Human Herpes Virus 6 (HHV-6)-associated Lymphadenitis: Pitfalls in Diagnosis in Benign and Malignant Settings.

Human herpes virus 6 (HHV-6) is a member of the ß-herpesvirinae subfamily. Most people acquire HHV-6 primary infection early in life and reactivation may occur, most often in immunocompromised individuals, leading to various clinical manifestations. HHV-6 infected cells may be identified in lymph nodes in both reactive and neoplastic conditions. Cases were retrieved from the hematopathology consultation service archives at National Institutes of Health from 2003 to 2017 in which infection by HHV-6 had been documented by immunohistochemical stains to HHV-6 gp60/110 envelope glycoprotein. Five cases of reactive lymphadenitis and 3 cases of lymphoma; 2 angioimmunoblastic T-cell lymphoma and 1 classic Hodgkin lymphoma, positive for HHV-6 were identified. The reactive lymph nodes showed marked paracortical hyperplasia and admixed large atypical lymphoid cells exhibiting pleomorphic nuclei, vesicular chromatin, and prominent eosinophilic intranuclear inclusions. Vascular proliferation and necrosis were also present, raising suspicion of peripheral T-cell lymphoma. The 3 cases of lymphoma showed similar viral inclusions, in addition to the characteristic features diagnostic of the lymphoma. Staining for HHV-6 was positive with a membranous and Golgi pattern and was restricted to cells with evident inclusions on hematoxylin and eosin. HHV-6 infected cells were positive for CD3 and CD4. HHV-6 lymphadenitis can present with morphologic atypia creating a diagnostic pitfall for lymphoma. In such cases, careful attention to the characteristic viral inclusions can lead to immunohistochemical analysis highlighting the replicating virus. In cases of lymphoma, identification of the inclusions is key in detecting the associated infection as well as in avoiding misinterpretation of the lymphoma subtype.

Human herpesvirus 6 lymphadenitis in drug rash with eosinophilia and systemic symptoms syndrome: a lymphoma mimic.

AIMS: Lymphadenopathy, haematological abnormalities and constitutional symptoms are among the non-specific manifestations seen in drug rash with eosinophilia and systemic symptoms (DRESS), an uncommon but potentially fatal cutaneous adverse drug reaction. The ubiquitous human herpesvirus 6 (HHV-6) plays a unique role in the pathogenesis of DRESS, with emerging data suggesting that reactivation occurs in most cases and contributes to the clinical manifestations, including lymphadenopathy. Further, in the appropriate clinical context, demonstration of HHV-6 reactivation may lend support to a diagnosis of DRESS. The histopathology of DRESS-associated HHV-6 lymphadenitis is reported rarely, with morphologic and immunophenotypic characteristics concerning for T cell lymphoma. The aim is to characterize the histopathology of HHV-6 lymphadenitis in the context of DRESS and to highlight this as an important cause of lymphadenopathy that may be a clinical, morphologic and immunophenotypic mimic of lymphoma. METHODS AND RESULTS: We describe a case of lymphoma-mimicking lymphadenitis in which the histopathological demonstration of reactivation of HHV-6 infection lent support to the clinical diagnosis of DRESS. CONCLUSION: Lymph node biopsies concerning for T cell lymphoma should be evaluated for HHV-6 involvement in a clinical context suggestive of DRESS.

The ubiquity of asymptomatic respiratory viral infections in the tonsils and adenoids of children and their impact on airway obstruction.

BACKGROUND: Airway obstruction due to enlargement of tonsils and adenoids is a common pediatric problem resulting in sleep disordered breathing. The cause for the relatively abnormal growth of tonsils and adenoids is poorly understood. METHODS: Non-acutely ill children undergoing tonsillectomy and adenoidectomy (T&A) for various reasons were enrolled prospectively in a study to determine the frequency of asymptomatic respiratory viral infections in each lymphoid tissue and to relate the number and types of virus to the degree of airway obstruction. Molecular techniques were used to detect 9 respiratory viruses while Brodsky scores and measurements of percentages airway obstruction were used to estimate the degree of airway compromise due to the tonsil and adenoid, respectively. RESULTS: Viruses were detected in 70.9% of tonsils and 94.7% of adenoids, p < 0.001. Adenovirus was the most common virus detected at 71.1%. Adenoids had an average of 2.4 viruses compared to 0.92 for tonsils, p < 0.001. Higher Brodsky scores were only associated with EBV in tonsils, p = 0.03, while greater percentages of airway obstruction in the adenoids were associated with adenovirus, EBV, corona virus, parainfluenza virus and rhinovirus, p ≤ 0.005. CONCLUSIONS: Asymptomatic viral infections are common and directly related to the degree of airway obstruction significantly more often in adenoids than tonsils.

