 37.28). Hartsock226 noted that intact or even focally accentuated. Another characteristic feature of follicular hyperplasia was present only in those nodes removed more this disease is the presence in the sinuses of clusters or “colonies” than 15 days after vaccination. These changes have been reproduced of lymphocytes in graduated sizes, from the small lymphocyte to experimentally.226 the large lymphoid cell or immunoblast, often with plasmacytoid Viral lymphadenitis resulting from herpes simplex infection may features.219 The immunoblasts usually have only one large vesicular be localized227 or generalized.228 The morphologic features are similar to those of postvaccinial lymphadenitis, particularly in reference to the marked immunoblastic proliferation.229,230 Intranuclear viral inclusions may be found, especially at the edge of necrotic areas.231–233 The nodal changes seen in herpes zoster lymphadenitis and infectious mononucleosis are of similar nature; the latter are discussed under a separate heading (see preceding section). It is likely that analogous morphologic changes occurring in the absence of these clinical conditions are, in most cases, the result of some unidentified viral infection. Prominent regional lymphadenopathy also may follow the administration of live attenuated measles virus vaccine. Microscopi- cally, the typical multinucleated giant cell of Warthin–Finkeldey (polykaryocytes) may be found (see Fig. 37.10).234 Mucocutaneous Lymph Node Syndrome Mucocutaneous lymph node syndrome, also known as Kawasaki syndrome, is a febrile disorder of unknown etiology usually affecting Figure 37.25 Lymph Node Involved by Infectious Mononucleosis. children, originally described in the Japanese literature but having There is a marked effacement of the architecture by a polymorphic a worldwide distribution.235 Fever, cervical lymphadenopathy, lymphoid infiltrate. pharyngeal and conjunctival inflammation, and erythematous skin 1552  Inflammatory/Hyperplastic Diseases 37 Figure 37.26 Various types of immunoblast seen in a lymph node involved by infectious mononucleosis. The binucleated form (shown in the fourth image) can simulate Reed–Sternberg cells. Note the basophilic character of the nucleus and the presence of a paranuclear hof. Also note the variability in size of background lymphocytes that also demonstrate a plasmacytoid appearance. This variability is characteristic of infectious mononucleosis. rashes are the most common clinical symptoms. Sometimes lymph- vasculitis. The main differential diagnosis is Kikuchi necrotizing adenopathy represents the dominant manifestation of the disease.236 lymphadenitis, but the presence of thrombi would favor Kawasaki Arthritis is present in approximately 40% of the cases. Coronary disease. Persistent damage to the coronary arteries occurs in approxi- arteritis may lead to fatal complications. The etiology is unknown, mately one-fourth of untreated children.239 but an infectious agent is suspected. Microscopically, the affected lymph nodes often show fibrin thrombi in the smaller vessels accompanied by patchy infarcts/areas Lupus Erythematosus of nongranulomatous necrosis with or without neutrophils.237,238 The lymph node changes in lupus erythematosus are generally of These changes have been interpreted as the expression of an acute a nonspecific nature and consist of moderate follicular hyperplasia 1553 37 Lymph Nodes Figure 37.29 Large accumulations of DNA-containing basophilic material in the subcapsular region of a lymph node in a patient with systemic lupus erythematosus. Figure 37.27 Demonstration of EBV EBER by in situ hybridization in a case of infectious mononucleosis. Note that both large and small cells are positive, in contrast to EBV+ Hodgkin lymphoma in which the EBV Rheumatoid Arthritis is primarily in large cells. Most patients with rheumatoid arthritis have generalized lymph- adenopathy at some time during their illness.245 The lymph node enlargement may precede the arthritis and raise the clinical suspicion of lymphoma. Microscopically, the most important changes are follicular hyperplasia and plasma cell proliferation, with formation of Russell bodies.246 Vascular proliferation is also a consistent finding. The appearance may be quite similar to that of the plasma cell type of Castleman disease. Small foci of necrosis and clumps of neutrophils are seen in some instances. The capsule is often infiltrated by lym- phocytes. Immunohistochemically, the plasma cell proliferation is polytypic.247 Adult-onset