Hypopigmented Interface T-Cell Dyscrasia and Hypopigmented Mycosis Fungoides: A Comparative Study.

Hypopigmented interface T-cell dyscrasia (HITCD) is a distinct form of lymphoid dyscrasia that may progress to hypopigmented mycosis fungoides (HMF). We compared both diseases as regards their CD4/CD8 phenotype and expression of granzyme B and tumor necrosis factor-alpha (TNF-α) and how these are affected by narrow-band UVB (nb-UVB). The study included 11 patients with HITCD and 9 patients with HMF. They received nb-UVB thrice weekly until complete repigmentation or a maximum of 48 sessions. Pretreatment and posttreatment biopsies were stained using anti CD4, CD8, TNF-α, and granzyme B monoclonal antibodies. Epidermal lymphocytes were CD8 predominant in 54.5% and 66.7% of HITCD and HMF cases, respectively, whereas dermal lymphocytes were CD4 predominant in 63.6% and 66.7%, respectively. Significantly, more dermal infiltrate was encountered in HMF (P = 0.041). In both diseases, granzyme B was only expressed in the dermis, whereas TNF-α was expressed both in the epidermis and dermis. No difference existed as regards the number of sessions needed to achieve repigmentation or cumulative nb-UVB dose reached at end of study. (P > 0.05). Narrow-band UVB significantly reduced only the epidermal lymphocytes in both diseases (P ≤ 0.05) with their complete disappearance in 8 (72.7%) HITCD and 6 (66.7%) HMF cases. In both diseases, nb-UVB did not affect granzyme B or TNF-α expression (P > 0.05). In conclusion, both diseases share the same phenotype, with HITCD being a milder form of T-cell dysfunction. In both diseases, epidermal lymphocytes are mainly CD8-exhausted cells lacking cytotoxicity, whereas dermal cells are mostly reactive cells exerting antitumor cytotoxicity. Tumor necrosis factor-alpha mediates hypopigmentation in both diseases and prevents disease progression. Repigmentation after nb-UVB in both diseases occurs before and independently from disappearance of the dermal infiltrate.

Altered lymphopoiesis and immunodeficiency in miR-142 null mice.

MicroRNAs (miRNAs) are a class of powerful posttranscriptional regulators implicated in the control of diverse biological processes, including regulation of hematopoiesis and the immune response. To define the biological functions of miR-142, which is preferentially and abundantly expressed in immune cells, we created a mouse line with a targeted deletion of this gene. Our analysis of miR-142(-/-) mice revealed a critical role for this miRNA in the development and homeostasis of lymphocytes. Marginal zone B cells expand in the knockout spleen, whereas the number of T and B1 B cells in the periphery is reduced. Abnormal development of hematopoietic lineages in miR-142(-/-) animals is accompanied by a profound immunodeficiency, manifested by hypoimmunoglobulinemia and failure to mount a productive immune response to soluble antigens and virus. miR-142(-/-) B cells express elevated levels of B-cell-activating factor (BAFF) receptor (BAFF-R) and as a result proliferate more robustly in response to BAFF stimulation. Lowering the BAFF-R gene dose in miR-142(-/-) mice rescues the B-cell expansion defect, suggesting that BAFF-R is a bona fide miR-142 target through which it controls B-cell homeostasis. Collectively, our results uncover miR-142 as an essential regulator of lymphopoiesis, and suggest that lesions in this miRNA gene may lead to primary immunodeficiency.

CD200 expression in plasma cells of nonmyeloma immunoproliferative disorders: clinicopathologic features and comparison with plasma cell myeloma.

The majority of plasma cell myelomas (PCMs) are positive for CD200, a membrane protein with immunosuppressive function. There are no flow cytometry data in the literature on plasma cell CD200 expression in other immunoproliferative disorders. Therefore we used flow cytometry to study the expression of CD200 on plasma cells in diagnostic bone marrow aspirates from 61 patients with monoclonal gammopathy of undetermined significance (MGUS) and 10 patients with lymphoplasmacytic lymphoma (LPL). For comparison, we evaluated CD200 expression in 74 PCM bone marrow biopsies. Thirty-three (54.1%) of 61 MGUS cases and 2 (20.0%) of 10 LPL cases were CD200+. Comparative clinicopathologic parameters for MGUS cases, based on CD200 expression status, showed no differences between the 2 groups. The proportion of CD200+ PCMs (73.0%) in our series was significantly higher than that of CD200+ MGUS (P = .030) and CD200+ LPL (P = .002) cases.