The role of giant viruses of amoebas in humans.

Since 2003, dozens of giant viruses that infect amoebas (GVA), including mimiviruses and marseilleviruses, have been discovered. These giants appear to be common in our biosphere. From the onset, their presence and possible pathogenic role in humans have been serendipitously observed or investigated using a broad range of technological approaches, including culture, electron microscopy, serology and various techniques based on molecular biology. The link between amoebal mimiviruses and pneumonia has been the most documented, with findings that fulfill several of the criteria considered as proof of viral disease causation. Regarding marseilleviruses, they have been mostly described in asymptomatic persons, and in a lymph node adenitis. The presence and impact of GVA in humans undoubtedly deserve further investigation in medicine.

Infectious lymphadenitis in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma: a rare, but important, complication.

The differential diagnosis of rapidly progressive or symptomatic lymphadenopathy in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) includes infectious lymphadenitis. We studied 286 (9%) of 3040 patients with CLL seen between 2003 and 2012 at Mayo Clinic Rochester who had 356 diagnostic lymph node biopsies to evaluate rapidly progressive or symptomatic lymphadenopathy. Most (85.4%) biopsies showed progressive CLL, 8.9% a second lymphoid malignancy, 3.9% infectious lymphadenitis, 1.1% reactive adenitis and 0.6% non-hematological malignancies. Of the 12 patients (14 biopsies) with infectious lymphadenitis, five patients had never been treated for their CLL, and seven had a specific microbiological diagnosis (herpes simplex n=3, Cryptococcus neoformans n=1, Mycobacterium n=1, coagulase negative Staphylococcus n=2). We conclude that infectious lymphadenitis is a rare complication of CLL with clinical characteristics similar to progressive CLL and transformation to a more aggressive lymphoma. Early recognition and antimicrobial therapy treatment of infectious lymphadenitis can be highly effective in these patients.

Herpes simplex virus lymphadenitis: the elusive doppelganger in immunocompromised patients.

Herpes simplex virus has protean manifestations and is an important cause of morbidity in the immunocompromised host. We report a case of recurrent lymphadenopathy and rash in a patient with chronic lymphocytic leukemia. The elusive clinical diagnosis eventually required core biopsy of a lymph node with immunohistochemistry and confirmation by polymerase chain reaction. This case illustrates the challenging clinical and laboratory diagnosis of herpes simplex virus lymphadenitis and the need to maintain a high index of suspicion for infection when treating an immunocompromised patient with unusual and/or persistent symptoms.

Spontaneous resolution of post-transplant localized cytomegalovirus lymphadenitis mimicking tumor recurrence.

Compromised T-cell immunity persists for up to 1 year after autologous stem cell transplantation (ASCT), and patients treated with ASCT are more likely to develop atypical lymphoid hyperplasia that mimics tumor recurrence. Here, we present a case of cervical lymphadenitis due to cytomegalovirus (CMV) reactivation in a patient who had undergone ASCT for Burkitt lymphoma, which mimicked tumor recurrence on computed tomography and positron emission tomography-computed tomography 6 months after ASCT. This lesion was confined to the regional lymph nodes and was not accompanied by signs of systemic involvement, such as fever, splenomegaly, an elevated C-reactive protein level, or viremia. The localized CMV lymphadenitis resolved spontaneously without treatment after 6 months (12 months after ASCT) and the elevated CMV immunoglobulin-M titer normalized 6 months after resolution. Our experience with this case suggests that cautious follow-up without anti-CMV treatment should be considered in cases of post-ASCT localized CMV lymphadenitis without systemic involvement in patients with complete engraftment.

Dermatopathic lymphadenitis associated with human papilloma virus infection and verruca vulgaris.