Still disease can also result in an intense hyperplastic change that can vaguely resemble peripheral T-cell lymphoma.248 Other immune-mediated diseases, such as lupus erythematosus, polyarteritis nodosa, and scleroderma, are usually not associated with this type of lymph node abnormality. Patients with rheumatoid arthritis treated with gold com- pounds can develop gold-associated lymphadenopathy.249 They are also said to have a slightly increased incidence of malignant Figure 37.28 Viral lymphadenitis showing scattered immunoblasts resulting lymphomas.250,251 in a “salt-and-pepper” appearance. Castleman Disease associated with increased vascularization and scattered immuno- Castleman disease (giant lymph node hyperplasia) represents a blasts and plasma cells; some of the latter contain PAS-positive morphologically distinct lymph node proliferation that in most cytoplasmic bodies that represent sites of immunoglobulin produc- cases is of unknown etiology. It occurs most commonly in adults, tion.240 Occasionally, one encounters a peculiar form of necrosis but it can also affect children.252 Two major clinical and micro- characterized by the deposition of hematoxyphilic material in scopic categories have been described that do not always correlate the stroma, in the sinuses, and on the wall of blood vessels (Fig. with each other253,254 The first microscopic category, designated as 37.29).241 These have been found to be composed of DNA derived hyaline-vascular type or angiofollicular, shows large follicles scattered from karyorrhectic nuclear material, presumably from lymphocytes. in a mass of lymphoid tissue. The follicles show marked vascular As mentioned previously, the microscopic appearance of lupus proliferation and hyalinization of their abnormal germinal centers; lymphadenitis may be indistinguishable from that of Kikuchi they have been confused with Hassall corpuscles and with splenic disease,242 and some patients originally diagnosed with Kikuchi white pulp, prompting in the first case a mistaken diagnosis of disease may actually represent an early presentation of systemic lupus thymoma and in the second of ectopic spleen (Fig. 37.30). Their erythematosus.112 The presence of hematoxylin bodies is considered appearance corresponds to that of regressively transformed germinal relatively specific for lupus over Kikuchi disease. On occasion the centers. Many of the large cells with vesicular nuclei present in the changes of lupus are morphologically similar to those of either the hyaline center are follicular dendritic cells, as evidenced by their hyaline vascular or intermediate types of Castleman disease.243,240 In strong immunoreactivity for CD21 and CD35.255 There is a tight other instances, Warthin–Finkeldey-like polykaryocytes have been concentric layering of lymphocytes at the periphery of the follicles numerous.244 The immunophenotype of lupus lymphadenitis is (corresponding to the mantle zone), resulting in an onion-skin nonspecific.241 appearance. The interfollicular stroma is also prominent, with 1554  Inflammatory/Hyperplastic Diseases 37 numerous hyperplastic vessels of the postcapillary venule type and The second major morphologic category of Castleman disease an admixture of plasma cells, eosinophils, and immunoblasts, as is known as the plasma cell type.254 It is characterized by a diffuse well as tight collections of CD123-positive plasmacytoid dendritic plasma cell proliferation in the interfollicular tissue, sometimes cells and frequently admixed TdT-positive T cells.256–259 Sinuses are accompanied by numerous Russell bodies. The hyaline-vascular characteristically absent. In the variant of the hyaline-vascular type changes in the follicles are inconspicuous or absent; instead, one described as the lymphoid subtype, the follicles have a marked expansion often encounters in the center of these follicles a deposition of an of the mantle zone and small, relatively inconspicuous germinal amorphous acidophilic material that probably contains fibrin and centers. This variant of Castleman disease merges with the process immune complexes. The overall appearance is reminiscent of that known as mantle zone hyperplasia, and it is the one more likely to be seen in the lymph nodes from patients with rheumatoid arthritis confused with malignant lymphoma of either follicular or mantle cell (Fig. 37.31). The abundant expression of interleukin-6 that has been type. Immunohistochemically, there is polyclonal immunoglobulin detected in this condition is thought