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Methotrexate is an immunosuppressant commonly used to treat inflammatory conditions, such as rheumatoid arthritis. However, albeit exceedingly rare, it can have serious adverse effects within the central nervous system (CNS), such as methotrexate-associated lymphoproliferative disorder (MTX-LPD). Literature describing the natural history, treatment options, and clinical outcomes of patients with CNS MTX-LPD remains sparse. We present a systematic literature review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and a case illustration of CNS MTX-LPD. A systematic review of the literature revealed 12 published cases of CNS MTX-LPD, plus the case presented herein, for a total of 13 included cases. The most common indication for MTX was rheumatoid arthritis. The most common treatment for the LPD was MTX cessation (12, 92.3%), adjunct chemotherapy (2, 15.4%), total tumor resection (3, 23.1%), or steroid therapy (1, 7.7%). Treatment usually led to improvement of neurological symptoms (9, 69.2%) along with regression of the lesions (3, 23.1%) with no recurrence (6, 46.2%). Death was reported in four cases (30.8%) with a mean time from onset of 11 months. CNS MTX-LPD should be considered in the differential diagnosis for patients who are taking MTX presenting with neurologic symptoms, as immediate withdrawal of MTX has demonstrated good prognosis. [ABSTRACT FROM AUTHOR]

Methotrexate (MTX) is a well-known agent that can potentially cause lymphoproliferative disorder (LPD), known as MTX-related LPD (MTX-LPD). Only two cases of thyroid MTX-LPD have been reported to date. This study aimed to report 11 cases of MTX-LPDs arising in the thyroid gland and discuss their clinicopathological characteristics. Of the 747 patients with cytologically suspected lymphoma, 11 had received MTX. The mean age of the patients with MTX-LPD was 70.2 years (range: 51–82 years), and all were female. The duration of MTX administration ranged from 5 to 31 years (mean: 19.5 years). Nine patients (81.8 %) tested positive for anti-thyroglobulin antibody and/or anti-thyroid peroxidase antibody. In three patients, the tumor decreased in size or disappeared without surgery or chemotherapy after withdrawal of MTX therapy. Histologically, all eight nodules examined were B-cell lymphomas, and seven were mucosa-associated lymphoid tissue (MALT) lymphomas. Epstein-Barr virus-encoded small RNA in situ hybridization showed negative results for all six nodules examined. All five patients who were followed-up at our hospital exhibited progression-free survival for >3 years without chemotherapy. Six patients were transferred to other hospitals, and their follow-up details are unknown. MTX-LPDs occurring in the thyroid are characterized by a high female predominance, positivity for anti-thyroid autoantibodies, high prevalence of MALT lymphomas, negativity for Epstein-Barr virus, and good outcomes without chemotherapy. We recommend that patients with thyroid lymphoma should be checked for a history of MTX. • Report of 11 cases of thyroid methotrexate-related lymphoproliferative disorder. • Most of MTX-LPD were MALT lymphomas. • EBER-ISH yielded negative results in all patients assessed. • All patients withdrawn from MTX exhibited tumor reduction or disappearance. • Patients with thyroid lymphoma should be checked for a history of MTX. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus-positive mucocutaneous ulcer (EBVMCU) is a benign lymphoproliferative lesion related to iatrogenic or age-related immunosuppression in patients with prior Epstein–Barr virus (EBV) infection. Although the clinical presentation may resemble malignant disease, the course of EBVMCU is indolent, and regression is expected when immunosuppression is reduced. We present a case of EBVMCU in the gingiva of a 59-year-old male patient with long-standing pemphigus vulgaris. The initial presentation was suspicious for oral cavity cancer, which was ruled out by biopsy. After reduction of immunosuppression, the ulceration regressed and an area of exposed necrotic bone remained. Complete healing was achieved after sequestrectomy and primary closure with a local gingival flap. [ABSTRACT FROM AUTHOR]

