Immunoglobulin Gene Rearrangement Studies Research Articles

Usefulness and Limitations of Current Diagnostic Strategies for Pulmonary Mucosa-Associated Lymphoid Tissue Lymphoma: Lessons Learned From a Large Cohort.

The pathologic diagnosis of pulmonary extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is challenging. To evaluate the diagnostic usefulness and limitations of current diagnostic strategies for pulmonary MALT lymphoma. A retrospective review of 120 cases of pulmonary MALT lymphoma from 2014 through 2021 was performed. Clinicoradiologic presentations overlapped with previous observations in patients with MALT lymphoma, such as a wide age range, female predominance, frequent association with autoimmune disease or immunodeficiency, and broad imaging findings. The histopathologic diagnosis was based on a combination of morphology, immunohistochemistry, and demonstration of B-cell lineage clonality. Two-thirds (76 of 113) of MALT lymphomas had lymphoplasmacytoid cytomorphology. Occasionally, MALT lymphomas were associated with granulomas/giant cells (29%, 35 of 120) or immunoglobulin deposition disease (21%, 25 of 120), including light chain/heavy chain deposition disease, amyloidosis, and/or crystal storing histiocytosis. While CD5, CD10, Bcl-2, and Bcl-6 rarely revealed aberrancies, aberrant CD43 expression either on B-cells or on plasma cells was detected in 42% (27 of 64) of cases, including cases for which proof of clonality could not be obtained. κ/λ in situ hybridization was particularly useful for tumors with lymphoplasmacytoid morphology but performed poorly in lymphomas having no plasmacytic differentiation. κ/λ immunohistochemistry showed no additional usefulness when applied together with κ/λ in situ hybridization. Immunoglobulin gene rearrangement studies by polymerase chain reaction achieved high detection rates of clonality in all cytomorphologic subgroups. Our study offers a practical evaluation of common diagnostic tests in pulmonary MALT lymphoma. We offer recommendations for a diagnostic workup that takes into consideration the usefulness and the specific limitations of the various diagnostic strategies.

Evaluation of Positive B- and T-Cell Gene Rearrangement Studies in Patients With Negative Morphology, Flow Cytometry, and Immunohistochemistry

The significance of positive immunoglobulin (IG) or T-cell receptor (TCR) gene rearrangement studies in the context of otherwise normal ancillary findings is unknown. To examine long-term hematologic outcomes of individuals with positive gene rearrangement studies with otherwise unremarkable blood or bone marrow studies in parallel. Data from patients who underwent IG or TCR gene rearrangement testing at the authors' affiliated Veterans Affairs Hospital January 1, 2013 to July 6, 2018 were extracted from medical records. Date of testing, specimen source, and morphologic, flow cytometric, immunohistochemical, and cytogenetic characterization of the tissue source were recorded. Gene rearrangement results were categorized as test positive/phenotype positive (T+/P+), test positive/phenotype negative (T+/P-), test negative/phenotype negative (T-/P-), or test negative/phenotype positive (T-/P+) based on comparison to other studies and/or final diagnosis. Patient records were reviewed for subsequent diagnosis of hematologic malignancy for patients with positive gene rearrangements but no other evidence for a disease process. A total of 136 patients with 203 gene rearrangement studies were analyzed. For TCR studies, there were 2 T+/P- and 1 T-/P+ results in 47 peripheral blood assays, as well as 7 T+/P- and 1 T-/P+ results in 54 bone marrow assays. Regarding IG studies, 3 T+/P- and 12 T-/P+ results in 99 bone marrow studies were identified. None of the 12 patients with T+/P- TCR or IG gene rearrangement studies later developed a lymphoproliferative disorder. Positive IG/TCR gene rearrangement studies in the context of otherwise negative bone marrow or peripheral blood findings are not predictive of lymphoproliferative disorders.

Sentinel case of Richter transformation from chronic lymphocytic leukaemia/small lymphocytic lymphoma to CD3+ diffuse large B-cell lymphoma

AimTo report the first case of a Richter syndrome where small lymphocytic lymphoma (SLL) progressed to a CD3+ diffuse large B-cell lymphoma (DLBCL).MethodsMacrodissection of small and large cell lymphomatous components...