to be responsible for the marked production by plasma cells, and large numbers of suppressor T cells plasma cell infiltration.261 are found in the interfollicular areas. An aberrant phenotype of Based on clinical presentation, Castleman disease has been divided Ki-B3–negative B lymphocytes has been detected in the mantle into a solitary and a multicentric form. The solitary form presents as zone cells.260 a mass located most commonly in the mediastinum but also described in the neck, lung, axilla, mesentery, broad ligament, retroperitoneum, soft tissues of the extremities (including subcutis and skeletal muscle),262 nasopharynx, meninges, and several other sites.263 Grossly, it is round, well circumscribed, with a solid gray cut surface and can measure 15 cm or more in diameter (Fig. 37.32). Although this form by definition presents as a single mass, microscopic changes suggesting an early stage of the same process are sometimes seen in adjacent nodes. Microscopically, over 90% of the cases are of the hyaline-vascular type (including the lymphoid subtype), and the remainder are of the plasma cell type. The former is usually asymp- tomatic, whereas the plasma cell type is often associated with fever, anemia, elevated erythrocyte sedimentation rate, hypergammaglobu- linemia, and hypoalbuminemia. The disease reported in Asia as idiopathic plasmacytic lymphadenopathy with polyclonal hypergamma- globulinemia is probably different from the plasma cell type of Castle- man disease but may represent IgG4-related lymphadenopathy in a significant proportion of cases.264,265 The treatment of solitary Castleman disease is surgical excision, which has been found to Figure 37.30 Castleman Disease of Hyaline Vascular Type. There is result in rapid regression of the associated abnormalities whenever a prominent germinal center showing well-developed changes. present.266 A B Figure 37.31 Castleman Disease of Plasma Cell Type. A, Low-power view showing follicular hyperplasia without hyaline vascular changes. B, High-power view of the interfollicular region showing a massive infiltration by plasma cells. Some of these plasma cells show multinucleation and mild nuclear atypia. 1555 37 Lymph Nodes Figure 37.33 Prominent network of CD21-positive dendritic follicular Figure 37.32 Gross appearance of Castleman disease of the hyaline cells in the abnormal germinal center of Castleman disease. vascular type. The multicentric or systemic form is nearly always of the plasma cell type,267 although occasional examples of the hyaline-vascular type (involving even the skin) are on record.268 It presents with generalized lymphadenopathy and may also involve the spleen.269–271 The etiology is unknown, the two main hypotheses (not mutually exclusive) being abnormal immune response and viral infection.272 Regarding the latter, a definite link has been documented between HHV8 and multicentric Castleman disease (this virus being also linked to Kaposi sarcoma and primary effusion sarcoma and can be identified by immunohistochemistry).273–275 Cases of HHV8+ Castleman disease are said to be characterized morphologically by dissolution of the lymphoid follicles.276 It has been hypothesized that HHV8 induces the changes of Castleman disease through the production of interleukin-6.277,278 Sometimes multicentric Castleman disease is seen in association with the POEMS syndrome, an acronymic designation for polyneu- ropathy, organomegaly, endocrinopathy, M-protein, and skin Figure 37.34 “Dysplasia” of Reticular/Dendritic Cells in Castleman Disease. These cells were immunoreactive for desmin. changes.279,280 The latter include a distinctive vascular lesion known as glomeruloid hemangioma.281 In other instances, Castleman disease has been reported in association with amyloid deposits.282,283 The long-term prognosis of systemic Castleman disease is poor; and molecular evidence of clonality (Fig. 37.34).292–294 Furthermore, the disease tends to persist for months or years and to result some- they may result in the formation of full-blown follicular dendritic times in renal or pulmonary complications.284 Furthermore, some cell tumors.295,296 Another type of proliferation involves the vascular of the patients have been found to have Kaposi sarcoma. Indeed, and related contractile (myoid) elements that are present in the the coexistence of multicentric Castleman disease and Kaposi sarcoma interfollicular tissue. Cases of Castleman disease in which these in the same tissue sample is not an uncommon phenomenon.285 