Methotrexate (MTX) is widely used as an anchor drug for the treatment of rheumatoid arthritis (RA) because of its ability to control pain and inflammation. However, few studies have shown that long-term MTX use can lead to lymphoproliferative disorders (LPDs) in these patients. Here we describe a rare case of intracranial MTX-associated LPD in a patient with RA. A 68-year-old woman was admitted to our hospital because of progressive right limb palsy. She was diagnosed with RA 15 years ago and has been receiving MTX therapy for the past 5 years. Magnetic resonance imaging of the head revealed a ring-enhancing lesion in the left parietal lobe. Open biopsy was performed for making a definite diagnosis and planning treatment. Hematoxylin-eosin stain revealed dense proliferation of atypical lymphocytes in the perivascular lesion. Immunohistochemistry results were positive for CD20; this lesion was observed as a strong nuclear signal on in-situ hybridization for the Epstein-Barr virus-encoded RNA. Finally, the patient was diagnosed with MTX-associated LPD. We discontinued MTX administration and initiated steroid therapy for RA. The intracranial lesion reduced in size, and her symptoms resolved after MTX discontinuation; no recurrence has been observed at 3 years after MTX discontinuation. Intracranial MTX-associated LPD is extremely rare. Here we describe a particular case and review the literature pertaining to intracranial MTX-associated LPD. More attention should be paid to LPD in a patient receiving immunosuppressive treatment for RA. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disorders (EBV-T/NK-LPD) is a group of rare disorders resulting from EBV-infected T/NK-cells. It manifests as a broad spectrum of clinical symptoms according to immunologic status and viral load of an infected patient. Here, we report a boy who developed central nervous system (CNS) vasculitis and myelopathy as possible neurologic manifestations of EBV-T/NK-LPD. A 16-year-old boy came to our hospital with a necrotic skin lesion on his right shoulder. He suffered from local skin reactions with high fevers after mosquito bites since he was 10 years old. During the evaluation of his skin lesion, he suddenly developed left facial palsy. Brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) showed acute infarctions of the pons and middle cerebellar peduncle and irregularities of both anterior inferior cerebellar arteries. Serologic testing showed an elevation of total Ig E levels, anti-VCA IgG levels, and anti-EA IgG titers. EBV DNA copy numbers of the whole blood and cerebrospinal fluid (CSF) were elevated. Biopsy of the right shoulder skin showed extranodal NK/T-cell lymphoma. According to clinical features and laboratory findings, he was diagnosed with EBV-T/NK-LPD. He was treated with chemotherapy and hematopoietic stem cell transplantation but developed recurrent infarctions during treatment. This case showed the diagnostic challenge of neurologic manifestations of EBV-T/NK-LPD. EBV-T/NK-LPD-associated CNS vasculitis needs to be considered as a differential diagnosis of CNS vasculitis, when it is accompanied by the typical clinical spectrum of EBV-T/NK-LPD such as severe mosquito bite allergy, extranodal NK/T-cell lymphoma. [ABSTRACT FROM AUTHOR]

• Methotrexate-associated lymphoproliferative disorder is known to occur in patients with rheumatoid arthritis treated with methotrexate. • FDG-PET/CT have showed FDG uptake in the nodule of methotrexate associated lymphoproliferative disorder. • In patients with lung cancer patients who were treated with methotrexate for rheumatoid arthritis, methotrexate-associated lymphoproliferative disorder should be considered as a differential diagnosis. Methotrexate (MTX)-associated lymphoproliferative disorder occurs in rheumatoid arthritis patients treated with MTX; however, patients with concomitant pulmonary lesions are rare. We present a case of lung cancer combined with MTX-associated lymphoproliferative disorder for which, for which it was necessary to differentiate these from possible pulmonary metastasis. A 72-year-old man was referred to our hospital for treatment of squamous cell carcinoma in the left upper bronchus. He was receiving oral MTX and prednisolone for rheumatoid arthritis for 15 years. However, chest computed tomography performed 1 week before surgery revealed a 1-cm-sized pulmonary nodule in the right lung. Surgical pulmonary resection of the right lung tumor revealed substantial B-cell lymphoma-type lymphoproliferative disorder. Left upper lobectomy for the squamous cell carcinoma in the left upper bronchus was performed 5 weeks after the first surgery. Chest CT performed 2 weeks after the first surgery revealed a new 1-cm-sized nodule in the lower left lung lobe. However, after discontinuing oral MTX therapy, the new lesion in the left lower lobe disappeared. In lung cancer patients treated with MTX for rheumatoid arthritis, MTX-associated lymphoproliferative disorder should be considered as a differential diagnosis. [ABSTRACT FROM AUTHOR]

Highlights • Castleman disease: heterogeneous group of hyperimmune lymphoproliferative disorders. • Unicentric type: localized disease; surgery is primary treatment; good prognosis. • Multicentric type: Serious systemic disease; 70% linked to HHV8; antiviral therapy. • Idiopathic Multicentric type: diagnosis by exclusion; Interleukin-6 blockade useful. Abstract Castleman Disease (CD) is a rare, heterogeneous group of hyperimmune lymphoproliferative disorders, not very familiar to surgeons. Unicentric Castleman Disease (UCCD) at one end of the spectrum is a localized disease, with little or no systemic symptoms. It may be an incidental radiological finding or detected while investigating for a symptomatic lymph node mass. Surgery is the primary treatment and has good long term prognosis. Multicentric Castleman Disease (MCCD) is a more serious systemic condition, often associated with constitutional symptoms. Exaggerated systemic inflammatory response secondary to "Cytokine storm" involving Interleukin-6 (IL-6) may cause multi-organ dysfunction. In addition, immunosuppression or malignant transformation can prove lethal. Human Herpes Simplex Virus 8 (HHV8) associated MCCD is a major subgroup occurring in immunocompromised individuals due to the viral trigger. Antiviral therapy is important in its treatment. Idiopathic MCCD (IMCCD) has no known biomarker and is diagnosed after excluding infective, autoimmune and malignant conditions of lymphoid tissue. IMCCD requires systemic therapy. We report a patient of UCCD who presented as a retroperitoneal mass in right iliac fossa causing pressure on femoral nerve. Following successful surgical excision she had good recovery. We report another patient who had large inguinal lymph node mass with constitutional symptoms. IMCCD was diagnosed after excision biopsy and comprehensive work up. Patient was started on corticosteroids followed by CD-20 targeted therapy. These two cases showcase the two ends of the clinical spectrum of CD requiring different management protocols. Awareness among surgeons and diligent work-up is imperative for early diagnosis and best outcome. [ABSTRACT FROM AUTHOR]

