III.	Specific Benign Entities that Can be Easily Misdiagnosed as a Lymphoma (continued) Marsha Kinney, James Cook and Steven Swerdlow

Case 2 Diagnosis: Kikuchi-Fujimoto Disease (KFD) (Synonym:Histiocytic Necrotizing Lymphadenitis) Clinical history: 17 year-old Caucasian male with right cervical lymphadenopathy and no evidence of autoimmune disease. Histology: Lymph node sections reveal reactive follicles and pale areas of paracortical alteration of nodal architecture by a variable mixture of histiocytes, large and small lymphocytes, and apoptotic debris. At low magnification, the paracortical areas have a "mottled" appearance due to numerous histiocytes. Focal areas of frank coagulative necrosis with considerable apoptotic debris are present. Neutrophils are notably absent. Numerous large lymphocytes and histiocytes are present in the paracortex, particularly surrounding the areas of necrosis. Phagocytic and non-phagocytic histiocytes with crescentic (or "C"-shaped nuclei) are admixed with immunoblasts and large transformed lymphocytes. Some of the large lymphocytes have atypical, folded nuclei with very prominent nucleoli. Some histiocytes have a plasmacytoid appearance with eccentric nuclei and abundant eosinophilic cytoplasm. Scattered plasma cells are present, and there are focal areas of monocytoid B-cell proliferation next to sinuses and near follicles. Other areas of the node (not on the digitized slide) reveal large foci of cortical/paracortical necrosis surrounded by foamy histiocytes and some involvement of the capsule. A few small vessels near the necrotic areas contain fibrin. Immunophenotyping: The follicles and only a few lymphocytes in the interfollicular areas are CD20+ B-cells. The paracortical T-cells show a marked predominance of the CD8+ subset. Many of the T-cells express the cytotoxic granule protein TIA-1. CD68+/ myeloperoxidase (MPO)+ histiocytes are present. Staining for CD123 highlights histiocytes with plasmacytoid morphology seen in the paracortex and around the necrotic areas. There is a minor population of scattered CD30+ large lymphocytes. Follow-up: The patient is a healthy college student who plays basketball and describes rare "episodes" similar to those when he was diagnosed with KFD. This case is presented to illustrate the difficulty in diagnosing lymphoproliferative disorders when the clinical setting is unusual (male, 17 years old) or the cytology is disturbing (numerous large atypical cells with large areas of necrosis). Contributor: This case was contributed by Lt. Col. Dale M. Selby, M.D., Wilford Hall Medical Center, San Antonio, TX. Background and Clinical Features: Histiocytic necrotizing lymphadenitis was first described in 1972 independently by Dr. Kikuchi and Dr. Fujimoto in Japan [1, 2] but has been reported in a wide geographic distribution. [3, 4] The first report outside of Japan was by Pileri et al. in 1982 and included predominantly patients from West Germany but also Italy, Iran, South Korea and Spain. [5] KFD is typically a self-limited cause of tender lymphadenopathy with low-grade fever in young adult Asian females under the age of 30 years. Patients may have an upper respiratory prodrome (30%-50%). The female to male predominance (4:1) varies and approaches 1:1 in recent studies from Eastern countries or in the pediatric population. [3, 6] The median age is 21-30 years (range 19 months-75 years). [3, 7, 8]C ervical lymphadenopathy is present in 56%-98% of cases most commonly in the posterior cervical triangle (88.5%) and is unilateral in 88.5%. Axillary adenopathy is the next most common site and generalized adenopathy is present in 1%-22%. [3] Lymph node size ranges from 0.5 to 4 cm with occasional lymph nodes being greater than 6 cm. Mediastinal, peritoneal and retroperitoneal involvement is rare. Laboratory abnormalities include high ESR, mild leukopenia (neutropenia), lymphocytosis with atypical lymphocytes (25%-31%), or anemia. [3] Lactate dehydrogenase and aminotransferase may be increased in some patients. CT and MRI examinations can mimic lymphoma and other nodal diseases with necrosis including infection and metastatic tumor. KFD symptoms typically disappear within 1-5 months, but recurrence has been reported in approximately10% of patients and in pregnancy. [8, 9] KFD rarely occurs in pediatric patients [6, 10, 11, 12, 13, 14, 15, 16, 17] with a median age 9.5-16 years and often with a male predominance. [6, 11] The distribution of disease (unilateral posterior cervical adenopathy in 83% with a size range of 0.5-3 cm, in 52.2% and 3-6 