elements are unduly prominent have been referred to as stroma rich Other cases have developed large cell lymphomas with plasmablastic (Fig. 37.35).256 Further proliferation of this component results in features, most of which are associated with HHV8 infection. Evidence the formation of angiomyoid proliferative lesions,296 and of lesions that of clonal rearrangement for immunoglobulin and T-cell receptor have been referred to as angiomatous hamartomas (Fig. 37.36)297 or genes has been found in cases of systemic Castleman disease together vascular neoplasms, the latter sometimes having hemangiopericytoma- with copies of the EBV genome; no such features having been detected like features.298 Finally, cases have been described of high-grade in the solitary form of the disease.286–289 This suggests that multicentric spindle cell sarcomas arising in Castleman disease, which have been Castleman disease is a disorder different from the classic localized originally interpreted as of probable vascular nature because of the type and one that may evolve into a clonal lymphoproliferation. presence of myoid tumor cells adjacent to vascular structures (Fig. Some authors actually regard it as a lymphoproliferative process 37.37).299 Whether these myoid cells are truly vessel related or whether rather than a reactive/inflammatory condition. they originate from yet another member of the reticulum/dendritic An important theme of the hyaline-vascular type of Castleman cell family (so-called fibroblastic reticulum cells, myoid reticulum disease is the active participation of a variety of nonlymphoid cellular cells, or dychthyocytes) is not clear. components. One such component is the follicular dendritic cell, In the light of the above information, one might conclude that which is prominently present in the hyalinized nodules that character- the neoplastic potentialities of Castleman disease tend to manifest ize the disease and which is thought by some authors to be at the themselves mainly through the development of lymphoid tumors core of the pathogenesis of this disorder (Fig. 37.33).290,291 These in the plasma cell type and of dendritic/stromal tumors in the cells can become atypical (“dysplastic”) both in the abnormal germinal hyaline-vascular type. However exceptions occur, in the sense that centers and in the intervening tissue291 and can manifest cytogenetic isolated cases of the latter have been accompanied or preceded by 1556  Inflammatory/Hyperplastic Diseases 37 Figure 37.35 Castleman disease of hyaline vascular type with a prominent stromal component which is richly vascularized (“stroma-rich” variant). A A B Figure 37.36 Castleman disease associated with vascular proliferation in the surrounding soft tissues. (Courtesy of Dr. Pietro Muretto, Pesaro, Italy.) plasmacytoma,300,301 follicular lymphoma,302,303 and particularly Hodgkin lymphoma.304–306 B C Figure 37.37 Castleman Disease Complicated by the Development Drug Hypersensitivity of Sarcoma. A, Gross appearance of a case located in the perirenal region. B, Microscopic appearance of another case. The tumor has a Antiepileptic drugs derived from hydantoin, such as diphenylhy- vaguely hemangiopericytomatous quality. C, High-power view. dantoin (Dilantin) and mephenytoin (Mesantoin), can result in a hypersensitivity reaction manifested by skin rash, fever, generalized lymphadenopathy (mainly cervical), and peripheral eosinophilia. is needed to diagnose appropriately and the diagnosis might only The reaction, which is quite uncommon, tends to occur within the be confirmed with clinical resolution after discontinuation of the first few months of therapy. The changes disappear if the drug is drug. discontinued. The nodal enlargement can occur in the absence of some of the other manifestations of the drug reaction. Microscopically, partial effacement of the architecture by a Dermatopathic Lymphadenitis polymorphic cellular infiltration is seen.307 Histiocytes, immunoblasts, Dermatopathic lymphadenitis (lipomelanosis reticularis of Pautrier) eosinophils, neutrophils, and plasma cells are all present. Some of is a form of nodal hyperplasia usually secondary to a generalized the immunoblasts have atypical nuclear features, including rare cases dermatitis, particularly those with exfoliative features. Pathogenetically, with Reed–Sternberg-like cells. Foci of necrosis were noted in the it represents a T-cell response to skin antigens processed and presented classic article by Salzstein and Ackerman in which this condition by