Castleman disease (CD) is a rare lymphoproliferative disorder of unknown etiology that may occur anywhere in the lymphatic system. Imaging plays an important role in detecting and staging this disease. Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) combines the metabolic information derived from nuclear medical imaging with the high soft tissue resolution from MRI. We review the features of CD in standard diagnostic imaging, analyze the specific imaging findings of CD in FDG-PET/MRI and discuss a potential benefit of PET/MRI based on the case of a 15-year-old female patient with retroperitoneal CD. [ABSTRACT FROM AUTHOR]

Extranodal NK/T cell lymphoma, nasal type (ENKL) developed in a patient with intestinal Epstein-Barr virus (EBV)-positive T/NK-cell lymphoproliferative disorder (LPD). The patient was a 46-year-old Chinese man who complained of diarrhea and abdominal pain without immune-deficiency. Endoscopy demonstrated ileum ulcers like Crohn’s disease, without histological granulomas. His symptoms continued waxing and waning for 3 years until he developed overt lymphoma (ENKL) in the nasal cavity. The ileum lesions exacerbated into a large deep ulcer, and the biopsy specimens from the ileum, including the one 3 years ago, showed infiltration of small lymphocytes containing many EBV-positive T/NK cells without atypia. Thus, the patient illness of intestine was revealed as intestinal EBV-positive T/NK-cell LPD, which might be closely associated with development of ENKL in this patient. In cases of inflammatory bowel disease without typical clinical courses and histological findings, check-up of EBV in the biopsy might help correct diagnosis. [ABSTRACT FROM AUTHOR]

Objectives: Epstein-Barr virus (EBV) is involved in the pathogenesis of approximately 40% of lymphoproliferative disorders (LPDs) arising in patients receiving immunosuppressive treatment (IST) for rheumatic diseases, but data from large cohorts are still not available. We aimed to identify clinicopathological features, management and outcome of this condition.Methods: We reviewed all published cases of EBV-encoded RNA (EBER)-positive LPDs and included in our analysis one unpublished patient diagnosed in our Hospital. We excluded those cases without an underling rheumatic condition, a specific IST or not reporting univocal data.Results: In the cumulative cohort of 159 patients, most were affected by rheumatoid arthritis (83.0%) and treated with methotrexate (75.4%). 68.5% of LPDs developed between the age of 40 and 70 years, after 13.3±9.6 years from rheumatic disease onset and 58.7±47.0 months of IST. LPDs were mostly B-cell lineage derived (39.0%), Ann Arbor disease's stage I (38.3%) and presented with extra-nodal involvement in 63.1%, which was most frequently represented by central nervous system (17.6%). The most common approach was IST withdrawal (93.3%), variably associated with radiotherapy(RT)/chemotherapy(CT) in 38.3% of cases. Overall, 61.7% of patients achieved a complete remission (CR; 30.2±24.0 months). Among published cases of patients that only suspended IS as first line treatment approach, 67.2% achieved CR. No significant demographic, clinical and histological differences between patients who achieved CR and who did not, and between who achieved CR by IST withdrawal alone and who did not were observed (P>0.05 in all comparison).Conclusions: The current study reviews all the published evidences of EBV-induced LPDs in patients receiving IST treatment for rheumatic conditions. [ABSTRACT FROM AUTHOR]