cm in 39.1%) is similar to adult patients. Other clinical features include; leukopenia (22%-82%), [6] fever (30.4%), and less commonly skin rash, hepatomegaly, weight loss, and mild liver dysfunction. Most pediatric patients have resolution of their symptoms within 6 months. However, up to 38% of pediatric patients can develop new symptoms compatible with an autoimmune process during follow-up with neurological symptoms being the most common. SLE has been reported in one patient five years after KFD. [6] These findings suggest long-term follow-up is necessary to monitor for the development of rheumatologic disease. A high ANA titer may be associated with a more protracted course. [15] Association with autoimmune disease: Similarities between KFD and SLE (young females, similar histologic features on lymph node biopsy, and tubuloreticular structures on electron microscopy) have led to speculation that KFD is an SLE-like autoimmune disease. The co-existence of SLE and KFD has been described in a small number of cases (reviewed in references 3 and 17). [3, 18] The diagnosis of KFD can precede (20%-30%), coincide (50%-60%), or occur after the diagnosis of SLE (10%-20%). Lymph node enlargement occurs in approximately two-thirds of SLE patients (approximately 40%-50% of cases are in the cervical region). As there are good serologic tests to diagnose SLE, a lymph node biopsy is not performed in most cases; therefore, it is difficult to determine how often KFD type changes are seen in SLE. When KFD-like lesions occur in patients with SLE, it is likely a manifestation of lupus rather than the simultaneous occurrence of two diseases; also, antecedent KFD may actually be an early manifestation of SLE. [19] Because it may be very difficult to distinguish KFD from lesions seen in SLE, serologic testing for SLE should be recommended in all cases. Other autoimmune or abnormal immune manifestations reported in patients with KFD include: polymyositis, polyarthritis, systemic juvenile rheumatoid arthritis, bilateral uveitis, [20] cutaneous necrotizing vasculitis and pulmonary hemorrhage, [3] asthma, chronic eczema, and hay fever. [8] Histology: The histologic appearance of KFD is variable. The characteristic findings include discrete or confluent pale paracortical areas of necrosis with abundant karyorrhectic or apoptotic debris, large numbers of histiocytes, and proliferation of immunoblasts or large lymphocytes. The lymphocytes in KFD are a mixture of small and large lymphocytes with the latter often predominating. The large lymphocytes are immunoblasts or large non-cleaved (or transformed) cells and often have an atypical cytologic appearance. Reed-Sternberg-like cells are not typically seen. Numerous histiocytes of various types are present including tingible body macrophages, nonphagocytic crescentic histiocytes (with C-shaped nuclei), and foamy (or xanthomatous) histiocytes. Plasmacytoid dendritic cells (also previously known as plasmacytoid T-cells or plasmacytoid monocytes) are also present. Histiocytes can be misinterpreted as abnormal large lymphocytes. Histiocytes with signet ring-like morphology are seen in approximately 10% of cases. [21] Necrosis can be patchy or confluent and vary from karyorrhexis and eosinophilic debris to frank coagulative necrosis. The capsule and surrounding soft tissue are involved in about 20% of cases. Thrombosed vessels are not a prominent feature but can be seen around the areas of necrosis. Neutrophils are absent and plasma cells are absent or scarce. Reactive lymphoid follicles are present in 50%-60% of cases with follicular hyperplasia in approximately 10%. [3] Sinus distension by focal clusters of monocytoid (parafollicular) B-cells may be present. Three histologic types or possible stages in evolution of the lesion have been described. [7] The proliferative type (~30%) has plasmacytoid dendritic cells, immunoblasts, and histiocytes with little or no necrosis. The second, necrotic type (~55%) has large areas of necrosis with extensive karyorrhexis and karyolysis. The third or xanthomatous type is characterized by resorption and return to normal histology. The earliest lesion consists of paracortical clusters of plasmacytoid monocytes with interspersed karyorrhexis and crescentic histiocytes. It is not known if the three different histologies represent different stages of the disease or reflect differences in the etiology or host response. Immunophenotype: The large lymphocytes are predominantly T-cells with few B-cells. Most T-cells are CD8+ TIA-1+ (cytotoxic granule protein) cytotoxic