Lymphoproliferative Lesions Research Articles

Lymphoproliferative Lung Disorders: A Radiologic-Pathologic Overview. Part II: Neoplastic Disorders

Lymphoproliferative pulmonary neoplasms can occur as primary pulmonary lymphomas or because of secondary pulmonary involvement. Neoplastic disorders may be difficult to differentiate from reactive pulmonary lymphoproliferative disorders, and immunohistochemical evaluation is often required to differentiate the 2 types of lesions. Neoplastic lymphoproliferative disorders are monoclonal lesions. Most affected patients present with systemic complaints, and imaging findings typically include nodules, masses, and lymphadenopathy. Primary pulmonary lymphomas are rare and account for less than 4% of the lymphomas that arise in extranodal sites. Secondary pulmonary lymphomas can affect the lung via hematogenous dissemination or by secondary involvement from tumor in adjacent or contiguous sites. Neoplastic lymphoproliferative lesions also include leukemia and plasma cell neoplasms. Posttransplantation lymphoproliferative disorders constitute a special type of lymphoid proliferation occurring in the setting of the chronic immunosuppression required for solid organ and bone marrow transplantation.

Lymphoproliferative lung disorders: clinicopathological aspects

Lymphoproliferative disorders are rarely observed as primary lesions in the lung, representing only 0.3% of all primary pulmonary malignancies, <1% of all the cases of non-Hodgkin lymphoma and 3–4% of all the extra nodal manifestations of non-Hodgkin lymphoma. The earliest comprehensive studies of pulmonary lymphomas were those of Saltzstein [1] and Papioannou and Watson [2], which were published in the 1960s. These investigators made important observations: low-grade neoplasms were more frequent than higher grade lymphomas (reticulum cell sarcomas) and both tumours had better clinical outcomes than their nodal-based counterparts. The authors also concluded that the majority of neoplasms with a low-grade cytological appearance should be considered as reactive proliferations, introducing the term “pseudo-lymphoma”. This hypothesis showed significant weak points and, approximately 20 years later, Addis et al. [3] concluded that “most if not all the cases of pseudo-lymphoma can be classified, when re-evaluated, as malignant lymphoma”. Knowledge of these entities expanded rapidly after the advent of new investigative tools such as immunohistochemistry and molecular biology techniques. The World Health Organization (WHO) classification of lymphoid neoplasm recently emphasised the importance of clinical features [4]. table 1 provides an overall classification of lymphoproliferative disorders, which are described as: reactive/non-neoplastic lymphoid lesions, malignant parenchymal lymphoproliferative lesions (primary or secondary) and post-transplant lymphoproliferative disorders. View this table: Table 1. Classification system for the pulmonary lymphoproliferative disorders ### Reactive pulmonary lymphoid diseases Three rare forms of benign hyperplasia of pulmonary lymphoid tissue, namely follicular bronchiolitis, pulmonary nodular lymphoid hyperplasia and lymphocytic interstitial pneumonia, are regarded as part of the spectrum of lymphoid hyperplasia of the bronchus-associated lymphoid tissue (table 1) [5, 6]. Follicular bronchiolitis is characterised by lymphoid follicular hyperplasia, often with reactive germinal centres, in the walls of bronchioles with narrowing of the lumen. Pulmonary nodular lymphoid hyperplasia (pulmonary pseudo-lymphoma) is a distinct form of reactive …

The differential diagnosis of CD8‐positive (“type D”) lymphomatoid papulosis

Cutaneous CD8(+) CD30(+) lymphoproliferative lesions are difficult to classify and encompass entities that follow a benign course to overt lymphoma. In order to identify histopathologic criteria for lesions in this spectrum, a series of such cases was reviewed. Twenty-eight biopsies from 27 patients with CD8(+) CD30(+) cutaneous lymphoid proliferations were evaluated. Seventeen cases were classified as lymphomatoid papulosis (LyP) 'type D', eight as cutaneous anaplastic large cell lymphoma (C-ALCL) and two as CD8(+) mycosis fungoides (MF) with CD30 expression. Features of LyP included spongiosis and/or parakeratosis (90%), epidermotropism by large lymphocytes (90%), with (80%) or without (10%) small lymphocytes; wedge-shaped infiltrate (70%) with perivascular (100%) and interstitial (80%) pattern; and relative uniformity of CD30(+) large atypical cells (90%). C-ALCL was characterized by ulceration (63%), epidermotropism restricted to small lymphocytes (100%), marked density (63%) and pleomorphism (62%) of CD30(+) large atypical cells, and at least focal extension of infiltrate to subcutaneous tissue (88%). CD8(+) CD30(+) MF had vacuolar interface change and a lichenoid pattern (100%). We concur with previous authors that distinction of CD8(+) LyP from lymphoma in its differential diagnosis is difficult based on histopathology alone. Nonetheless, we propose that certain histopathologic clues may be helpful in this differential diagnosis.