Background The prognosis of the CD8 + subtype of mycosis fungoides (MF) is controversial. Although most authors believe that determining the presence of this cell surface antigen has no prognostic value, others have observed a more indolent course for CD8 + MF compared with CD4 + MF. Objectives To review the cases of CD8 + MF in the pediatric and adult populations seen at our institution. Methods This is a retrospective review of clinical and pathologic data. Age, stage at presentation, and outcomes of patients at our institution were compared with those of 2 large MF cohorts that predominantly were CD4 + from the relevant literature. Results Sixty-seven patients of a median age of 46 years were included. A higher frequency of early-stage disease was observed for CD8 + MF patients at diagnosis when compared with other cohorts, including 31 (47%) patients with stage IA, 33 (50%) with stage IB, and 2 (3%) with stage IIB ( P = .001, P = .001, and P = .002, respectively). With a median follow-up (5.5 years, range 0.2-21 years) similar to other cohorts, a higher rate of complete remission was achieved (65.5%, P = .001), and a lower rate of progression was observed ( P = .004). Limitations This is a retrospective review. Conclusion Our experience with CD8 + MF confirms a more indolent course of disease with this MF variant. Our results warrant a conservative treatment approach limited to skin-directed therapies and observation in most patients. [ABSTRACT FROM AUTHOR]

A 53-year-old man with hyperthyroidism presented with asymmetric proptosis and diplopia. Thyroid-stimulating immunoglobulin was elevated, suggesting active thyroid eye disease. Imaging of the orbits revealed enlargement of the extraocular muscles, including irregular enlargement of the left lateral rectus muscle. Biopsy of the lateral rectus muscle demonstrated infiltration of the muscle with Bcl-2 positive B lymphocytes consistent with chronic lymphocytic leukemia (CLL). Evaluation for systemic lymphoproliferative disease was negative. The patient was treated with orbital radiotherapy at specific dosages for both TED and CLL. He responded well to therapy with a reduction in proptosis and diplopia and no evidence of recurrent CLL. [ABSTRACT FROM AUTHOR]

Objective The purpose of this study was to verify the characteristics of methotrexate (MTX)-related oral lymphoproliferative disorders (LPDs) in rheumatoid arthritis (RA) patients. Methods Twenty-eight cases of MTX-related oral LPDs with RA, which included 14 cases from English articles and 14 cases from Japanese literature, were collected. Data on demographic characteristics, clinical features, pathological diagnosis, weekly and total amount of MTX, concomitant drugs for RA, treatment, and follow-up period and outcomes were analyzed. Results Gingiva was the most frequent site (19, 67.9%), followed by tongue (4, 14.3%). Histopathologically, 15 cases (78.9%) were diffuse large B-cell lymphoma. All oral cases except for one case were Epstein–Barr virus (EBV)-positive. As an initial treatment, MTX was withdrawn for all cases including two cases of firstly decreasing the dose of MTX. Recurrence was reported in one case (4.8%). In gingival 19 cases, ulceration was found in 16 cases (84.2%), pain in 13 cases (68.4%) and alveolar bone exposure in 11 cases (57.9%). Conclusions The occurrence of MTX-related oral LPDs showed a predilection for gingiva with frequent characteristics of ulceration, pain and bone exposure. Almost all cases were EBV-positive. [ABSTRACT FROM AUTHOR]

Waldenström's Macroglobulinemia (WM) is characterized by the presence of an IgM monoclonal protein regardless of its size, 10% or more bone marrow infiltration by small lymphocytes with a plasmacytoid or plasma cell differentiation. These cells usually have the following markers: IgM+, CD5 − , CD10 − , CD19 + , CD20 + and CD23 − . Chronic lymphocytic leukemia as well as other lymphoproliferative disorders such as mantle cell, marginal zone and mucosa-associated lymphoid tissue (MALT) lymphoma must be excluded. Weakness or fatigue from anemia, fever, night sweats, or weight loss represent the most common symptoms. Hepatosplenomegaly may be a major feature. Anemia, thrombocytopenia, hyperviscosity or peripheral neuropathy may be prominent features. Systemic amyloidosis, renal insufficiency and cryoglobulinemia may also be seen. WM must be differentiated from smoldering Waldenström's Macroglobulinemia (SWM) which is an intermediate disease state characterized by an IgM protein ≥3 g/dL and/or a bone marrow containing ≥10% bone marrow lymphoplasmacytic infiltration but no end-organ damage such as symptomatic anemia, constitutional symptoms, hyperviscosity, symptomatic hepatosplenomegaly or lymphadenopathy. [ABSTRACT FROM AUTHOR]

Lymphocytic interstitial pneumonia (LIP) is a rare opportunistic illness in human immunodeficiency virus (HIV)-infected adults, although it is relatively common among HIV-infected children. Most adult cases have been reported in African and Afro-Caribbean patients and few cases have been reported from Asia. Acute exacerbation of HIV-related LIP has not been well described. Here we report a pathologically proven case of acute exacerbation of adult-onset HIV-related LIP. The patient was an African immigrant living in Japan who presented with chronic dyspnea and diffuse bilateral pulmonary infiltrates. His clinical, radiological, and pathological findings were consistent with those of LIP. After a diagnostic surgical lung biopsy, his hypoxemia and pulmonary infiltrates exacerbated rapidly over a few days, although his condition had not progressed during the previous year. LIP may be an important differential diagnosis among adult patients in Asian countries, especially patients of non-Asian ethnicity. [ABSTRACT FROM AUTHOR]