T-cells. [22] The histiocytes variably express CD68, lysozyme, myeloperoxidase (MPO), and CD4. [23] The expression of MPO in histiocytes is useful in the differential diagnosis as other benign causes of lymphadenopathy (except SLE) and lymphomas lack MPO+ histiocytes. [24] Plasmacytoid dendritic cells express CD123 (IL-3 receptor alpha chain). CD30 is usually expressed in 10% or less of the T-cells but may be seen in 25%-50% of the T-cells in 20% of cases. [24] Studies to detect EBV are negative. Other sites of disease: Extranodal disease is relatively rare in KFD. Bone marrow involvement and liver dysfunction have been reported. Nonspecific cutaneous findings have been reported in up to 40% of cases. The gross appearance of skin lesions is non-specific and includes rashes, nodules, erythematous-crusted papules, indurated erythematous lesions, erythema multiforme, and erythematous maculopapular eruptions mainly affecting the face and upper body. [3, 23] Histologic examination reveals vacuolar interface change with necrotic keratinocytes, superficial and deep perivascular and interstitial lymphohistiocytic infiltrate (similar to that of the lymph node) with varying amounts of papillary dermal edema and abundant karyorrhectic debris and absent neutrophils. [25] These features resemble SLE, but papillary dermal edema is an exception in lupus dermatitis. Patients with Sjogren syndrome may have painful indurated skin lesions mimicking KFD [26] and rare coexistent KFD and Sjogren syndrome have been described. [27, 28] Biology and Pathogenesis: The etiology of KFD remains speculative. The clinical symptoms suggest a viral infection (upper respiratory prodrome, atypical lymphocytosis, lack of response to antibiotics, etc.). Proposed agents include parasites (e.g. Toxoplasma), bacteria (e.g., Brucella, Yersinia enterocolitica), and viruses (e.g., EBV, CMV, parvovirus B19, HHV-6 and HHV-8, rubella, parainfluenza, and varicella-zoster) (reviewed in reference 3). Bartonella henselae gene sequence has also recently been detected in lymph nodes of children. [29] Giardia lamblia intestinalis infection has been reported two months prior to the onset of KFD. [30] Others have suggested KFD represents a common pattern of response to variety of agents rather than a specific clinicopathologic entity. [31] Another consideration is an exuberant T-cell response (hyperimmune reaction) in genetically susceptible people to a variety of non-specific stimuli. HLA class II alleles DPA1*01 and DPB1*0202 (genes more commonly expressed in Korean, Japanese, French and Italian individuals) are higher in patients with KFD than in control patients. By ultrastructural analysis, tubular reticular structures (seen in viral infection and autoimmune diseases) have been identified in lymphocytes and histiocytes, suggesting KFD could represent a self-limited SLE-like autoimmune condition, but standard rheumatologic tests have been negative except for in the small number of patients with SLE and KFD (discussed on previous page). Other triggers of KFD include pacemaker implantation and silicone from a leaking breast implant. [3] The predominant lymphocyte in KFD is a cytotoxic CD8+ TIA-1+ T-cell that might act as killer and victim (reviewed in reference 3). [3, 22, 32] KFD is likely a cell-mediated process sustained by activated CD8+ T-cells. Activation of the FAS-FASL and perforin pathways and endonuclease DNase gamma support the apoptotic nature of cell death in the cellular debris seen in KD. [22, 33] The presence of CD123+ plasmacytoid dendritic cells that are capable of producing large amounts of type I interferon may promote a Th1 T-cell reaction and a cytotoxic immune response, suggesting that CD8+ T-cell mediated death is histiocyte dependent. Additional chemokines and cytokines such as interleukin-18, monokine induced by gamma interferon, and Cys-X-Cys chemokine IFN-g -inducible protein-10 are increased. A curious feature of KFD is the striking absence of granulocytes despite the prominent necrotizing features. The MPO+/CD68+ histiocytes likely correspond to a similar population of peripheral blood monocytes that can substitute for neutrophilic MPO for the production of advanced glycation products at sites of inflammation. Plasmacytoid dendritic cells are frequently seen in KFD often in the uninvolved parenchyma rather than as a prominent component of the lesion. They lack MPO and express CD68. [24] Dendritic cells are hematopoietic cell derived migratory antigen presenting cells that can be divided into myeloid (CD11c+, mDC) and