Value of immunohistochemistry in the diagnosis of malignant cervical lymph nodes

The cervical lymph nodes are relevant due to the diversity of clinical entities. The use of immunohistochemistry is a real method to elucidate the diagnosis of adenopathy, both primary and metastatic neoplasms. ObjectiveTo assess the value of immunohistochemistry in the diagnosis of cervical lymph nodes malignancies. MethodRetrospective study of the database histopathological specimens from 2009 to 2011. ResultsOut of 32 biopsies of cervical lymph nodes, in 16 (50%) the immunohistochemistry was employed, being 68.75% (11) in hematological neoplasms and 31.25% (5) in carcinomas. It was used in all cases of lymphoma. ConclusionThe immunohistochemistry was used in 50% of the biopsies of lymph nodes under suspicion of malignancy, being 31.25% in epithelial lesions and 68.75% in lymphoproliferative lesions.

Signaling mediated by the NF-κB sub-units NF-κB1, NF-κB2 and c-Rel differentially regulate Helicobacter felis-induced gastric carcinogenesis in C57BL/6 mice

The classical nuclear factor-kappaB (NF-κB) signaling pathway has been shown to be important in a number of models of inflammation-associated cancer. In a mouse model of Helicobacter-induced gastric cancer, impairment of classical NF-κB signaling in the gastric epithelium led to the development of increased preneoplastic pathology, however the role of specific NF-κB proteins in Helicobacter-associated gastric cancer development remains poorly understood. To investigate this C57BL/6, Nfkb1−/−, Nfkb2−/− and c-Rel−/− mice were infected with Helicobacter felis for 6 weeks or 12 months. Bacterial colonization, gastric atrophy and preneoplastic changes were assessed histologically and cytokine expression was assessed by qPCR. Nfkb1−/− mice developed spontaneous gastric atrophy when maintained for 12 months in conventional animal house conditions. They also developed more pronounced gastric atrophy after short-term H. felis colonization with a similar extent of preneoplasia to wild-type (WT) mice after 12 months. c-Rel−/− mice developed a similar degree of gastric atrophy to WT mice; 3 of 6 of these animals also developed lymphoproliferative lesions after 12 months of infection. Nfkb2−/− mice developed minimal gastric epithelial pathology even 12 months after H. felis infection. These findings demonstrate that NF-κB1- and NF-κB2-mediated signaling pathways differentially regulate the epithelial consequences of H. felis infection in the stomach, while c-Rel-mediated signaling also appears to modulate the risk of lymphomagenesis in gastric mucosa-associated lymphoid tissue.

Chromosomal Rearrangements of 6p25.3 Define a New Subtype of Lymphomatoid Papulosis

Lymphomatoid papulosis (LyP) is an indolent cutaneous lymphoproliferative disorder with clinical and pathologic features overlapping those of both reactive conditions and aggressive lymphomas. Recurrent genetic abnormalities in LyP have not been previously identified. Here, we describe the clinical, immunophenotypic, and genetic characteristics of cutaneous lymphoproliferative lesions showing distinctive and previously undescribed histologic features in 11 patients. All patients were older adults (67 to 88 y) with predominantly localized lesions and clinical presentations suggesting benign inflammatory dermatoses or low-grade epithelial tumors. Histologically, lesions showed a biphasic growth pattern, with small cerebriform lymphocytes in the epidermis and larger transformed lymphocytes in the dermis. All had a T-cell immunophenotype. The pathologic features raised the possibility of an aggressive T-cell lymphoma such as transformed mycosis fungoides. However, no patient developed disseminated skin disease or extracutaneous spread. Untreated lesions regressed spontaneously. All cases harbored chromosomal rearrangements of the DUSP22-IRF4 locus on 6p25.3. The overall findings suggest that these cases represent a newly recognized LyP subtype characterized by 6p25.3 rearrangements. The benign clinical course in all 11 patients despite pathologic features mimicking an aggressive lymphoma emphasizes the importance of clinicopathologic correlation, incorporating molecular genetic analysis when possible, during the evaluation of cutaneous lymphoproliferative disorders.