Here we present a pediatric case of human papilloma virus associated with dermatopathic lymphadenitis (DL). A 5-year-old boy presented to the pediatric oncology clinic with swelling of the neck and warts on his lower jaw. His blood chemistry and complete blood count were normal, as was chest x-ray. HIV, EBV, CMV, and parvovirus serologies were negative. The patient was investigated for malignancy and lymphoma but no association was found. Histopathologic examination of the lymph node and the lesion revealed DL and verruca vulgaris, respectively. DL represents a benign form of reactive lymph node hyperplasia and described in patients with HIV and EBV infections. It is a rare entity described in patients with human papilloma virus infection. To our knowledge, this is the first report of DL in a patient with human papilloma virus infection.

Pathogenic characterization of a cervical lymph node derived from a patient with Kawasaki disease.

Kawasaki disease (KD) is the most common cause of multisystem vasculitis in childhood. Although cervical lymphadenitis is one of the major symptoms in KD, lymph node biopsy is rarely performed, because KD is usually diagnosed by clinical symptoms. A cervical lymph node biopsy was taken from a girl aged 1 year and 8 months who had suspected lymphoma, but she was diagnosed with KD after the biopsy. The cervical lymph node specimen was analyzed with multivirus real-time PCR that can detect >160 viruses, and unbiased direct sequencing with a next-generation DNA sequencer to detect potential pathogens in the lymph node. Histologically, focal necrosis with inflammatory cell infiltration, including neutrophils and macrophages, was observed in the marginal zone of the cervical lymph node, which was compatible with the acute phase of KD. Multivirus real-time PCR detected a low copy number of torque teno virus in the sample. Comprehensive direct sequencing of the cervical lymph node biopsy sample sequenced more than 8 million and 3 million reads from DNA and RNA samples, respectively. Bacterial genomes were detected in 0.03% and 1.79% of all reads in DNA and RNA samples, respectively. Although many reads corresponded to genomes of bacterial environmental microorganisms, Streptococcus spp. genome was detected in both DNA (77 reads) and RNA (2,925 reads) samples. Further studies are required to reveal any association of microbial or viral infection with the pathogenesis of KD.

In immunocompromised patients, Epstein-Barr virus lymphadenitis can mimic angioimmunoblastic T-cell lymphoma morphologically, immunophenotypically, and genetically: a case report and review of the literature.

The development of lymphomas and solid malignancies in association with immunosuppression is a well-documented occurrence in the medical literature. We report the case of a young man who developed progressive diffuse lymphadenopathy with associated extremely high levels of serum Epstein-Barr virus in the setting of chronic immunosuppressive treatment of glomerulonephritis. Excisional biopsy of a right inguinal node revealed a sclerosing process with the morphologic appearance of angioimmunoblastic T-cell lymphoma with a CD3(+), CD4(+) immunophenotype. In situ hybridization of Epstein-Barr virus-encoded RNA was positive. Molecular probe studies demonstrated a clonal T-cell population. Upon reduction of immunosuppression, the patient's lymphadenopathy and Epstein-Barr virus titer have resolved without recurrence over 2 years time. This case demonstrates that a benign Epstein-Barr virus-associated process can mimic angioimmunoblastic T-cell lymphoma and should be considered particularly in the setting of immunosuppression, emphasizing the need for close communication with the treating physician in the interpretation of lymph node biopsies.

A case of HIV-associated lymphoproliferative disease that was successfully treated with highly active antiretroviral therapy.

We report a case of a 41-year-old male with human immunodeficiency virus (HIV)-associated lymphoproliferative disease (LPD) who was successfully treated with highly active antiretroviral therapy (HAART). He presented with epigastralgia, and an upper endoscopic examination revealed submucosal tumors and ulcerations in his stomach. Histopathologic examination of a biopsy specimen resulted in a diagnosis of diffuse large B-cell lymphoma. He also showed systemic lymphadenopathy; whereas, a concurrent inguinal lymph node biopsy produced a diagnosis of follicular hyperplasia. He was treated with CHOP chemotherapy but the response was poor. He demonstrated several immunological abnormalities, such as eosinophilia and bone marrow insufficiency, and was suspected to be in an immunocompromised state. He was examined for HIV infection and turned out to be positive. The gastric and inguinal lymph node specimens were re-evaluated and diagnoses of HIV-LPD and HIV lymphadenitis were made, respectively. He was treated with HAART and achieved complete remission and has remained tumor-free for 20 months. To the best of our knowledge, there is no previous report in which HIV-LPD was successfully treated with antiretroviral therapy alone. It is assumed that HAART resulted in the restoration of anti-tumor immunity in this case, which led to the eradication of LPD cells.