lymphoid (CD11c-, plasmacytoid, pDC) types. DCs capture foreign antigens in peripheral tissue through pattern recognition receptors such as the Toll-like receptors (TLRs 1-10) of the innate immune system. The ligands of some TLRs are known. TLR-9 recognizes unmethylated CpG rich DNA of bacterial or viral origin. Stimulated by foreign antigens, immature DCs migrate toward lymph nodes, mature and present antigen to T-cells to initiate a primary immune response. [34] In a recent study by Lin CW et al., 2005, TLR7 was found in every KFD case, confirming the universal presence of pDCs. [6] Transcripts of TLR9 (another receptor on pDCs for microbial unmethylated CpG-rich DNA) were correlated with the presence of oligoclonal T-cells implying T-cell expansion in response to a microbe. [6] PCR of bacterial 16S rDNA has been negative indicating a bacterial origin is unlikely, but a virus would be a candidate. PDC lack the maturation marker CD83 suggesting ineffective stimulation of T-cells. Differential Diagnosis: The differential diagnosis of KFD includes benign and neoplastic disorders causing necrotizing lymphadenopathy. See table on page 25. Malignant Lymphoma: In early studies up to 40% of KFD were initially diagnosed as lymphoma [35, 36] but even more recent reports emphasize KFD can still be confused with lymphoma. [8] The clinical circumstances and pathologic features in KFD that suggest lymphoma include: Unilateral cervical adenopathy with little fever, systemic symptoms Clinical symptoms are unresponsive to antibiotics and can persist for up to 5 months [8] CT scan may show homogeneous enhancing lesions without necrosis, suggesting lymphoma [37] Necrosis and large atypical cells Organism stains/molecular studies are negative Predominance of CD8+, TIA-1+ T-cells T-cells can be oligoclonal No definitive laboratory tests are available to confirm the diagnosis Rare cytogenetic abnormalities have been described [38] Features in KFD that are compatible with a benign process and useful in distinguishing it from lymphoma include: [39] Most lymph nodes involved by lymphoma are not tender Patent sinuses in non-pathologic areas Partial preservation of architecture Prominent mottling by histiocytes or transformed lymphocytes in the intervening paracortical areas between the necrotic foci Although histiocytes have atypical crescentic nuclei, their chromatin is bland similar to other histiocyte nuclei Lack of a "starry sky" appearance; karyorrhectic debris outside of histiocytes (in lymphoma the macrophage cytoplasm contains the debris) Plasmacytoid dendritic (histiocytes) cells at the periphery or immediately outside the pathologic foci As the pattern of infiltration in KFD is paracortical, and the predominant large cell is a CD8+ cell, the differential would include a peripheral T-cell lymphoma. Most node-based lymphomas arise from CD4+ T-cell populations. CD8+, TIA+ lymphomas typically occur at extranodal sites; many of these lymphomas spread to other extranodal sites and only rarely involve lymph nodes. Anaplastic large cell lymphoma (ALCL) can arise, in a small number of cases, from CD8+ cytotoxic T-cells. ALCL is excluded based on the lack of sinus involvement; CD30 is expressed only in a subset of large cells, and lack of EMA, ALK-1, and clusterin expression. (ALCL will be discussed further in Case 8). Other extranodal CD8+ TIA-1+ lymphomas tend to have a mixture of small, medium, and large cells and can express CD56, have a γδ phenotype (hepatosplenic lymphoma, cutaneous γδ T-cell lymphoma), [40] and be associated with EBV (nasal/nasal type NK/T-cell lymphoma). Viral Infection: Viral driven lymphoproliferations, particularly infectious mononucleosis (IM), are in the differential of KFD and can be confused with lymphoma. The presence of atypical clinical features (older age; lack of fever, pharyngitis, and splenomegaly; asymmetrical tonsillar enlargement; and negative serology) lead to biopsy and risk for misdiagnosis as lymphoma. The histologic appearance of IM varies with the stage of disease. Initially the follicles are large with prominent germinal centers with many transformed lymphocytes, mitoses, and tingible body macrophages. With disease progression, the follicles are disrupted by expansion of the paracortical region by immunoblasts, Reed-Sternberg (RS) like cells, plasma cells, and histiocytes. The immunoblastic proliferation can become extensive and obscure the germinal centers and sinuses. The sinuses are expanded by a similar population of cells but are preserved (as best seen on a PAS stain). Capsular