Diagnosis of primary cerebral lymphomas: possible value of PCR testing in equivocal cases requiring rebiopsy

Introduction. Rebiopsy rates as high as 12% have been reported in previous studies of Primary Central Nervous System Lymphoma (PCNSL). This can lead to secondary operations, increasing risks of morbidity to the patient and costs for the NHS. Polymerase Chain Reaction (PCR) testing for clonality in haematological malignancies has been applied to cases of lymphoma outwith the central nervous system (CNS), but is less commonly used in the diagnosis of CNS lymphomas. Clonality in B- and T-cell populations may indicate the presence of malignancy. We aimed to identify factors to reduce the rebiopsy rate in PCNSL. Methods. We examined a cohort of 102 suspected cerebral lymphoma cases biopsied at Frenchay Hospital, Bristol over a 10-year period (2000–2010). Clinical data, including age, sex, location, pre-biopsy steroid use, the need for rebiopsy and histological diagnosis, were collected. We retrospectively reviewed rebiopsied cases and they subsequently underwent PCR testing for clonality. Results. Overall, 96/102 (94%) cases achieved a histological diagnosis after one or more biopsies. 81/96 (84%) of these were lymphomas involving the brain and 15/96 (16%) were spinal lymphomas. The majority of these were B-cell lymphomas (95/96 (99%)), with one case of peripheral T-cell lymphoma (1/96 (1%)). Due to insufficient histological evidence of PCNSL after the first biopsy, 9/102 (9%) of cases had required rebiopsy. In 7/9 (78%) of these cases, we undertook PCR testing for clonality on tissue from the first biopsy. We found 3/7 (43%) cases were monoclonal for B or T populations, raising the possibility of PCNSL. Conclusions. We recommend that all CNS lymphoproliferative lesions be assessed by haematopathologists, with the inclusion of PCR testing particularly in equivocal cases. This would reduce the number of patients going for rebiopsy and reduce the patient morbidity and costs for the NHS.

Flow cytometry significantly improves the diagnostic value of fine needle aspiration cytology of lymphoproliferative lesions of salivary glands

Lymphoid proliferations of the salivary glands can be either reactive or malignant. Diagnosis based solely on fine needle aspiration (FNA) cytology may be troublesome in view of the difficulty in distinguishing low-grade B-cell and mucosa-associated lymphoid tissue (MALT) lymphomas from reactive lymphoid proliferations. We report our experience with FNA cytology combined with flow cytometry (FC) immunophenotyping for the diagnosis of lymphoproliferative processes affecting the salivary glands. Sixty-one FNA specimens, obtained from salivary glands over a 10-year period, were analysed by cytology and FC. The results were correlated with histological follow-up if available. A diagnosis of lymphoma was given in 37 of 61 (61%) specimens; 22 of 61 (36%) specimens were considered as benign/reactive or non-lymphomatous processes; two of 61 (3%) specimens were considered as suspicious for lymphoma on cytological analysis and negative on FC. Histological control was available in 23 malignant, four non-lymphomatous and one cytologically suspicious case. Data obtained by the combination of cytology and FC were confirmed in all but one case: the case suspicious on cytology received a histological diagnosis of carcinoma. Four of seven cases with small populations of clonal cells (less than 15%) were histologically confirmed as lymphoma, whereas two remain under surveillance and one was reactive. Correlation with histological data showed a sensitivity of 100% and a specificity of 83% for the combination of cytology and FC. FC is fundamental for the diagnosis of lymphoproliferative lesions of the salivary glands. It may solve cytologically suspicious cases and detect the presence of neoplastic B or T cells. This combined approach reduces the time to therapy and may prevent unnecessary surgical biopsies.

Immunohistological recognition of cyclin D1 expression by non-lymphoid cells among lymphoid neoplastic cells

Cyclin D1 immunostaining of non-neoplastic cells has been a source of diagnostic confusion especially in lymphoproliferative lesions. This study has reviewed these in two hundred and thirty-one haematopathological samples stained for cyclin D1. Most cases were formalin-fixed except for a few bone marrow trephines, which were B-5 fixed, and EDTA decalcified. Overall, 94% (216/231) of cases showed one or more types of non-neoplastic cells expressing Cyclin D1 of variable intensity. Endothelial cells and histiocytes were the most commonly identified Cyclin D1 positive cells being positive in 92% (214/231) of cases. Other normal cell types identified included fat cells, stromal fibroblasts, glial cells, spermatocytes, smooth muscle cells, osteoblasts and where present epithelial cells. Many normal cell types can express cyclinD1. Knowledge of these is useful to prevent misinterpretation of cyclin D1 positive tumours.