interdigitating dendritic cells. It may occur in any skin disorder was first described.308 In some of the cases, the microscopic appearance in which itching and scratching are prominent; this includes inflam- may mimic viral infections, postvaccinial lymphadenopathy and matory dermatoses such as psoriasis and neoplastic diseases such even angioimmunoblastic T-cell lymphoma and classical Hodgkin as mycosis fungoides. Rarely, the morphologic changes of dermato- lymphoma. Detailed medication history and clinical information pathic lymphadenitis are seen in the absence of clinical skin disease.309 1557 37 Lymph Nodes A Figure 37.39 Rosai–Dorfman Disease. Low-power view showing massive distension of the sinuses by the histiocytic infiltrate. immunohistochemistry and molecular pathology. Dermatopathic lymph nodes that are also involved by mycosis fungoides may show loss of CD7 and CD62L expression, and sometimes also loss of the pan–T-cell markers CD5, CD3, and CD2.315 At the molecular level, clonal rearrangements of T-cell receptor genes may be dem- onstrated in cases involved by mycosis fungoides.316 The presence of dermatopathic lymphadenitis in a patient with known mycosis B fungoides, even in the absence of involvement by mycosis fungoides, Figure 37.38 Dermatopathic Lymphadenitis. A, Massive expansion is considered an abnormal finding and results in an N1 staging of the paracortical region, resulting in a wide, pale area between the status and the need for molecular studies for T-cell receptor gene capsule and the lymphoid follicles. B, High-power view of the paracortical rearrangements.317,318 region showing numerous cells with oval vesicular nuclei, which correspond to an admixture of interdigitating dendritic cells and Langerhans cells with nuclear grooves. Scattered cells containing pigment are also present. Rosai–Dorfman Disease Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy (SHML), presents in its most typical Grossly, the lymph node is enlarged, the cut surface bulging, and form as massive, painless, bilateral lymph node enlargement in the the color pale yellow. In florid cases, black linear areas are seen in neck, associated with fever, leukocytosis, elevated erythrocyte sedi- the periphery, representing clumps of melanin pigment and simulating mentation rate, and polyclonal hypergammaglobulinemia.319,320 Most the appearance of malignant melanoma. cases occur during the first or second decade of life, but any age Microscopically, the nodal architecture is preserved. The main group can be affected. A few cases have affected two members of change is represented by a marked pale widening of the paracortical the same family.321 There is a predisposition for the condition in zone, which stands out prominently on low-power examination blacks. Although the disease has a widespread geographic distribution (Fig. 37.38).310 Most of the large nonlymphoid cells occupying this and most of the reported cases have been from the United States area are thought to be of three types: histiocytes, Langerhans cells, and Western Europe, there is a disproportionally high number of and interdigitating dendritic cells marking with a mix of CD163, cases from Africa and the Caribbean region.319 The cervical region CD1a, langerin, and S100 positivity.311,312 Many of the histiocytes is by far the most common and most prominent site of involvement, contain phagocytosed melanin and neutral fat in their cytoplasm. but other peripheral or central lymph node groups can be affected, Plasma cell infiltration and follicular hyperplasia are often present. with or without cervical disease. A scattering of eosinophils also may be seen. Grossly, the nodes are matted together by prominent perinodal Nodes affected by dermatopathic lymphadenitis may be confused fibrosis. Their cut surface varies from gray to golden yellow, depending with Hodgkin lymphoma, mycosis fungoides, monocytic leukemia, on the amount of fat present. or LCH. The differential diagnosis with mycosis fungoides is of Microscopically, there is a pronounced dilation of the lymph particular concern because of the fact that mycosis fungoides is one sinuses, resulting in partial or complete architectural effacement of the cutaneous disorders that can be associated with dermatopathic (Fig. 37.39). These sinuses are occupied by lymphocytes, plasma lymphadenitis.313,314 Diagnostic assistance can be obtained from cells, and—most notably—by numerous cells of histiocytic appearance 1558  Inflammatory/Hyperplastic Diseases 37 Figure 37.41 