The prognostic significance of monoclonal immunoglobulin gene rearrangement in conjunction with histologic B‐cell aggregates in the bone marrow of patients with diffuse large B‐cell lymphoma

Bone marrow involvement (BMI) is a well‐known poor prognostic factor in patients with diffuse large B‐cell lymphoma (DLBCL). This study robustly investigated the significance of monoclonal immunoglobulin gene rearrangement combined with histologic B‐cell aggregates in bone marrow (BM) in the detection of a poor prognostic group. Pretreatment BM samples of 394 DLBCL patients were analyzed via the immunoglobulin gene rearrangement study and the microscopic examination. Monoclonal immunoglobulin gene rearrangement was detected in 25.4% of cases. Histologic B‐cell aggregates with the features of large B‐cell lymphoma aggregates, small cell B‐cell lymphoma aggregates, or B‐cell aggregates of unknown biological potential were observed in 12% of cases (6.9%, 1.3%, and 3.8%, respectively). Histologic B‐cell aggregates were more associated with monoclonality than polyclonality. Cases with both monoclonality and histologic B‐cell aggregates demonstrated close association with poor prognostic factors such as a higher International Prognostic Index score and showed an inferior overall survival rate when compared to cases with only monoclonality or only histologic B‐cell aggregates. From the findings, a combination of monoclonality and histologic B‐cell aggregates within the bone marrow was highly associated with poor prognosis and could be used to determine high‐risk DLBLC patients with greater sensitivity and specificity than conventional microscopic examination or immunoglobulin gene rearrangement study alone.

Mantle Cell Hyperplasia of Peripheral Lymph Nodes as Initial Manifestation of Sickle Cell Disease.

Sickle cell disease (SCD) is a well known hemoglobinopathy with usual manifestations including anemia, hyperbilirubinemia, and vasoocclusive complications. Despite presence of mild splenomegaly in early phase of the disease, lymphadenopathy is not an often finding of SCD. We introduce an undiagnosed case of SCD who presented in third decade of his life with multiple cervical lymphadenopathies and mild splenomegaly persistent for about five years. Histopathologic examination of the resected lymph nodes showed expansion of the mantle cell layers of secondary follicles as well as several monomorphic mantle cell nodules. To rule out possibility of a malignant process involving lymph nodes, an immunohistochemical panel was ordered which was in favor of benign mantle cell hyperplasia. Immunoglobulin gene rearrangement study showed no clonal bands and confirmed benign nature of the process. Respecting mild abnormalities on Complete Blood Count, peripheral blood smear was reviewed revealing some typical sickle red blood cells as well as rare nucleated red blood cells. Solubility test for hemoglobin (HB) S was positive. Hemoglobin electrophoresis confirmed diagnosis of homozygous HbS disease.

Cutaneous plasmacytosis: a clinicopathologic study of 12 cases in Taiwan revealing heterogeneous underlying causes.

Cutaneous plasmacytosis is clinically characterized by multiple pigmented papules and plaques that occur mainly on the trunk and many plasma cells in the lesional skin. Most of the cases reported have occurred in Japan. Whether cutaneous plasmacytosis is a unique reactive disease or a neoplastic condition has not been established. We collected 12 cases fulfilling the criteria for a diagnosis of cutaneous plasmacytosis at our institution from 2001 to 2013. We analyzed clinicopathologic features and performed immunohistochemical and immunoglobulin gene rearrangement studies. All 12 patients presented with characteristic cutaneous lesions mainly on the trunk and proximal extremities. Many plasma cells were observed in the lesional skin, and the basal layer was hyperpigmented. Four patients had numerous plasma cells in lymph nodes, and one patient also had increased plasma cells in bone marrow. One patient fulfilled the criteria for immunoglobulin G4 (IgG4)-related lymphadenopathy. Elevated serum IgG and IgG4 concentrations were found in seven patients. Monoclonal immunoglobulin gene rearrangements were detected in four patients. The median duration of follow-up was four years. One patient was lost from follow-up. Partial remission of the cutaneous lesions was observed in five patients, and progressive disease was noted in five patients. One patient died of respiratory failure. Our study suggests that the so-called "cutaneous plasmacytosis" has heterogeneous underlying causes with or without systemic involvement and may be associated with clonal immunoglobulin gene rearrangements and IgG4-related lymphadenopathy. No effective treatment is available for this condition.

Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations.

Lymphomatoid granulomatosis (LYG) is a rare angiocentric and angiodestructive Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorder. It is hypothesized that these patients have dysregulated immune surveillance of EBV. We reviewed the biopsies of 55 patients with LYG who were referred for a prospective trial at the National Cancer Institute (1995 to 2010) and evaluated the histologic, immunohistochemical, in situ hybridization, and molecular findings of these biopsies in conjunction with clinical information. Grading of the lesions was based on morphologic features and the number of EBV-positive B cells. The median age was 46 years (M:F 2.2:1). Clinically, all patients had lung involvement (100%), with the next most common site being the central nervous system (38%). No patient had nodal or bone marrow disease. All patients had past EBV exposure by serology but with a low median EBV viral load. We reviewed 122 biopsies; the most common site was lung (73%), followed by skin/subcutaneous tissue (17%); other sites included kidney, nasal cavity, gastrointestinal tract, conjunctiva, liver, and adrenal gland. Histologically, the lesions showed angiocentricity, were rich in T cells, had large atypical B cells, and were positive for EBV. Grading was performed predominantly on the lung biopsy at diagnosis; they were distributed as follows: LYG grade 1 (30%), grade 2 (22%), and grade 3 (48%). Necrosis was seen in all grades, with a greater degree in high-grade lesions. Immunoglobulin gene rearrangement studies were performed, and a higher percentage of clonal rearrangements were seen in LYG grade 2 (50%) and grade 3 (69%) as compared with grade 1 (8%). LYG is a distinct entity that can usually be differentiated from other EBV-associated B-cell lymphoproliferative disorders on the basis of the combination of clinical presentation, histology, and EBV studies. Grading of these lesions is important because it dictates the treatment choice.

The DG75 B-cell lymphoma line exhibits biclonal immunoglobulin gene rearrangement

Immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangement (GR) studies have been successfully employed to investigate the clonality and cell lineage of various lymphoid malignancies. Several lymphoma cell lines, such as BJAB, RAJI, DG75 and Jurkat cell lines, were often used as the positive controls in GR detection assays. Of those, the DG75 B-cell lymphoma line was found to exhibit biclonality [two or more homoduplex and heteroduplex bands in a polymerase chain reaction (PCR) product of clonality assay] in the PCR of GR detection assays. To further explore these characteristics of the biclonal phenomenon, the PCR products were purified and cloned into a pEGM-T clone vector. The sequences were analyzed using DNA analysis software. The results demonstrated that the two bands originated from two forms of GR of DG75 cell lines, i.e., DG75 is a biclonal cell line in Ig GRs, which has not been reported before.

Langerhans/dendritic cell sarcoma arising from hairy cell leukemia: a rare phenomenon