Atypical lymphoid proliferations: the pathologist’s viewpoint

Lymphoid proliferations are traditionally thought to be either benign conditions (reactive hyperplasia and lymphadenitis) or malignant lymphomas. However, not all lymphoid lesions at present can be precisely placed into one of these categories. Therefore, in addition to these two extremes, there also exist a third group of lymphoid proliferations – the atypical lymphoid proliferations (AtLP). AtLP is a descriptive term used when it is not possible for the pathologist to differentiate between the benign and the malignant nature of a given lymphoid infiltrate. AtLP represent biologically indeterminate lesions that have some worrisome clinicopathologic features but cannot be interpreted as malignant lymphomas using all criteria currently available. They have some likelihood for subsequent transformation into lymphomas, and therefore AtLP occupy a middle ground between benign and malignant lymphoid proliferations. Nevertheless, sometimes AtLP are not necessarily premalignant and may very well represent a fully benign situation mimicking malignancy. In the author’s opinion, when confronted with a challenging lymphoproliferative lesion, the pathologist should marshall all resources available to interpret it as precisely as possible and therefore place it into one of the two categories: unequivocally benign condition or malignant lymphomas. The resources should include immunohistochemical and molecular studies, obtaining expert opinion and rebiopsy. However, if clinical, morphologic and molecular findings are not sufficient for diagnosis of a benign condition versus lymphoma, the descriptive term AtLP can be used. In the author’s opinion, the use of this descriptive term AtLP may obviate the need to force some lymphoid proliferations (equivocal lesions or mimickers of lymphomas) into either the benign or malignant categories.

Florid Follicular Lymphoid Hyperplasia of the Hard Palatal Mucosa Managed With Intralesional Steroids: A Case Report and Review of the Literature

Follicular lymphoid hyperplasia of the palate is a benign lymphoproliferative lesion of unknown pathogenesis. It presents usually in female patients as a painless, firm, well-demarcated, usually nonulcerated, slow-growing lesion on the palate that histopathologically may resemble a lymphoma. The authors describe a patient with this condition that was successfully treated with intralesional steroid injections. Previously reported cases were reviewed to assess the results of various treatment modalities and disease-free outcome. A nonsurgical approach to the management of follicular lymphoid hyperplasia may have better patient acceptance and satisfaction without recurrence.

Non-Hodgkin Lymphoma in the Periapical Region of a Mandibular Canine

IntroductionImages and clinical characteristics of some lesions may lead to misinterpretations between diseases of endodontic and non-endodontic origin. Non-Hodgkin lymphomas occur in extranodal sites and may arise primarily in the oral cavity or jaws. MethodsA case of lymphoma associated with the roots of teeth #21–23 in a 38-year-old woman is described. The patient sought dental care because of continuous discomfort at palpation of the periapical area of teeth #21–23, which had been treated endodontically. Radiographic and clinical exams revealed no inflammatory signs. The patient reported losing 24 pounds in the last 2 months. Intraoral examination revealed an expansion of the buccal surface, a solid hard mass, and normal mucosa color. ResultsConventional radiographs showed a diffuse bone radiolucent area, and cone-beam computed tomography images confirmed destruction of the buccal cortical bone, which was suggestive of malignancy. Incisional biopsy was performed, and microscopy showed a lymphoproliferative lesion of uncertain nature with pleomorphic lymphocyte-like round cells, hyperchromatic nuclei, and atypical mitoses. Immunohistochemistry was used to investigate the nature of these cells and the type of lymphoproliferative disorder, and results showed an area of diffuse large B-cell lymphoma. ConclusionsNon-Hodgkin lymphoma should be part of the differential diagnosis of other jaw lesions such as apical periodontitis. The patient was treated with chemotherapy and did not report any abnormalities after 2 years of treatment.