invasion, large numbers of immunoblasts, RS-like cells, and vascular proliferation are features shared with lymphoma. Necrosis is often present and can be focal, patchy or extensive. [41] RS-like cells are not typically seen in KFD and immunophenotypically the large lymphocytes/immunoblasts in IM are predominantly B-cells rather than the T-cells seen in KFD. [42] The large cells are often CD30+ and express EBV-LMP or are EBER+ (EBV encoded RNA). [43] Plasma cells and granulocytes are usually seen with the necrosis of IM. Atypical mononucleosis-like infections due to CMV can have similar features and the RS-like cells can be CD15+! [44] CMV inclusions may be present. See Table 1 for comparison of IM with lymphoma. A rare case of parvovirus B19 associated hemophagocytic syndrome with lymphadenopathy resembling KFD has been described. [45] Herpes simplex and Herpes zoster infection are also in the differential and may be distinguished by the presence of viral inclusions. Herpes simplex in particular may have associated necrosis with cellular debris resembling KFD, but neutrophils are often present. Note: Another potential pitfall is the presence of large cell proliferations associated with viral infection in patients with small B-cell lymphoma or chronic lymphocytic leukemia may be misinterpreted as large cell transformation of the neoplasm. [46] Table 1. Comparison of Immunophenotypic and Molecular Features of Infectious Mononucleosis and Malignant Lymphoma Antigen IM Classical Hodgkin Lymphoma B-NHL ALCL CD45 RB (LCA) +/- - +/- +/- CD20 +/- -/+ + - T-cell antigens -/+ rare - +/- CD15 -* + - -/+ CD30 + + -/+ + LMP/EBER + +/- -/+ - EMA - -** -*** +/- BCL-2 variable variable variable variable IgH rearrangement polyclonal polyclonal^ monoclonal - * CMV "atypical IM" may be CD15+ **Lymphocyte predominant HL is EMA+ in a subset *** Rare NHL, ALK+ B-NHL is EMA+; small subset of other B-NHL may express EMA ^ HL is monoclonal by microdissection and sensitive PCR + > 75% +/- = 25%-75% -/+ = 5%-24% - = < 5% Autoimmune disease: The most difficult, if not impossible, entity to distinguish from KFD histologically is SLE. Focal or large areas of necrosis that may be acellular or contain karyorrhectic debris with or without neutrophils are present in SLE. Plasma cells are more prominent in SLE than in KFD. The presence of hematoxylin bodies (PAS+ amorphous, 5-12 um round structures representing karyorrhectic lymphocyte nuclei) and necrosis and thrombosis of small arterioles are findings that are more specific of SLE. The deposition of basophilic material around blood vessels, similar to that seen in oat cell carcinoma ("Azzopardi effect"), has been described. The KFD-like lesions in SLE predominantly show necrosis and do not have the proliferative or xanthomatous type lesions of KFD. [19 ]In addition, the increase in cytotoxic lymphocytes present in KFD is not seen. All this aside, the "bottom line" is that SLE must be ruled out (with serologic testing) before a final diagnosis of KFD is made. Bacterial Infection: Bacterial infection often causes microabscess formation. Cat scratch disease (Bartonella henselae) typically has stellate microabscess with numerous neutrophils surrounded by palisading histiocytes. These lesions are in the lymph node cortex and can be associated with capsular thickening and plasmacytosis. Monocytoid B-cell proliferation can be present in the sinuses. Small coccobacilli in endothelial cells, macrophages, or adjacent to the abscesses or germinal centers may be identified on Warthin-Starry or Steiner stains (note: use formalin-fixed tissue). Yersinia enterocolitica adenitis (typically mesenteric in location) shows microabscesses with granulocytes frequently in follicle germinal centers and aggregates of epithelioid histiocytes. [47] Rare patients with KFD-like lesions have been described with Yersinia enterocolitica serogroups 3 and 9. [48] Protozoal Infection: Rare cases of toxoplasma lymphadenitis show necrosis raising the differential with KFD. The presence of follicular hyperplasia, clusters of epithelioid histiocytes abutting the germinal centers, and prominent proliferation of monocytoid B-cells around the sinuses is characteristic of toxoplasma. Toxoplasma trophozoites or cysts are only rarely seen. Unknown etiology: Kawasaki disease (mucocutaneous lymph node syndrome), predominantly a disease of young children, is a rare cause of lymphadenopathy in adults and is in the differential of KFD. In Kawasaki disease there is patchy lymph node necrosis with neutrophils, necrosis of follicles, and