Morphologic features of extrahepatic manifestations of hepatitis C virus infection.

Cirrhosis and hepatocellular carcinoma are the prototypic complications of chronic hepatitis C virus infection in the liver. However, hepatitis C virus also affects a variety of other organs that may lead to significant morbidity and mortality. Extrahepatic manifestations of hepatitis C infection include a multitude of disease processes affecting the small vessels, skin, kidneys, salivary gland, eyes, thyroid, and immunologic system. The majority of these conditions are thought to be immune mediated. The most documented of these entities is mixed cryoglobulinemia. Morphologically, immune complex depositions can be identified in small vessels and glomerular capillary walls, leading to leukoclastic vasculitis in the skin and membranoproliferative glomerulonephritis in the kidney. Other HCV-associated entities include porphyria cutanea tarda, lichen planus, necrolytic acral erythema, membranous glomerulonephritis, diabetic nephropathy, B-cell non-Hodgkin lymphomas, insulin resistance, sialadenitis, sicca syndrome, and autoimmune thyroiditis. This paper highlights the histomorphologic features of these processes, which are typically characterized by chronic inflammation, immune complex deposition, and immunoproliferative disease in the affected organ.

Somatic KRAS mutations associated with a human nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis.

Somatic gain-of-function mutations in members of the RAS subfamily of small guanosine triphosphatases are found in > 30% of all human cancers. We recently described a syndrome of chronic nonmalignant lymphadenopathy, splenomegaly, and autoimmunity associated with a mutation in NRAS affecting hematopoietic cells, and initially we classified the disease as a variant of the autoimmune lymphoproliferative syndrome. Here, we demonstrate that somatic mutations in the related KRAS gene can also be associated with a nonmalignant syndrome of autoimmunity and breakdown of leukocyte homeostasis. The activating KRAS mutation impaired cytokine withdrawal-induced T-cell apoptosis through the suppression of the proapoptotic protein BCL-2 interacting mediator of cell death and facilitated proliferation through p27(kip1) down-regulation. These defects could be corrected in vitro by mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1 or phosphatidyl inositol-3 kinase inhibition. We suggest the use of the term RAS-associated autoimmune leukoproliferative disease to differentiate this disorder from autoimmune lymphoproliferative syndrome.

Angiocentric immunoproliferative lesion and angiocentric lymphoma of lymph node in children. A report of two cases.

AIM: To report two examples of an angiocentric immunoproliferative lesion (AIL) and angiocentric angiodestructive lymphoma (AL) presenting in lymph nodes in children. Most commonly involving extranodal sites, AIL/AL rarely presents in the spleen and lymph nodes. METHODS/RESULTS: Case 1 presented as a cervical lymphadenopathy in a 3 year old girl being treated for pre-B cell acute lymphoblastic leukaemia. Histological and immunohistochemistry studies revealed an Epstein-Barr virus positive (EBV+), large B cell (CD20 and CD30+) AIL with large areas of necrosis, the whole resembling lymphomatoid granulomatosis. Case 2 presented as a large supraclavicular lymphadenopathy in a 13 year old boy. Histology and immunohistochemistry revealed an EBV-, large T cell (CD45RO, CD56, and CD30+) AL, presenting the features of so called angiocentric T cell/natural killer cell lymphoma, nasal type. CONCLUSIONS: The term AIL/AL refers to a heterogeneous group of conditions not unique to a particular type of lymphoid cell. These lesions are easily recognised by the histopathologist because of their extremely unusual angiocentric pattern. Although rare, AIL/AL may present as nodal lesions in children ab initio.

A case of lymphomatoid granulomatosis/angiocentric immunoproliferative lesion with long clinical course and diffuse brain involvement.