Lymphoid Proliferations Associated With Human Immunodeficiency Virus Infection

Individuals who are immune deficient are at an increased risk for developing lymphoproliferative lesions and lymphomas. Human immunodeficiency virus (HIV) infection is 1 of 4 clinical settings associated with immunodeficiency recognized by the World Health Organization (WHO) in which there is an increased incidence of lymphoma and other lymphoproliferative disorders. To describe the major categories of benign lymphoid proliferations, including progressive HIV-related lymphadenopathy, benign lymphoepithelial cystic lesions, and multicentric Castleman disease, as well as the different types of HIV-related lymphomas as defined by the WHO. The characteristic morphologic, immunophenotypic, and genetic features of the different entities will be discussed in addition to some of the pathogenetic mechanisms. The WHO classification of tumors of hematopoietic and lymphoid tissues (2001 and 2008), published literature from PubMed (National Library of Medicine), published textbooks, and primary material from the authors' current and previous institutions. HIV infection represents one of the clinical settings recognized by the WHO in which immunodeficiency-related lymphoproliferative disorders may arise. Although most lymphomas that arise in patients with HIV infection are diffuse, aggressive B-cell lesions, other lesions, which are "benign" lymphoid proliferations, may also be associated with significant clinical consequences. These lymphoproliferations, like many other immunodeficiency-associated lymphoproliferative disorders, are often difficult to classify. Studies of HIV-associated lymphoid proliferations will continue to increase our understanding of both the immune system and lymphomagenesis.

Dose Response to Radiation Therapy for Primary Ocular Lymphomas

Lympho proliferative lesions are the most common primary orbital malignancies. Primary lymphoma of the orbit and ocular adnexa accounts for 59 years [4]. Orbital Lymphoma (OL) commonly presents with proptosis and is typically a painless, progressive orbital lesion; however, the conjunctival lesions appear clinically as fleshy salmon patch lesions [5,6]. The treatment options are surgical excision, chemotherapy, Radiation Therapy (RT), or combination of chemoradiation. Radiation therapy alone is the most effective treatment modality for the orbital lymphoma with excellent local tumor control [7-12]. The local and systemic relapse rate was reported to be less after treatment of OL by RT due to the indolent nature of the MALT variants. Different radiation techniques and doses (with or without adjuvant chemotherapy) were used by the several authors depending on the extent of the disease and severity. Kennerdell et al. reported 100% complete response of the lymphoid lesions of the orbit and ocular adnexa with low-dose RT (24-25.5 Gy) with very few acute and chronic side effects [8]. Several authors advocated 30-40 Gy for low to intermediate grade lymphomas with good local control and better 5 year survival. In a retrospective chart review of 31 cases of orbital MALT lymphoma, Le et al. observed a complete local control of the tumor with an overall 10 year survival of 73%. However, they did not find a significant difference in the outcomes among patients treated with RT dose of ≤ 30 Gy versus the >30 Gy and recommended that RT dose of 30-30.6 Gy provides excellent local control of tumor with minimal long-term side effects [9]. Galieni et al. observed complete response to the radiotherapy in seven patients of low-grade MALT lymphoma treated with RT dose of 36-40 Gy over a median follow-up of 51 months. However, among the patients treated with chemotherapy, local relapse was observed in 3/15, which resolved completely to the local irradiation [13]. In a multi-institutional, retrospective study by Uno et al. complete tumor response was seen in 26 patients (mean RT dose 36 Gy) and partial response in 20 others (mean RT dose 37.5 Gy) [11]. The local tumor recurrence was noted in 6 of the patients with partial or no response. They concluded that the age ( 60 years), gender, location (conjunctiva versus others), laterality (unilateral versus bilateral) or the dose of radiation therapy (≤ 30 Gy versus >30 Gy) did not contribute to the local tumor recurrence and felt the initial tumor response to RT influenced the probability of local recurrence. The overall 5-year survival rate for all the patients was 91% with a median follow-up of 46 months. Fung et al. noted 4 cases with local recurrence of the 98 cases of MALT lymphoma. Three of the 4 had stage I disease (primary orbital tumor treated with RT dose of 30 Gy) [7]. The systemic relapse-free survival rate among the stage I MALT lymphoma patients which comprise major group in their study was 75% at 5 years and the overall 5-year survival rate was 95%. However for the stage III-IV MALT lymphoma in the same study the 5 year disease specific survival rate was 49% and the overall survival rate was 39%. To summarize, excellent local tumor control rates were observed with radiation therapy with doses 2430 Gy in most studies.