Dear Editor, A 66-year-old female was diagnosed in 2000 with hairy cell leukemia (HCL). Flow cytometry from her bone marrow biopsy (BMB) demonstrated a monotypic B cell population expressing CD11c, CD22, CD25, and CD103. She was successfully treated with cladribine [1]; however, in 2003, she relapsed, and BMB showed a monotypic B cell population. Cytogenetic analysis revealed an abnormal hyperdiploid karyotype in 2 of 20 metaphase cells: 48,XX,+4,del(6)(q23), del(8)(p21)x2,+12,del(14)(q24), add(17)(p13) (Fig. 1). She was again treated with cladribine and rituximab [2]. In 2008, imaging revealed splenomegaly. Splenectomywas performed, and pathology showed HCL. BMB revealed extensive involvement by a monotypic B cell population negative for CD5, CD10, CD103, and CD25. This phenotype was the same as reported on previous BMB, but differed in that it was CD25 and CD103 negative. Five months later, the patient presented with a left pyriform sinus mass (SUV of 32.8 on PET scan) which was biopsied (Fig. 2). BMB revealed involvement by the previously diagnosed HCL with a monoclonal B cell population demonstrating a phenotype similar to that observed in previous studies. Based on histologic and immunophenotypic findings, this tumor was classified as Langerhans/dendritic cell sarcoma (L/DCS) (expression S100, CD1a; negative for B and T cell markers and CD30). Cytogenetic evaluation identified the hyperdiploid complex karyotype: 47,XX,+4,del(6)(q23),del(8)(p21)x2,+12, -13,del(14)(q24),add(17)(p13). This karyotype and the one obtained in 2003 BMB positive for HCL were essentially identical, although L/DCS presented with monosomy 13. In addition, clonal immunoglobulin gene rearrangements identified by polymerase chain reaction from both specimens were also identical. Combined, cytogenetic, and immunoglobulin gene rearrangement studies suggest that both the HCL and L/DCS developed from the same precursor cells. The patient was treated with three cycles of gemcitabine and docetaxel [3]. However, due to significant progression, the patient opted for hospice. Clinical data have shown that two hematopoietic populations in the same patient may share identical genetic changes or abnormalities, raising the possibility that tumors expressing the phenotype of one hematopoietic lineage might “transdifferentiate” into a genetically similar but phenotypically distinct tumor of a different lineage [4]. Histiocytic/dendritic cell sarcomas (H/DCS) arising from follicular lymphoma (FL) have been reported earlier (eight patients) [5]. In six of these patients, both lesions possessed the same genetic aberration, namely the FL-associated IGH/BCL2 gene rearrangement associated with the t(14;18)(q32;q21). The remaining two demonstrated identical BCL2/JH or clonal IGH gene rearrangements or both. Based on these observations, the authors suggested a clonal relationship between FL and H/DCS. Feldman et al. also demonstrated a common clonal origin in a patient with acute lymphoblastic leukemia and subsequent histiocytic sarcoma, based on identical IGH and TCRγ gene rearrangements in both lesions [6]. Zhang et al. described a Electronic supplementary material The online version of this article (doi:10.1007/s00277-011-1399-5) contains supplementary material, which is available to authorized users. A. Muslimani :M. M. Chisti (*) : I. Boxwala : I. Jaiyesimi Department of Hematology and Oncology, Oakland University William Beaumont School of Medicine, William Beaumont Hospital, 3577 W 13 Mile Rd, Suite 202, Royal Oak, MI 48073, USA e-mail: mohsinchisti@yahoo.com

Coexisting and Clonally Identical Classic Hodgkin Lymphoma and Nodular Lymphocyte Predominant Hodgkin Lymphoma

We report a case of concurrent nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and classic Hodgkin lymphoma (cHL), of nodular sclerosis subtype, in an otherwise healthy 24-year-old man with a strong family history of cHL. The patient was found to have a parotid mass, which was diagnosed as NLPHL, and a thymic mass diagnosed as cHL, of nodular sclerosis subtype concurrently. The lesion in the parotid showed features typical of NLPHL by morphology and immunophenotype. The LP cells were positive for PAX5, CD20, Oct2, weakly positive for CD30, and negative for CD15. The thymic lesion, diagnosed as cHL, of nodular sclerosis subtype, showed prominent bands of fibrosis and Hodgkin/Reed-Sternberg and lacunar cells positive for CD30 and CD15. These cells were variably positive for CD20 and negative for Oct2. PAX5 was weakly positive. Immunoglobulin gene rearrangement studies by polymerase chain reaction were carried out on microdissected Hodgkin/Reed-Sternberg and LP cells, which were shown to have identically sized peaks. NLPHL and cHL are 2 distinct diseases and are almost never seen concurrently. We present a case in which polymerase chain reaction analysis indicated that the tumor cells of these 2 distinct entities were clonally identical.

Sequential Development of Histiocytic Sarcoma and Diffuse Large B-cell Lymphoma in a Patient With a Remote History of Follicular Lymphoma With Genotypic Evidence of a Clonal Relationship