PD-1 expression in T-cell lymphomas and reactive lymphoid entities: potential overlap in staining patterns between lymphoma and viral lymphadenitis.

Peripheral T-cell lymphomas are a heterogeneous group that often requires the use of ancillary testing for accurate diagnosis. This is particularly applicable to the diagnosis of angiommunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, unclassified (PTCLU), because of their histologic and immunophenotypic overlap with reactive lymphoid proliferations. Recently, immunohistochemistry for programmed death-1 (PD-1), a marker of follicular helper T cells, was shown to be sensitive in the detection of AITL and PTCLU. The sensitivity of this marker in reactive entities, however, has not been adequately evaluated. We confirm that PD-1 staining is a highly sensitive marker in the diagnosis of peripheral T-cell lymphomas: increased extrafollicular PD-1-positive cells were seen in 93% (76/82) of AITL, 62% (16/26) of PTCLU, and 11% (2/18) of anaplastic-lymphoma-kinase (ALK)-negative anaplastic large-cell lymphomas. The majority of reactive lymphadenopathies including Cat-scratch disease, Kikuchi lymphadenitis, Castleman disease, and reactive follicular hyperplasia showed no PD-1 staining outside follicles. Some reactive lymph nodes, showed increased extrafollicular PD-1-positive cells in a pattern similar to AITL and PTCLU, and include progressive transformation of germinal centers, viral lymphadenitis (Epstein-Barr virusand human immunodeficiency virus) and Rosai-Dorfman disease. This study shows that PD-1-positive cells may be increased in a number of settings other than T-cell lymphomas. We conclude that staining for PD-1 in reactive and atypical lymphadenopathies should be interpreted with caution and in the context of other ancillary immunophenotypic and molecular studies before a diagnosis of AITL or PTCLU is entertained.

Dermatopathic lymphadenitis with generalized erythroderma in a patient with epstein-barr virus-associated hemophagocytic lymphohistiocytosis.

Here, we describe a patient with Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH) who simultaneously presented with generalized erythroderma and dermatopathic lymphadenitis (DL). A 63-year-old Korean woman presented at our hospital with fever, hepatosplenomegaly, axillary lymphadenopathy, and generalized erythrodermic eruption. The bone marrow biopsy findings were consistent with the diagnosis of HLH, and EBV DNA was detected using the polymerase chain reaction. Based on serologic tests that indicated a primary EBV infection, the patient was diagnosed with EBV-associated HLH. Histopathologic analysis of enlarged lymph nodes was consistent with DL, and EBV-encoded small nuclear RNA-positive mononuclear cells were detected. We assume that activated histiocytes, lymphocytes, and proinflammatory cytokines in HLH may have important roles in the development of generalized erythroderma and DL. Disrupted epidermal/dermal junctions owing to erythroderma may also be involved in the development of DL.

Pathological features of diseases associated with human T-cell leukemia virus type I.

In the early 1980s, the first human retrovirus, human T-cell leukemia virus type I (HTLV-I), was isolated and its characterization opened up the new field of human viral oncology. Adult T-cell leukemia/lymphoma (ATLL), which is associated with HTLV-I, is characterized clinically by the appearance of characteristic flower cells, a rapid clinical course, occasional skin lesions, lymphadenopathy and hepatosplenomegaly. Severe opportunistic infections are occasionally accompanied. In addition, HTLV-I infection is associated with autoimmune and reactive disorders, such as HTLV-I-associated myelopathy and uveitis, and is also related to immunodeficient infectious diseases. Pathological findings of ATLL in the lymph nodes, skin, liver and other organs have been described. Common histological features are a diffuse proliferation of atypical lymphoid cells that vary in size and shape. In addition to ATLL, non-neoplastic organopathies have been documented in many organs, such as the central nerve system, lung, skin, lymph nodes and gastrointestinal tract. To clarify the HTLV-I-associated diseases, it is important to understand the pathological variations.