Cutaneous CD30‐positive lymphoproliferative disorders with CD8 expression: a clinicopathologic study of 21 cases

Lymphomatoid papulosis (LyP) and cutaneous anaplastic large cell lymphoma (ALCL) belong to the spectrum of cutaneous CD30+ lymphoproliferative disorders, an indolent form of T-cell lymphoproliferative disease. We reviewed 21 cases of CD30+ lymphoproliferative lesions expressing cytotoxic profile (CD8+). Seven cases of cutaneous ALCL, 2 cases of systemic ALCL involving the skin, and 12 cases of LyP. The cases of LyP were predominated by small lymphocytes exhibiting a prominent epidermotropic pattern consistent with either type B or type D LyP. Four cases showed co-expression of CD56. The ALCL cases included myxoid features, pseudoepitheliomatous change, and an intravascular component. In all cases that were primary in the skin an indolent clinical course was seen while one patient with systemic myxoid ALCL is in remission following systemic multiagent chemotherapy. The paucity of other neutrophils and eosinophils and concomitant granulomatous inflammation were distinctive features in cases of type B and type D LyP. CD30 and CD45 Ro positivity and a clinical course typical of LyP were useful differentiating features from an aggressive cytotoxic CD8+ T cell lymphoma. In all cases that were primary in the skin an indolent clinical course was observed. CD30 and CD45 Ro positivity and a clinical course typical of LyP were useful in preventing a misdiagnosis of an aggressive cytotoxic CD8+ T cell lymphoma.

Conjunctival lymphoma arising from reactive lymphoid hyperplasia

Extra nodal marginal zone B-cell lymphoma (EMZL) of the conjunctiva typically arises in the marginal zone of mucosa-associated lymphoid tissue. The pathogenesis of conjunctival EMZL remains unknown. We describe an unusual case of EMZL arising from reactive lymphoid hyperplasia (RLH) of the conjunctiva. A 35-year-old woman had fleshy salmon-pink conjunctival tumors in both eyes, oculus uterque (OU). Specimens from conjunctival tumors in the right eye, oculus dexter (OD), revealed a collection of small lymphoid cells in the stroma. Immunohistochemically, immunoglobulin (Ig) light chain restriction was not detected. In contrast, diffuse atypical lymphoid cell infiltration was noted in the left eye, oculus sinister (OS), and positive for CD20, a marker for B cells OS. The tumors were histologically diagnosed as RLH OD, and EMZL OS. PCR analysis detected IgH gene rearrangement in the joining region (JH) region OU. After 11 months, a re-biopsy specimen demonstrated EMZL based on compatible pathological and genetic findings OD, arising from RLH. This case suggests that even if the diagnosis of the conjunctival lymphoproliferative lesions is histologically benign, confirmation of the B-cell clonality by checking IgH gene rearrangement should be useful to predict the incidence of malignancy.

Flow cytometry of lesional skin enhances the evaluation of cutaneous B‐cell lymphomas

Cutaneous B-cell lymphoproliferative lesions can pose diagnostic challenges. This study investigates the utlility of flow cytometry in 42 cases of suspected cutaneous B-cell lymphoma. All available cases were reviewed [World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification]. Flow cytometry, immunohistochemistry and polymerase chain reaction-immunoglobulin H (PCR-IgH) analysis of blood and/or lesional skin were performed on primary cutaneous B-cell lymphoma (pcBCL, 17 cases), secondary cutaneous BCL (scBCL, 8 cases) and atypical lymphoid hyperplasia (ALH, 17 cases). Flow cytometry of skin detected a B-cell clone in 3/13 cases of ALH, 8/8 cases of pcBCL and 4/4 cases of scBCL, while PCR detected a clone in 3/14 cases of ALH, 4/15 cases of pcBCL and 6/8 cases of scBCL. Of eight cases of pcBCL analyzed by both methods, all eight were positive by flow while only three were positive by PCR. All cases positive by PCR were also positive by flow. Of five cases with both flow and light chain immunohistochemistry, all five showed light chain restriction by flow, while only two were positive by immunohistochemistry. Flow cytometry is more sensitive than PCR in detecting B-cell lymphoproliferative disorders (12/12 cases, 100% vs. 10/23 cases, 43%; p < 0.001). Furthermore, flow cytometry complements immunohistochemistry in the detection of light chain restriction.