Lymphomatoid granulomatosis (LYG)/angiocentric immunoproliferative lesions (AIL) consist of angiocentric and angiodestructive lymphoreticular proliferation predominantly involving the lungs and other extranodal sites, such as the central nervous system (CNS). This clinical entity is considered as a B cell process related to Epstein-Barr virus (EBV) infection and EBV positive diffuse large B-cell lymphoma. The CNS is involved in 20% of cases of LYG, but initial involvement is rare. In cases without pulmonary symptoms, diagnosis may be difficult. We report a rare case involving initial progression of CNS symptoms followed by a pulmonary abnormality.A 14-year-old girl suffered from high fever, ataxic gait and paraparesis. MRI revealed diffuse T2 high signals with multiple gadolinium enhancements in the cerebellum, brain stem and cerebral white matter. Her symptoms briefly improved after steroid therapy, but ataxia gradually progressed. Dyspnea due to pulmonary interstitial involvement appeared when she was 18 years old. Steroid therapy proved effective for respiratory symptoms. At 20 years old she suffered from disseminated intravascular coagulopathy (DIC) and hemophagocytic syndrome (HPS) with respiratory symptoms and repeated seizures. Her symptoms improved after the administration of cyclophosphamide. Mild hemiparesis and gait disturbance appeared when she was 22 years old. MRI revealed new lesions at the basal ganglia and subcortical white matter, brain atrophy and diffuse T2 high intensity of cerebral white matter. Cyclophosphamide was effective and there has been no recurrence of symptoms in the last 5 years. We reviewed the non-tumorous LYG/AIL involving the CNS, and discussed the clinical features, MRI imaging and diagnosis of the LYG/AIL.

Angiocentric immunoproliferative lesion of the lung.

Angiocentric immunoproliferative lesion (AIL) is the angiocentric and angiodestructive process of lymphoreticular cells with vascular invasion. AIL of the lung is rare. We treated a 57-year-old woman with AIL of the lung in whom chest radiography and computed tomography showed ground-glass opacity in the left lower lobe and lingular segment. Since macroscopical and intraoperative lung biopsy findings could not rule out the possibility of malignancy, including malignant lymphoma, we conducted left pneumonectomy. Immunohistological examination of the tumor showed that infiltrating lymphocytes consistent with AIL. Because tumor markers such as serum LDH and soluble IL-2 receptor increased postoperatively, we conducted systemic chemotherapy, after which elevated serum tumor markers decreased.

Polyclonal systemic immunoblast proliferation: an unusual hematologic entity presenting as a medical examiner case.

A 43-year-old woman who was receiving oral antibiotics for several days for a superficial foot infection developed a persistent rash, fever, and lymphadenopathy, despite discontinuation of the antibiotic and administration of steroids for a presumed drug reaction. Hours after a subsequent visit to the emergency room for worsening symptoms, she died at home. At autopsy, there was a florid, systemic proliferation of polyclonal plasma cells and immunoblasts infiltrating nearly every organ and tissue of the body, most notably the lymph nodes and spleen. The polyclonal nature of the process was confirmed by immunofixation electrophoresis and immunohistochemistry. Cases of fatal polyclonal systemic immunoblast proliferations are extremely rare, and the trigger for such proliferations is not always known. We review the literature on this unusual entity and discuss the clinical and pathologic findings.

Detection of immunoglobulin heavy chain genes rearrangements in B-cell leukemias, lymphomas, multiple myelomas, monoclonal and polyclonal gammopathies.

Polymerase chain reaction (PCR) based assays were found to be a realistic alternative to Southern blot hybridization for the assessment of clonal immunoglobulin heavy chain gene rearrangements. However, a comparison of the different PCR based studies reveals considerable variation in experimental design and marked differences in the reported results. This study compared different single- and double-step PCR assays relying on various FR3, FR2, FR1 and JH based primers for the detection of B cell clonality in acute lymphoblastic leukemias (ALL), non-Hodgkin's-lymphoma (NHL), multiple myeloma (MM), monoclonal gammopathies of unknown significance (MGUS) and three polyclonal gammopathies (PG). The highest monoclonality rate was observed using seminested CDR-III region amplification. This method achieved a monoclonal product in 6 of 13 pro-B ALL 21 of 29 c-ALL, 7 of 8 pre-B-ALL, 18 of 21 B-ALL, 14 of 17 B-NHL (intermediate or high grade) with bone marrow involvement, 0 of 9 B-NHL without bone marrow involvement, 9 of 9 low grade B-NHL (immunocytoma and including chronic lymphocytic leucemia), 13 of 19 MM, 2 of 9 MGUS, and 0 of 3 PG. Additional monoclonality was detected with nested CDR I PCR in 1 pro-B-ALL, 1 c-ALL, and 2 MM. CDR III IgH PCR has been confirmed as an efficient method for determining clonality in B-cell neoplasias. Some additional monoclonal products can be seen with CDR I-based PCR. Detection of monoclonality depends on the maturation grade of the neoplastic B-cell population.