Rosai–Dorfman Disease. Oil red O stain showing abundant neutral lipid in the cytoplasm of the histiocytes. Figure 37.40 Rosai–Dorfman Disease. High-power view showing lymphocytophagocytosis by the sinus histiocytes. with a large vesicular nucleus and abundant clear or lightly eosino- philic cytoplasm that may contain large amounts of neutral lipids. Many of these histiocytes have within their cytoplasm numerous intact lymphocytes, a feature that has been designated as emperipolesis or lymphocytophagocytosis. Although not specific, this is a constant feature of RDD (as least in the lymph node location) and is therefore of great diagnostic significance (Fig. 37.40). Sometimes other cell Figure 37.42 Strong immunoreactivity of the sinus histiocytes for S100 types are present within the cytoplasm of the histiocytes, such as protein in Rosai–Dorfman disease. plasma cells and red blood cells. The intersinusal tissue exhibits a variable but sometimes impressive number of mature plasma cells, some of which may contain Russell tissue (perhaps more commonly in Asia),334–339 skeletal system,340 bodies. Capsular and pericapsular inflammation and fibrosis are and central nervous system.341–343 However, the disease has been common, but intranodal fibrosis is minimal or absent. In a minority reported in many other sites, including gastrointestinal tract,344–346 of cases, small microabscesses or foci of necrosis are found within pancreas,347 salivary glands,348 genitourinary tract, thyroid,349 medi- the dilated sinuses. Ultrastructurally, the histiocytes located in the astinum,350 breast,351,352 uterine cervix,353 and bone marrow.354 In sinuses have extensive pseudopodia and lack Birbeck granules; viral some instances, widespread nodal and extranodal dissemination is particles or other evidence of infection is consistently lacking. The found.355 Organs that stand out because of their almost universal sinus histiocytes contain cytoplasmic fat (Fig. 37.41) and are strongly sparing by the disorder are lung, and spleen, and bone marrow (the reactive for S100 protein322 and CD68 (Fig. 37.42) but negative for latter exclusive of the focal bone lesions mentioned previously). CD1a; some of them are also positive for immunoglobulin, presum- The histopathologic features of RDD in extranodal sites are similar ably phagocytosed from the surroundings. Their immunohistochemi- to the nodal disease except for the fact that fibrosis tends to be more cal profile (including the adhesion molecules pattern) suggests that pronounced and emperipolesis less conspicuous. they are monocytes that have been recently recruited from the The etiology of RDD remains unknown, the two most likely circulation.323–326 The plasma cells show a polyclonal pattern of possibilities (not mutually exclusive) being infection by a virus or immunoglobulin expression. Some cases show an increase in IgG4- some other microorganism and the manifestation of a subtle positive plasma cells and the relationship between RDD and IgG4- undefined immunologic defect. It has been suggested that stimulation related disease requires clarification.327–329 The lymphocytes present of monocytes/macrophages via macrophage colony-stimulating factor are an admixture of B and T cells. (M-CSF) leading to immune suppressive macrophages may be the In over one-fourth of the cases, RDD involves extranodal sites.319 main pathogenetic mechanism.356 Despite some suggestive early data This usually occurs in the presence of massive lymphadenopathy, derived from serologic tests, most studies fail to demonstrate an and the disease is therefore easily recognized. However, in some infectious etiology.357,358 Molecular studies done on involved tissue cases these extranodal manifestations represent the predominant or have failed to show evidence of clonality, in keeping with their even exclusive manifestation of the disease. Practically all organ presumed reactive nature. This contrasts with the findings in at least systems have been recorded as being the site of the disease. The some studies of LCH, a disease that it otherwise resembles in many most common are eyes and ocular adnexa (especially orbit),330 head clinical, morphologic, and phenotypic aspects,325,359,360 and with and neck region,331 upper respiratory tract,332,333 skin and subcutaneous which it can coexist.361,362 1559 37 Lymph Nodes A B Figure 37.43 A and B, Lymph node involvement by Kimura disease. There is follicular hyperplasia and massive perinodal inflammation, which is predominantly composed of eosinophils. (Courtesy of Dr. T.