Abstract: The association of sarcoidosis with multiple myeloma is not well known. Including this case report, 12 cases of patients with both sarcoidosis and multiple myeloma have been reported in the literature. The skeletal lesions of both conditions have many clinical and radiological similarities, and unless clinicians are aware of the association and the possibility of dual pathologies, the diagnosis of multiple myeloma in patients known with sarcoidosis may be missed. We present a case of a patient known with longstanding sarcoidosis who was found to have multiple lesions on magnetic resonance imaging (MRI) involving the pelvis and both proximal femurs. Histological analysis revealed the presence of both non-necrotising granulomas consistent with sarcoidosis, and sheets of plasma cells consistent with a plasma cell neoplasm. [Copyright &y& Elsevier]

Abstract: A 60-year-old immunocompromised patient developed rapidly progressive proptosis that was secondary to mucormycosis. This life-threatening fungal infection usually is associated with chemosis, proptosis, ophthalmoplegia, and visual loss. The fungus may invade ocular structures, sinuses, and extend into the brain. The standard of care includes correction of the underlying condition, administration of liposomal amphotericin B with posaconazole, and surgical debridement of infected and necrotic tissue. We present a case of unilateral proptosis due to mucormycosis in an immunocompromised patient. The patient was successfully managed medically without exenteration. The indications for exenteration are currently unclear, and no clinical guidelines exist. [Copyright &y& Elsevier]

Abstract: Two lymphotropic human gamma herpesviruses can cause lymphoproliferative disorders: Epstein Barr virus (EBV, formally designated as human herpesvirus 4) and Kaposi sarcoma herpesvirus (KSHV, also called human herpesvirus 8). Individuals with inherited or acquired immunodeficiency have a greatly increased risk of developing a malignancy caused by one of these two viruses. Specific types of lymphoproliferations, including malignant lymphomas, occur in individuals with HIV infection, transplant recipients and children with primary immunodeficiency. Some of these diseases, such as Hodgkin’s and nonHodgkin lymphoma resemble those occurring in immunocompetent patients, but the proportion of tumors in which EBV is present is increased. Others, like primary effusion lymphoma and polymorphic post-transplant lymphoproliferative disorder are rarely seen outside the context of a specific immunodeficient state. Understanding the specific viral associations in selected lymphoproliferative disorders, and the insights into the molecular mechanisms of viral oncogenesis, will lead to better treatments for these frequently devastating diseases. [Copyright &y& Elsevier]

Abstract: Castleman disease is a rare disorder of the lymphoid tissue, characterized by lymph node enlargement with distinctive histologic features. It usually occurs within the mediastinum and rarely within the abdomen. It is usually indistinguishable from other mediastinal and hilar masses before determining a surgical approach. We present two cases of Castleman disease within the abdomen mimicking a neoplasm. [Copyright &y& Elsevier]

Abstract: We report a case of Epstein Barr virus-associated large B cell lymphoproliferative disorder, with an abdominal cutaneous localization, in an adult treated for 10 years with immunosuppressive agents for a dermatomyositis. This is the third case of immunosuppressive induced lymphoproliferative disorder localized to skin in a patient with dermatomyositis. Diagnosis was unexpectedly obtained by the histologic examination of surgical samples of skin necrosis possibly induced by edetate calcium disodium subcutaneous injections in calcinosis cutis. [Copyright &y& Elsevier]

Abstract: Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is a lymphoid proliferation or lymphoma in a patient immunosuppressed with MTX, which is usually administered for treating autoimmune diseases. The majority of MTX-LPD cases develop in patients with rheumatoid arthritis and occasionally with psoriasis who had been treated with MTX. Here, we report on a 50-year-old Taiwanese male with severe psoriasis, who received high doses of MTX. The patient developed EBV-positive MTX-LPD at nodal and extranodal sites. The diffuse and polymorphic lymphoid infiltrate consisted predominantly of immunoblasts and plasmablasts expressing B-cell markers, CD138, Epstein–Barr virus (EBV)-LMP1, and EBNA2, and these were monotypic for kappa light chain. The tumor cells were also positive for EBV by in situ hybridization. These findings indicated a type III latency infection of EBV. The patient died of progressive disease after 19 months. A review of the previously reported cases shows that MTX-LPD, in association with psoriasis, occurs in middle-aged males. The tumors are diffuse large B-cell lymphomas with immunoblastic morphology, and frequently show plasmacytic differentiation. [Copyright &y& Elsevier]