Follicular lymphoma (FL) often transforms to diffuse large B-cell lymphoma (DLBCL) during its protracted clinical course. Rarely, histiocytic sarcoma (HS) occurs secondary to or concurrent with FL, although the biological relationship between these 2 morphologically and immunophenotypically distinct entities in the same individual has not been well characterized. We report a unique case showing the sequential occurrence of first, HS and then DLBCL in a patient with a remote history of FL. In this case, HS developed 17 years after the diagnosis of FL and was shown to partly retain the immunophenotypic features characteristic of FL, while showing the morphologic and immunophenotypic profiles diagnostic of HS. DLBCL occurred 18.5 years after FL. Both HS and DLBCL harbored the IGH/BCL2 fusion gene, a hallmark of FL, per interphase fluorescence in situ hybridization analysis. Immunoglobulin gene rearrangement studies showed a clonal rearrangement of the IGH gene in both HS and DLBCL with identical amplicons, suggesting a shared origin of the neoplastic clones. These data support the hypothesis of transdifferentiation or transevolution in a mature B-cell neoplasm, and, in addition, suggest the possibility of a divergent (bilineal) neoplastic transformation of FL in a single individual.

Concurrent classical Hodgkin lymphoma and plasmablastic lymphoma in a patient with chronic lymphocytic leukemia/small lymphocytic lymphoma treated with fludarabine: a dimorphic presentation of iatrogenic immunodeficiency-associated lymphoproliferative disorder with evidence suggestive of multiclonal transformability of B cells by Epstein-Barr virus

A small fraction of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma develop Epstein-Barr virus-positive B-cell lymphoproliferative disorders. These Epstein-Barr virus-B-cell lymphoproliferative disorders are thought to be related to immune suppression induced by fludarabine/other chemotherapeutic regimens. As in other immunodeficiency-associated lymphoproliferative disorders, these disorders demonstrate a heterogeneous histological spectrum that ranges from polymorphic to monomorphic to classical Hodgkin lymphoma-like lesions. We report a case of concurrent classical Hodgkin lymphoma and plasmablastic lymphoma in a patient with chronic lymphocytic leukemia/small lymphocytic lymphoma treated with fludarabine. Both classical Hodgkin lymphoma and plasmablastic lymphoma were positive for Epstein-Barr virus-encoded RNA, whereas classical Hodgkin lymphoma was also positive for Epstein-Barr virus- latent membrane protein 1, suggesting a different viral latency. Immunoglobulin gene rearrangement studies demonstrated distinct clones in the plasmablastic lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma. These findings suggest biclonal secondary lymphomas associated with iatrogenic immunodeficiency. Epstein-Barr virus-B-cell lymphoproliferative disorders in the setting of chronic lymphocytic leukemia/small lymphocytic lymphoma, in particular those arising after chemotherapy, should be separated from true Richter's transformation, and be categorized as (iatrogenic) immunodeficiency-associated lymphoproliferative disorder.

Solitary plasmacytoma of bone: a clinicopathologic, immunohistochemical and immunoglobulin gene rearrangement study

To investigate clinicopathologic features of solitary plasmacytoma of bone (SPB) and the role of immuno-phenotype and immunoglobulin gene rearrangement detection in the diagnosis and differential diagnosis of SPB. A total of 21 cases of SPB were selected during a period from 1990 to 2008. A retrospective clinicopathologic study and immunohistochemistry (EnVision or EliVision methods) of 17 antigens were performed. In addition, universal IgH (FR3A/LJH/VLJH) primers and BIOMED-2 PCR multiplex tubes were used for IgK and IgL rearrangement analysis. The age of patients ranged from 36 to 72 years with a media of 50 years. Axial skeleton was the most common site of involvement, accounting for 66.7% of the cases (14 of 21), followed by the extremities of 33.3% (7 cases). Low serum level of M-components was found in 5 cases, including two of IgG type (21.4 g/L) and three of IgA type. Clinical manifestations were closely related to the anatomic sites involved, such as pain due to bone destruction, symptoms and signs caused by compression of spinal cord or nerve root, and pathological fracture. All cases presented as a solitary osteolytic lesion. According to the histological grading criteria, grade I tumor was seen in 12 of 21 cases (57.1%). The remaining were grade II (5 cases, 23.8%) and grade III (4 cases, 19.0%). Immunohistochemically, the neoplastic cells expressed two or more plasma cell antigens, including CD138, CD38 and PC, but no CD19 and CD20. CD79a expression detected in 23.8%(5/21) of the cases. Expression of CD56, CD27 and CD44v6 were 57.1% (12/21), 15.0% (3/20) and 23.8% (5/21), respectively. Follow-up data were available in 12 of the 21 patients (57.1%). Five patients were alive and 7 died. Three patients developed multiple myeloma (MM) and died of the tumor. SPB is a rare tumor with bone pain as the most common presenting symptom due to bone destruction. The diagnosis of EMP can only be established after exclusion of an extramedullay invasion by MM. Immunophenotype and IgH gene rearrangement analysis play important roles in the diagnosis of SPB.