CD20 Antigen Expression by Lymphoproliferative Disorders after Kidney Transplant is Independently Associated with a Poor Outcome: PTLD.Int Survey

Antigen expression by neoplastic cells is important because of its effects on the behavior and survival of patients. We sought to gather data on renal transplant recipients who had developed posttransplant lymphoproliferative disorders in their posttransplant era, and had a documented report on CD20 antigen testing. A comprehensive search of the literature was done for reports that indicate test results for the CD20 antigen in kidney recipients having lymphoproliferative disorders after transplant. Their demographics, disease characteristics, and prognoses were analyzed. CD20-positive posttransplant lymphoproliferative disorder patients had a significantly shorter time from transplant to developing posttransplant lymphoproliferative disorder (P < .001). None of patients who had early onset posttransplant lymphoproliferative disorder was CD20 negative. Bone marrow involvement was significantly more prevalent among CD20-negative patients (P < .05) with no CD20-positive patient developing a bone marrow metastasis. Log-rank test showed a relatively worse survival for renal recipients expressing the CD20 antigen (P = .07). CD20-positive posttransplant lymphoproliferative disorder lesions in kidney transplant patients are significantly more likely to develop early after transplant and represent an inferior outcome. We suggest that all renal transplant recipients who develop posttransplant lymphoproliferative disorder within their early time after surgery should be given anti-CD20 therapy. Future prospective studies are required to confirm our conclusions.

Persistence of inclusions and antigens of chicken anemia virus in Marek’s disease lymphoma

The pathogenesis of the co-infection of CAV to MDV is complicated. In order to investigate the impact of CAV on the transformation phase of MD, MDV and, subsequently, CAV, were inoculated at 1day and 4weeks of age, respectively. Chickens were divided into six groups; vvMDV, vvMDV-CAV, vMDV, vMDV-CAV, CAV and a control group. The CAV inclusions and antigens were continuously detected in MD lymphomas in the vMDV-CAV and vvMDV-CAV groups in large bizarre-shape (presumably CD4+ T cells) and small MD lymphoid cells (presumably CD8+ T cells). The MD lymphomas were composed primarily of CD4+ T cells, but CD8+ T cells were infiltrated singly or in clusters. CAV enhanced the MDV-induced brain lesions in the vMDV-CAV group. The lymphoproliferative lesion (LP) in the vvMDV-CAV and vMDV-CAV groups was non-significantly higher than those in vvMDV and vMDV groups, respectively. CAV significantly increased the LP lesion in sciatic nerves. In conclusion, MD lymphomas enabled CAV replication and dissemination. The depletion of CTLs by CAV did not significantly affect progression of MD lymphoma, although they are essential for possible transition of lymphomatous to inflammatory lesion.

Epstein-Barr Virus Infection of Naïve B Cells In Vitro Frequently Selects Clones with Mutated Immunoglobulin Genotypes: Implications for Virus Biology

Epstein-Barr virus (EBV), a lymphomagenic human herpesvirus, colonises the host through polyclonal B cell-growth-transforming infections yet establishes persistence only in IgD+ CD27+ non-switched memory (NSM) and IgD− CD27+ switched memory (SM) B cells, not in IgD+ CD27− naïve (N) cells. How this selectivity is achieved remains poorly understood. Here we show that purified N, NSM and SM cell preparations are equally transformable in vitro to lymphoblastoid cells lines (LCLs) that, despite upregulating the activation-induced cytidine deaminase (AID) enzyme necessary for Ig isotype switching and Ig gene hypermutation, still retain the surface Ig phenotype of their parental cells. However, both N- and NSM-derived lines remain inducible to Ig isotype switching by surrogate T cell signals. More importantly, IgH gene analysis of N cell infections revealed two features quite distinct from parallel mitogen-activated cultures. Firstly, following 4 weeks of EBV-driven polyclonal proliferation, individual clonotypes then become increasingly dominant; secondly, in around 35% cases these clonotypes carry Ig gene mutations which both resemble AID products and, when analysed in prospectively-harvested cultures, appear to have arisen by sequence diversification in vitro. Thus EBV infection per se can drive at least some naïve B cells to acquire Ig memory genotypes; furthermore, such cells are often favoured during an LCL's evolution to monoclonality. Extrapolating to viral infections in vivo, these findings could help to explain how EBV-infected cells become restricted to memory B cell subsets and why EBV-driven lymphoproliferative lesions, in primary infection and/or immunocompromised settings, so frequently involve clones with memory genotypes.