Summary: Cytogenetic abnormalities in B-cell posttransplant lymphoproliferative disorders (PTLD) have not been well characterized. We thus performed cytogenetic analysis of 28 cases of B-cell PTLD, 1 infectious mononucleosis (IM)–like lesion, 9 polymorphic PTLD, 17 monomorphic PTLD, and 1 classical Hodgkin lymphoma (HL), and correlated the karyotypic findings with the phenotype, Epstein-Barr virus infection status, and clinical outcome. Karyotypes of 19 cases of posttransplant florid follicular hyperplasia (FFH) were also analyzed. Informative karyotypes were obtained in 20 (71.4%) of 28 PTLDs and 18 (94.7%) of 19 FFHs. Clonal karyotypic abnormalities were detected in 13 (65%) of 20 PTLDs, including 9 (75%) of 12 monomorphic PTLDs, 2 (33.3%) of 6 polymorphic PTLDs, 1 IM-like lesion, and 1 HL, and 2 (11.1%) of 18 FFHs. Recurrent chromosome breaks at 1q11-21 (n = 6, including 1 FFH), 14q32 (n = 3, including 1 FFH), 16p13 (n = 3), 11q23-24 (n = 2), and 8q24 (c-MYC) (n = 2); gains of chromosome 7 (n = 4), X (n = 3), 2 (n = 3), 12 (n = 2); and loss of chromosome 22 (n = 2, including 1 IM-like lesion) were identified. The presence of cytogenetic abnormalities did not correlate with PTLD phenotype, Epstein-Barr virus infection, or clinical outcome. We describe novel karyotypic aberrations in PTLD and report clonal cytogenetic abnormalities in posttransplant FFH and an IM-like lesion for the first time. Our findings provide validation of the current World Health Organization classification of PTLD and also suggest incorporation of FFH as the earliest recognizable precursor of PTLD. [Copyright &y& Elsevier]

Abstract: We report a case of myasthenia gravis associated with marked expansion of an unusual CD16+CD56−2B4+ NK subset. These atypical cells were characterized by poor cytotoxicity against CD48+ target cells and high proliferation due to 2B4/CD48 interaction. IL18, IFN-γ and TGF-β levels were profoundly different in this patient than in healthy donors. Immunosuppressive treatment induced disease remission and decreased the CD16+CD56−2B4+NK cells count. Our data suggest that expansion of this NK subset in myasthenia gravis patients may account for the deleterious NK cell functioning that occurs in this autoimmune disease. [Copyright &y& Elsevier]

Abstract: We conducted clinicopathological and immunohistochemical analyses to investigate the prevalence of Epstein–Barr virus (EBV) among 13 cases with methotrexate (MTX)-associated lymphoproliferative disorder (LPD). The subjects of this study were four men and nine women ranging in age from 53 to 78 years (mean: 63 years). All 13 patients had received low dose MTX therapy for 1–13 years before the onset of LPD (mean: 5.8 years). LPDs were found at extranodal sites in six cases, and the disease stage was advanced in seven cases. The present study confirmed certain aspects of a previous observation made in the USA, including the following findings (i) the cases commonly showed diffuse large B-cell lymphomas (n=4) and Hodgkin lymphomas (HL) (n=3), (ii) EBV-encoded small RNA (EBER)+cells were identified in seven cases (60%), which is a much higher percentage than would be expected in lymphomas occurring in a general population, and (iii) three cases of polymorphous small lymphocytic or lymphoplasmacytic infiltrate achieved spontaneous remission of LPDs after MTX withdrawal. Of seven cases of EBER+in our series, three cases were PSLLPI, and two were HL. EBER+tumor cells were detected in only two (30%) of the seven cases with non-Hodgkin lymphomas. The present study suggests that EBV- associated non-Hodgkin lymphomas comprise only a portion of all non-Hodgkin lymphomas among MTX-associated LPDs. [Copyright &y& Elsevier]

Malignancy is a well defined complication of chronic immunosuppression. Post transplant malignancies appear to be related to cumulative doses of immunosuppression, and in pediatric patients, acute infection of previously naive patients. The most commonly encountered malignancy in this age population is Post Transplant Lymphoproliferative Disorder (PTLD). PTLD is not a single entity but rather represents a continuum of disease. Treatment of PTLD should be initiated with immunosuppression reduction. Standard dose chemotherapy leads to significant morbidity. With the introduction of anti-CD20 antibody treatment with rituximab, chemotherapy has become second line therapy. The occurrence of solid malignancy appears to be associated with chronic immunosuppression. These cancers include those of skin, gynecologic organs, and the rectum, all of which appear to have the strongest association with viral mediators. Several strategies have been postulated to minimize the occurrence of malignancy. These include ganciclovir prophylaxis for the prevention of PTLD and the use of mychophenolic acid and TOR inhibitor maintenance to diminish the incidence of PTLD and solid malignancies. This leaves transplant physicians with several new and novel immunosuppressive agents with uncertain oncologic potentials that will need to be examined over the next decade. [Copyright &y& Elsevier]