BIOMED-2 Multiplex Immunoglobulin/T-Cell Receptor Polymerase Chain Reaction Protocols Can Reliably Replace Southern Blot Analysis in Routine Clonality Diagnostics

To establish the most sensitive and efficient strategy of clonality diagnostics via immunoglobulin and T-cell receptor gene rearrangement studies in suspected lymphoproliferative disorders, we evaluated 300 samples (from 218 patients) submitted consecutively for routine diagnostics. All samples were studied using the BIOMED-2 multiplex polymerase chain reaction (PCR) protocol. In 176 samples, Southern blot (SB) data were also available, and the two types of molecular results were compared. Results of PCR and SB analysis of both T-cell receptor and immunoglobulin loci were concordant in 85% of samples. For discordant results, PCR results were more consistent with the final diagnosis in 73% of samples. No false-negative results were obtained by PCR analysis. In contrast, SB analysis failed to detect clonality in a relatively high number of samples, mainly in cases of low tumor burden. We conclude that the novel BIOMED-2 multiplex PCR strategy is of great value in diagnosing patients with suspected B- and T-cell proliferations. Because of its higher speed, efficiency, and sensitivity, it can reliably replace SB analysis in clonality diagnostics in a routine laboratory setting. Just as with SB results, PCR results should always be interpreted in the context of clinical, immunophenotypical, and histopathological data.

Immunoglobulin gene analysis reveals 2 distinct cells of origin for EBV-positive and EBV-negative Burkitt lymphomas

AbstractThe normal counterpart of the neoplastic B cells in Burkitt lymphoma (B11111112121) is still unclear. Based on immunoglobulin gene rearrangement studies, some authors suggest an origin from germinal center cells and others from memory B cells. However, most of these studies rely on cell lines or on a small series of cases. To help clarify the cell of origin of BL, semi-nested polymerase chain reaction (PCR) was performed to amplify the VDJ rearrangements of the immunoglobulin heavy chain (VH) genes, and the resultant amplificates were sequenced for comparison with known germline VH segments. The results of this approach revealed that all cases (15 endemic BL [eBL], 10 sporadic BL [sBL], and 6 AIDS-related BL) harbor mutated VH genes, with different mutation ranges among the 3 types of BL. The eBL and AIDS-related forms showed considerably higher mutation rates than the sBL form (5.1%, 5.4%, and 1.5%, respectively). The mutations in eBL and AIDS-related BL also showed signs of antigen selection, whereas no signs of antigen selection were found in sBL. Finally, after subcloning the amplificates, sequence analysis revealed no signs of ongoing mutations in any of the cases analyzed. Given that one of the main differences between eBL and AIDS-related BL on the one hand and sBL on the other hand is the association with Epstein-Barr virus (EBV), we compared EBV-positive and EBV-negative BLs independently of their geographic origin and HIV status. The differences in the number of somatic mutations and antigen selection were even more evident when this approach was used. According to our molecular results, it appears that EBV-positive and EBV-negative BL may originate from 2 distinct subsets of B cells, pointing to a particular role for the germinal-center reaction in the pathogenesis of these tumors. The different types of C-MYC translocation reported in BL may also be related to the different stages of B-cell maturation.

Primary Intraocular T-Cell–Rich Large B-Cell Lymphoma

We report a primary intraocular T-cell-rich large B-cell lymphoma in a 57-year-old woman who underwent 3 diagnostic vitrectomies for a presumed diagnosis of panuveitis. She developed no light perception in the left eye and underwent enucleation. Histopathologic and immunohistochemical studies on the enucleated globe disclosed a primary intraocular large B-cell lymphoma involving the choroid, vitreous, and retina. A large population of T cells was identified among the neoplastic B-cell population. B-cell immunoglobulin gene rearrangement and T-cell receptor gene rearrangement studies using the polymerase chain reaction method indicated that a monoclonal immunoglobulin kappa light chain population was present and that the T-cell population was not monoclonal. This case highlights the importance of interpreting cytologic features in vitreous aspirates in the context of the clinical situation.