-T. Kuo, Taipei, Taiwan.) RDD is relatively unaffected by therapy, although chemotherapy transformed type. These germinal centers are often well vascularized has proved effective in some cases,363–365 occasionally with allegedly and contain polykaryocytes, interstitial fibrosis, and deposition of complete and permanent results.366 In many cases, RDD undergoes a proteinaceous material. There is also extensive infiltration by quick and complete spontaneous resolution. In others, it follows a mature eosinophils, with occasional formation of eosinophilic protracted clinical course for years or decades. The latter is particularly abscesses (Fig. 37.43). Hyalinized vessels are often seen in the true in cases with widespread extranodal involvement. In some paracortical region, and there is a variable degree of sinus and instances the disease disappears, only to come back years later at paracortical sclerosis. An increase in the number of plasma cells another site. Some patients have died as a result of RDD, either and mast cells has been noted in the paracortex,375 together with because of extensive disease affecting vital organs or because of proliferation of postcapillary venules.374 Some cases are associated complications related to the immunologic abnormalities that may with increases in IgG4-positive plasma cells, a feature of unclear be present,367,368 such as amyloidosis.369 significance.376 The differential diagnosis of RDD includes nonspecific sinus Despite early statements to the contrary, current evidence strongly hyperplasia (in which the cells lack emperipolesis and are S100 suggests that Kimura disease and the disease known to dermatologists protein-negative), LCH (in which the cells are positive for S100 as angiolymphoid hyperplasia with eosinophilia are different entities protein, langerin, and CD1a), leprosy, rhinoscleroma (with which (see Chapter 3); specifically, the former disorder lacks the epithelioid it can apparently coexist370), and metastatic malignant melanoma. (histiocytoid) endothelial cells that are the morphologic hallmark Perhaps the condition that resembles it most is the sinus histiocytosis of the latter.377–380 The differential diagnosis of Kimura disease includes induced by cobalt-chromium and titanium that can occur in pelvic parasitic infections as well as tissue manifestations of chronic lymph nodes after hip replacement.344 eosinophilic leukemia and the related clonal eosinophilic disorders It should also be noted that focal RDD-like changes can sometimes reviewed in Chapter 39. be seen in lymph nodes involved by other processes, such as Hodgkin371 or non-Hodgkin lymphoma, a phenomenon analogous to that sometimes seen in LCH.372 Similar changes can also occur Chronic Granulomatous Disease in lymph nodes involved by ALPS.52 Chronic granulomatous disease is the result of a genetically determined enzymatic defect of granulocytes and monocytes.381–383 These cells ingest microorganisms but are unable to destroy them Kimura Disease because of their inability to generate superoxide anion (O2–). Kimura disease is an inflammatory disorder of unknown etiology This is due to a defect in any one of five components of NADPH seen in an endemic form in Asia373 but also in other parts of the oxidases, the enzyme responsible for the generation of the anti- world, including the United States and Europe.374 It usually presents microbial oxidants.382 A pattern of X-linked inheritance is seen in as a mass lesion in the subcutaneous tissue of the head and neck approximately 65% of the patients and results from mutations in region or the major salivary glands, often associated with regional the gene that encodes the g91-phox subunit of the cytochrome lymphadenopathy. Sometimes lymph node enlargement is the only b558 component of the oxidase. The remaining 35% of patients manifestation of the disease. inherit the disease in an autosomal recessive manner resulting Microscopically, the involved nodes show marked hyperplasia from mutations in the genes that encode the other three oxidase of germinal centers, a few of which may be of the progressively components.384–386 1560  Malignant Lymphoma 37 The traditional laboratory technique for the detection of the in association with long-term total parenteral nutrition therapy for disease is the nitro blue tetrazolium test although detection of dihy- short bowel syndrome.394 drorhodamine oxidation can be performed by flow cytometry.383,387 Whipple disease can result in marked enlargement