thrombosed small vessels. [49] The diagnosis of Kawasaki disease is made based on clinical features: children < 5 years of age with fever, polymorphous exanthem, bilateral non-exudative conjunctivitis, inflammation of the lips and oral mucosa (red lips, strawberry tongue, diffuse injection of the oral and pharyngeal mucosa, palmar and plantar erythema and/or edema, with later desquamation, and cervical adenopathy (usually >1.5 cm, unilateral). In adults, the median age is 27.6 +/- 10.3 years (range 18-68); 74% are < 30 years. [50] Adenopathy is present in 93% of adult patients (as compared to 75% of children) and is painful, symmetrical, and sometimes unilateral and most frequent in the cervical region. Axillary, subclavicular, and inguinal adenopathy can also occur. Articular involvement is more common and meningitis less frequent in adults than in children. Fewer coronary aneurysms are seen in adults (5% of cases) than children (20% of cases). Treatment of Kawasaki disease in the first seven to ten days with high dose intravenous immunoglobulin has been show to reduce the incidence of coronary abnormalities seen in this disease. Other Neoplasms: It should be mentioned that other large cell neoplasms (metastatic carcinoma, melanoma, acute leukemia, malignant histiocytosis) can involve the paracortical/sinus areas of the lymph node and may be associated with necrosis. These diseases would be distinguished by the appropriate immunostaining with antibodies to keratin, melanocytic markers (S-100, HMB-45, Mart1), and histiocytic antigens (S-100, CD1a, CD68, CD21). Note: Malignant lymphoma, acute leukemia, and metastatic carcinoma can cause massive infarction due to vascular thrombosis, tumor compression/invasion of vessels, or production of inflammatory cytokines. There is coagulative necrosis with cell ghosts and variable degrees of inflammation. Previous surgical trauma (or FNA) may also be responsible for the infarction. Differential Diagnosis of Kikuchi-Fujimoto Disease Diagnosis Clinical Distribution Morphology Immunophenotype Other Differential Features Kikuchi-Fujimoto Disease Predominantly cervical LN Proliferative; necrotic; xanthomatous Increased cytotoxic CD8+, TIA-1+ T-cells CD68+ MPO+ histiocytes; crescentic histiocytes; plasmacytoid dendritic cells T-Cell Lymphoma (TCL) Nodal or extranodal Large areas of necrosis with extracellular apoptotic debris are unusual; Most nodal T-cell lymphomas are CD4+; CD8+ TCL are primarily extranodal; use CD56 and EBER in situ hybridization to rule out nasal type NK/TCL; CD30, EMA, ALK-1, clusterin to rule out ALCL Clonal TCR gene rearrangement; admixed histiocytes are CD68+, MPO- Infectious Mononucleosis Adenopathy, splenomegaly Necrosis, immunoblasts, RS-like cells Large cells are predominantly B-cells; EBV+ EBV serology+ Systemic Lupus Erythematosus Lymphadenopathy in 60%-70%; 40%-50% in cervical region Necrosis with apoptotic debris; hematoxylin bodies; necrosis/ thrombosis of small arteries; plasma cells Note: may also have MPO+/CD68+ histiocytes + ANA; + dsDNA Yersinia Enterocolitica Mesenteric LN Microabscess formation with numerous neutrophils often in germinal centers; aggregates of epithelioid histiocytes Cat Scratch Disease (CSD) Axillary, cervical; epitrochlear, inguinal LN Microabscess formation with numerous neutrophils Warthin-Starry or Steiner stain for CSD: small coccobacilli Kawasaki Disease (Mucocutaneous lymph node syndrome) Children usually < 5 yrs. Acute febrile illness with inflamed lips and oral mucosa; desquamation of palms and soles Necrosis with adjacent intracapillary fibrin thrombi Herpes Simplex Lymphadenopathy is uncommon with involvement of various sites; if localized usually inguinal Histiocytic and atypical large lymphocyte infiltrate with necrotic nuclear and eosinophilic debris; viral inclusions; multinucleated cells with ground glass nuclei; neutrophils often present Large lymphocytes are T-cells; viral immunostains against HSV may be positive Mucocutaneous lesions Herpes Zoster Cervical, supraclavicular, axillary LN; tender Atypical large lymphocytes; tingible body macrophages; plasma cells; intranuclear viral inclusions Large lymphocytes are T-cells Cutaneous lesions Other Large Cell Proliferations (Metastatic Adenocarcinoma, Acute Leukemia, Malignant Histiocytosis) Various sites Use antibodies against keratins, myeloid (CD15, CD68, CD117, myeloperoxidase), immature cell antigens(CD34, TdT), and histiocyte antigens (S-100, CD1a, CD68) to rule out References: Kikuchi M. 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