[Angiocentric T-cell lymphoma of the lung]. / A tüdö angiocentrikus t-sejtes lymphomája.

Angiocentric T-cell lymphoma of the lung. The case history of a patient with primary angiocentric T-cell lymphoma of the lung having an unusually long survival period (> 10 years) is presented. Attention is paid to the possibilities of differential diagnosis that should be taken into account in the analysis of certain lymphocytic infiltrates of the lung. In accordance with relevant data of the literature, this case shows that pleiomorphic small cell T-lymphomas may have a protracted course, and the disease free periods repeatedly achieved in this patient by irradiation and chemotherapy are thought to be noticeable. Authors refer to some recent findings which may give new insights in the pathobiology of extranodal T-cell lymphomas, and result in recognition of new disease entities.

Ultrasonographic findings in a basenji with immuno-proliferative enteropathy.

The ultrasonographic findings in a one-and-a-half-year-old female basenji with immunoproliferative enteropathy are described. On ultrasonographic examination, generalised thickening of the small bowel wall was found, ranging between 4 and 6 mm. The normal layered appearance of the intestinal wall was replaced by three distinct layers; an innermost enlarged hyperechogenic layer; an enlarged poor echogenic layer, and an outer hyperechogenic layer. These findings are consistent with the histopathological appearance of this particular chronic inflammatory bowel disease, since the inner layer probably represents the infiltrated mucosa, the middle layer the infiltrated lamina propria and the outer layer the serosa. Thus, the ultrasonographic finding of generalised thickening of the intestinal wall in a basenji presenting with chronic diarrhoea, weight loss, anorexia or vomiting is strongly indicative of immunoproliferative enteropathy.

Spindle cell tumor of lymph node of probable reticulum cell origin associated with multiclonal gammopathy.

We describe a case of a 48 year old man who presented repeatedly with a neck lymph node tumor. The tumor grew insidiously over 11 years and the patient died at the age of 58 with the generalization of the tumor into the right cervical, paratracheal lymph nodes and spleen. The tumor was composed of spindle shaped cells with occasional intranuclear cytoplasmic pseudoinclusion. At the ultrastructural level the tumor revealed membrane bound crystalline inclusions, which were locally in direct contact with both the nuclear envelope and confronting cisternae of the endoplasmic reticulum. The tumor was associated with multiclonal gammopathy composed of two subsets of IgG/lambda and one subset of IgA/lambda positive paraprotein produced by lymphoid cells surrounding the tumor. We diagnosed the tumor as "spindle cell tumor of lymph node of probable reticulum cell origin associated with multiclonal gammopathy" and consider the lymphoid tissue producing the paraprotein to be reactive.

Angiocentric immunoproliferative lesion associated with chronic active Epstein-Barr virus infection in an 11-year-old boy. Clonotopic proliferation of Epstein-Barr virus-bearing CD4+ T lymphocytes.

We report a pulmonary angiocentric immunoproliferative lesion (AIL) in an 11-year-old boy with chronic active Epstein-Barr virus (EBV) infection. The phenotypes of the proliferating lymphoid cells in the biopsied pulmonary lesion were CD2+, CD3+, CD4+, CD5+, CD7+, and HLA-DR+. EBV DNA was detected in the tumorous and the nontumorous tissue by Southern-blotting studies. Dual immunostains and combined immunohistochemistry/in situ hybridization showed the simultaneous presence of EBV-determined nuclear antigen or EBV-encoded small RNAs and T-cell markers in the lymphoid cells. Molecular genetic analysis of the tumorous lesion diagnosed as AIL grade III showed no clonal rearrangement of the T-cell receptor beta gene but a single type of fused terminal band of EBV. No such evidence of monoclonality was identified in the surrounding nontumorous tissue diagnosed as AIL grade I or II. The present case was a rare example of AIL in childhood and provides further histopathologic and molecular biological evidence supporting the concept of AIL as a continuous spectrum from premalignant lymphoproliferative disorders to monoclonal, overt malignant lymphoma.