Renal graft loss with plasma cell‐rich acute rejection in cadaveric renal transplantation: a case report

We reported a case of renal graft loss in cadaveric renal transplantation. An episode biopsy with renal dysfunction showed plasma cell predominant inflammatory infiltration in the interstitium without a finding of vascular or glomerular rejection, and was diagnosed as plasma cell-rich acute rejection (PCAR). Despite intensive immunosuppressive therapy, the renal histology of repeated biopsies showed persistent plasma cell infiltration and the graft was finally lost. Immunohistological staining and immunoglobulin gene rearrangement studies to estimate the clonality of inflammatory cells revealed that the infiltrating plasma cells were polyclonal in origin. Epstein-Barr virus was not detected by in situ hybridization. From these results, we excluded the possibility of post-transplant lymphoproliferative disorder (PTLD); however, a precise definition and differential diagnosis between PCAR and PTLD has not yet been fully determined. As therapeutic regimens for PCAR and PTLD are different, definite guidelines for diagnosis and treatments of PCAR need to be established.

Cutaneous and Systemic Plasmacytosis

A 67‐year‐old Chinese man presented with a longstanding history of asymptomatic, brown‐red macules that diffusely involved his trunk and the extremities and was associated with generalized lymphadenopathy. His serum protein electrophoresis revealed a polyclonal hypergammaglobulinemia. No monoclonal Bence Jones protein was detected in the urine. Flow cytometry of his peripheral blood revealed a normal polyclonal population of B and T cells. Histopathologic examination demonstrated a dense nodular infiltrate of lymphocytes and numerous mature plasma cells in the reticular dermis. Immunoperoxidase studies for kappa and lambda light chains failed to demonstrate clonality. In addition, immunoglobulin gene rearrangement studies failed to reveal a monoclonal band. A bone marrow biopsy showed no abnormality. Cutaneous and systemic plasmacytosis is a rare lymphoproliferative disorder that is an important consideration in the differential diagnosis of cutaneous infiltrates in which plasma cells predominate.

Nodal Plasmacytoma with Significant Paraproteinaemia

We present a case of primary nodal plasmacytoma in an elderly Chinese woman that was associated with significant paraproteinaemia and paraproteinuria. Clinical and laboratory features of the patient satisfied Durie's criteria for the diagnosis of multiple myeloma. The present case was unusual in two aspects. Firstly, there was no evidence of clonal plasma cell proliferation elsewhere in the body after extensive radiological investigations, repeated bone marrow examinations, and polymerase chain reaction for immunoglobulin gene rearrangement study. Secondly, the clinical behaviour was indolent despite the large amount of paraprotein production, and showed satisfactory disease control with local radiotherapy. The differential diagnoses of plasmacytosis in the lymph node are also discussed.

Recurrent epstein-barr virus-associated post-transplant lymphoproliferative disorder: Report of a patient with histologically similar but clonally distinct metachronous abdominal and brain lesions

A liver transplant patient developed a single central nervous system (CNS) intraparenchymal lesion 5 months after the diagnosis of an intraabdominal diffuse large B-cell post-transplant lymphoproliferative disorder (PTLD). Biopsy of the new CNS lesion showed a diffuse large B-cell PTLD morphologically and immunohistochemically indistinguishable from the abdominal lesion. In addition, both lesions were positive for Epstein-Barr virus (EBV) DNA by polymerase chain reaction (PCR) and for EBV-encoded RNA by in situ hybridization. Although these results were consistent with a metastatic origin for the CNS lesion, the finding of an intraparenchymal lesion without leptomeningeal or dural spread was suggestive of a new primary CNS lymphoma. Proof that the brain lesion was a second primary and not a metastasis was obtained by immunoglobulin gene rearrangement studies and assessment of EBV clonality. Multiple primary lymphoid neoplasms arise at higher frequency in the setting of immunosuppression, and molecular investigations of tumor clonality can provide clinically relevant staging and prognostic information.