Summary: Epstein-Barr virus (EBV) is a ubiquitous viral pathogen in humans that has a unique ability to immortalize B-cells. In immunosuppressed individuals, EBV can produce non-neoplastic lymphoproliferative disorders involving various organs. We describe a case report of EBV-associated lymphoproliferative disorder in an immunocompetent 14-year-old male. The case provides a description of EBV-associated lymphoproliferation affecting the upper and lower respiratory tract. The massive submucosal infiltration of B-cells in the lingual tonsils, trachea, and bronchi produced near-complete airway obstruction resulting in tracheotomy. Neither surgical reduction of lingual tonsils nor treatment with steroids was of benefit. An extensive evaluation for immunodeficiency and neoplasia was normal. Treatment with rituximab, an anti-CD20 antibody, resulted in near-complete resolution of the infiltrative process, sufficient to allow decannulation. Rituximab is a treatment option for the rare occurrence of non-neoplastic, EBV-associated, lymphoproliferative disorders. [Copyright &y& Elsevier]

Summary: Rosai–Dorfman disease (RDD) is an idiopathic, non-neoplastic, lymphoproliferative disorder characterized by sinus histiocytosis and massive lymphadenopathy. When RDD involves the central nervous system the lesion simulates a meningioma. Histological and immunohistochemical confirmation is essential for a definitive diagnosis. In this paper, ten cases of RDD confined to the central nervous system are reported. Another case with orbital RDD was excluded. Nine cases involved the cranial cavity alone; in one, the cervical extradural region was also involved. Treatment consisted of surgical excision or biopsy. Histology and immunohistochemistry revealed a mixed cell population of predominantly mature histiocytes with evidence of emperipolesis and strong positivity for S100 protein in all cases. No recurrence was observed during follow up ranging from three months to eight years. [Copyright &y& Elsevier]

Background: Lymphoproliferative disease (PTLD) is a life-threatening complication of organ transplantation. In matched, allogeneic, non-T-cell-depleted stem-cell transplantations (SCT) the disease develops early but has been thought to be rare. Objectives: We determined by strict histopathological criteria the incidence of fatal Epstein–Barr-virus (EBV)—related PTLD in a large number of SCT, and assessed the diagnostic value of a real-time quantitative polymerase chain reaction (qPCR) for EBV-DNA in serum specimens. Study design: Of the 257 SCT performed in Helsinki during 1994–1999, 132 (51%) recipients were alive and 125 (49%) had succumbed by June 2001. The necropsies were analyzed for EBV-related PTLD as evidenced by disseminated lymphocytic infiltrates labeled histochemically for antigens and RNA (EBER 1 and 2) detectable by in situ technology. From a subset of the PTLD cases (N=12) and a series of corresponding stem-cell recipient controls (N=36), consecutive samples of serum (N=103 and 364, respectively) were studied by qPCR for EBV-DNA, and the clinical data were reviewed. Results: The post-mortem analysis revealed 18 cases of PTLD (14% of the deceased), all of whom had received intensive immunosuppressive treatment including anti-thymocyte globulin for treatment or prophylaxis of graft versus host disease (GVHD). By using qPCR all the PTLD patients became EBV-DNA positive, in progressively rising copy numbers. EBV-DNA was first detectable 70 (median; range 24–154) days after SCT or 23 (4–86) days before death; i.e. earlier than the symptoms which appeared 15 (2–85) days before death. Among the SCT controls, EBV-DNA occurred sporadically (in only 3.9% sera). Conclusions: qPCR for EBV-DNA in serum is a highly sensitive (100%) and specific (96%) diagnostic approach. Intensely immunosuppressed stem-cell recipients are at a great risk of developing PTLD, and should be carefully monitored for EBV-DNA, for pre-emptive treatment of this life-threatening disorder. [Copyright &y& Elsevier]

Background: Lymphoproliferative disorder (LPD) caused by Epstein-Barr virus (EBV) is a severe complication of bone marrow transplantation. The EBV strain causing LPD is of either donor or recipient origin, however, available data are limited to only a small number of cases. To obtain solid evidence, comparison of the EBV strain that caused the EBV-LPD with pre-stem cell transplantation (SCT) EBV strains of donor and recipient is imperative. Available techniques rely on the production of EBV transformed lymphoblastoid cell lines and lack sensitivity. Objective: The aim of this study was to develop a simple method for EBV sequence analysis on mouth washings (MWs) and peripheral blood mononuclear cells (PBMCs). Study design: EBV DNA was extracted from MWs and PBMCs that were collected from 20 healthy individuals. DNA was used for sequence analysis, using a polymerase chain reaction for the C-terminus of the LMP-1 gene. Results: In seropositive individuals EBV DNA could be detected in 11/14 (79%) MWs and in 13/14 (93%) PBMC samples. Sequence analysis showed that in 11 out of 14 (79%) healthy individuals sequence patterns could be established. In these 11 healthy individuals 13 sequence patterns could be detected. Eleven of these 13 patterns (84.6%) were unique. These results encouraged us to explore the feasibility of this method on EBV DNA isolated from plasma from 9 EBV-LPD patients at time of EBV reactivation. In 7 EBV-LPD patients 8 sequence patterns were detected. Six out of 8 sequence patterns (75%) were unique. Conclusion: Our method is suitable for strain identification and we intend to use this technique to evaluate EBV origin in EBV-LPD patients. [Copyright &y& Elsevier]