of mesenteric The main clinical features are recurrent lymphadenitis, hepato- lymph nodes, with formation of numerous lipophagic granulomas.395 splenomegaly, skin rash, pulmonary infiltrates, anemia, leukocytosis, Collections of histiocytes containing a PAS-positive glycoprotein are and hypergammaglobulinemia.388–390 Microscopically, granulomas also present.396 Under oil immersion and with electron microscopy, with necrotic purulent centers are seen in lymph nodes and other the characteristic bacillary bodies can be identified. Collections of organs. They closely simulate the appearance of cat-scratch disease PAS-positive histiocytes can also develop in peripheral nodes and and lymphogranuloma venereum. Collections of histiocytes contain- may be the first clue to the diagnosis in a patient with gradual weight ing a lipofuscin-like pigment are also commonly observed and loss, weakness, and polyarthritis. Steatorrhea, the other classic represent an important clue to the diagnosis.391 symptom of the disease, may appear only in a later stage. In the presence of suggestive findings in routinely stained sections, confirma- tion of the diagnosis can now be obtained by the demonstration of Lipophagic Reactions the responsible organism (Tropheryma whipplei) by immunohisto- Accumulation of neutral lipid with formation of foamy macrophages chemistry or PCR.397–399 (xanthoma cells) can be seen as an inconsequential secondary event Lymphangiography, a procedure now largely abandoned, induces in a variety of inflammatory and neoplastic conditions of lymph a lipophagic granulomatous reaction that may persist for several nodes, including LCH, RDD, Erdheim–Chester disease, and Hodgkin months. The sinuses are markedly distended and lined by histiocytes, lymphoma. There are, in addition, conditions in which the lipophagic many of which are multinucleated. Eosinophils may be present in granuloma is the primary alteration. The lipophagic granuloma is appreciable numbers in the medullary cords. This is preceded by a defined as a collection of mononuclear and multinucleated giant predominantly neutrophilic infiltration.400 cells, both of them exhibiting a cytoplasmic foamy appearance and lacking a significant participation of other cell types. By far the most common situation in which this occurs (so common as to be nearly Malignant Lymphoma universal, at least in Western countries) is represented by the incidental Malignant lymphoma is the generic term given to tumors of the microscopic finding in periportal and mesenteric nodes in asymp- lymphoid system and specifically of lymphocytes and their precursor tomatic individuals, probably the result of mineral oil ingestion cells, whether of T, B, or null phenotypes. Tumors now known to (Fig. 37.44).392 Boitnott and Margolis393 found this change in 78% be composed of histiocytes, and other cells of the accessory immune of a series of 49 autopsied adults. Their chemical and histochemical system were previously included in the category of malignant studies showed that the oil droplets represent deposits of liquid- lymphoma but are now regarded separately for both conceptual saturated hydrocarbons. Mineral oil is extensively used in the food and practical reasons. Many tumors that were designated in the past processing industry, as a release agent and lubricant in capsules, as histiocytic lymphomas or reticulum cell sarcomas, however, are tablets, bakery products, and dehydrated fruits and vegetables. in reality of lymphocytic nature and therefore true malignant Lipophagic granulomas of an extensive degree have been reported lymphomas and an interrelationship between some true histiocytic tumors and malignant lymphomas is becoming clear.401 Although some overlapping exists, the term malignant lymphoma is reserved for those neoplastic processes that initially present as localized lesions and are characterized by the formation of gross tumor nodules. Conversely, neoplastic lymphoid proliferations that are systemic and diffuse from their inception are usually termed leukemias (see Chapter 39). The malignant lymphomas can be divided into two major catego- ries: Hodgkin lymphoma and all the others, which, for lack of a better term, are known collectively as non-Hodgkin lymphomas.402–406 Both groups are further subdivided into several more or less distinct subcategories, with the most currently and widely accepted classifica- tion being the 2016 WHO revision.407 This classification has incorporated a wealth of information gathered from the fields of