Abstract: Although atelectasis is common in children, its persistence or refractoriness to treatment should lead prompt evaluation to identify causal mechanism. We describe the case of a child presenting in first year of life with persistent left upper lobe atelectasis, recurrent wheezing and respiratory infections refractory to medical therapy, submitted to partial lobectomy when he was 3 years old age. Histopathological examination revealed follicular bronchiolitis. Systemic underlying diseases were excluded. Clinical improvement was initially achieved using inhaled corticosteroids, but oral therapy was needed due to clinical relapse, with favorable response. Follicular bronchiolitis, a rare pulmonary primary lymphoid lesion, consists of numerous reactive lymphoid follicles in a peribonchiolar distribution. Its precise cause is unknown, particularly in children, in which few cases have been reported. Treatment usually includes steroids and prognosis is generally good. [Copyright &y& Elsevier]

Abstract: Castleman''s disease (CD) is an atypical lymphoproliferative disorder. Since it was first described in 1956, it has been referred to as follicular lympho-reticuloma, angiofollicular mediastinal lymph node hyperplasia, and benign giant lymphoma. CD is a heterogeneous disease that can be either localized or systemic (multicentric). The localized form can be divided into two types: the hyaline-vascular (HV) type or the plasma cell (PC) type. The former usually produces few symptoms and histological features include abnormal follicles and increased interfollicular vascularity. The PC type, in which, histopathologically, the presence of sheets of mature plasma cells is the distinguishing feature, is more likely to produce clinical symptoms such as fever, night sweats, and lymphadenopathy. The multicentric form mimics the PC type of localized CD, and patients present with systemic symptoms. In this report, we discuss the spectrum of clinical and pathological findings in localized and multicentric CD. [Copyright &y& Elsevier]

Tonsillectomy is a common procedure in the pediatric population, with subsequent microscopic examination of the specimen for cancer and other rare diagnoses occurring routinely. A 17 year-old female with a history of autoimmune vasculitis underwent adenotonsillectomy for severe obstructive sleep apnea. Pathology demonstrated small, medium and large lymphocytes and plasma cells obscuring the lymphoid follicles and germinal centers, with few Epstein-Barr virus positive lymphocytes. Tingible body macrophages were seen in the vaguely nodular areas. This reactive histologic pattern represents an atypical lymphoproliferative disorder never before documented in tonsils. Histopathologic images will be shown. [ABSTRACT FROM AUTHOR]

Lymphomatoid papulosis (LyP) is a CD30+ lymphoproliferative disorder that is rare and not well described within the pediatric subpopulation. We sought to review the literature and characterize clinical and pathologic features among pediatric and adolescent patients diagnosed with LyP at a tertiary care center. A retrospective cohort of 27 pediatric and adolescent patients (defined as <20 years old) diagnosed with LyP at the Weill Cornell Medicine Dermatopathology division from 2006 to 2016 was identified. Subsequently, we reviewed the histopathologic characteristics and collected clinical follow-up data from patients and their providers. The parameters assessed included the pathological LyP subtype including the immunohistochemical staining pattern, the development of secondary lymphoma, disease duration and rate of remission. While type A was the most prevalent subtype, B and C subtypes were also frequently observed. CD8 predominance was a common finding, especially among type B LyP patients and those with eccrinotropic granulomatous features. None of the patients with clinical follow-up have developed secondary lymphoma, and some patients experienced remission of their disease. While type A appears to be the dominant variant described in children, types B, C, and even the newly described variants E and F may occur more often than previously reported. Pediatric LyP may be more indolent than the adult variant, but close clinical follow-up is still warranted. • Lymphomatoid papulosis is rare and not well described in pediatrics. • While type A is the most prevalent subtype, B and C subtypes are also frequently observed. • CD8 predominance is a common finding. [ABSTRACT FROM AUTHOR]

Abstract: An 8-year-old boy presented with a mass located in the portal hilum and hepatosplenomegaly, and the presumed initial diagnosis was lymphoma. The pathology result was Castleman disease of hyaline vascular type. Castleman disease is an unusual diagnosis that should be kept in mind in the differential diagnosis of portal masses. In the case of solitary lesions, total excision can be curative. [Copyright &y& Elsevier]