Uterine leiomyoma with prominent lymphoid infiltrate.

We present a case of a 35-year-old woman whose myomectomy specimen revealed a leiomyoma nodule diffusely infiltrated by lymphocytes which were shown to be clonal in nature. Lymphoid infiltration of leiomyomas is a rare occurrence, and this is the first case with molecular analysis.

Isolated metastasis of malignant melanoma into follicular carcinoma of the thyroid gland.

A 38-yr-old woman with a history of malignant melanoma (MM) presented with a thyroidal nodule. Fine needle aspiration biopsy of the thyroid was consistent with metastatic MM. The patient underwent thyroidectomy: microscopic examination revealed a follicular carcinoma nodule harboring a focus of metastatic melanoma. On review of the fine needle aspiration biopsy specimen, the population of cells with more uniform nuclei with focal follicle formation, which initially was interpreted as cells originating from normal thyroid tissue, was seen to actually represent the follicular carcinoma component. Tumor-to-tumor metastasis is an interesting phenomenon and there are only few cases of MM metastasis to other tumors. MM metastasis into a neoplastic thyroid nodule is a very rare combination and may be explained because the nodule in question represents the most highly vascularized component of the thyroid.

Coincidental detection of T-cell rich B cell lymphoma in the para-aortic lymph nodes of a woman undergoing lymph node dissection for cervical cancer: a case report.

The diagnosis of cervical squamous cell carcinoma with concurrent T-cell rich B cell lymphoma in dissected lymph nodes has not been reported to our knowledge. In our case, the biopsy of an exophytic lesion at the uterine cervix showed squamous cell carcinoma in a 50-year-old woman presenting with postcoital bleeding. Type III hysterectomy, bilateral salpingo-oophorectemy, bilateral pelvic, para-aortic lymph node dissections were performed. Pathologic examination revealed a T-cell rich B cell lymphoma in some lymph nodes beside squamous cell carcinoma in several of others. ELISA for human immuno-deficiency virus (HIV) was negative. The cervical carcinoma was staged as FIGO clinical stage IB1 and the lymphoma as Ann Arbor IIA. Six cycles of CHOP (cyclophosphamide, adriamycin, vincristine, and prednisolon) chemotherapy for the lymphoma and concomitant pelvic chemoradiotherapy with cisplatin for cervical cancer were given. In this rare coincidence, the best available therapy for each of the diseases should be considered individually. We also suggest that HIV screennig test be carried out, because both diseases may be related to human immuno-deficiency virus, although our patient is HIV-negative.

Coincidental detection of T-cell rich B-cell lymphoma in the paraaortic lymph nodes of a woman undergoing lymph node dissection for cervical cancer.

The diagnosis of cervical squamous cell carcinoma with concurrent T-cell rich B-cell lymphoma in dissected lymph nodes has not been reported to our knowledge. We report such a case. The biopsy of an exophytic lesion at the uterine cervix showed squamous cell carcinoma in a 50-year-old woman presenting with postcoital bleeding. Type III hysterectomy, bilateral salpingo-oophorectemy, bilateral pelvic, paraaortic lymph node dissections were performed. Pathologic examination revealed a T-cell rich B-cell lymphoma in some lymph nodes beside squamous cell carcinoma in several of others. ELISA for human immuno-deficiency virus (HIV) was negative. The cervical carcinoma was staged as FIGO clinical stage IB1 and the lymphoma as Ann Arbor IIA. Six cycles of CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone) chemotherapy for the lymphoma and concomitant pelvic chemo-radiotherapy with cisplatin for cervical cancer were given. In this rare coincidence; the best available therapy for each of the diseases should be considered individually. We also suggest that HIV screening test be carried out, because both diseases may be related to human immuno-deficiency virus, although our patient was HIV-negative.

Myasthenia gravis and lymphoblastic lymphoma involving the thymus: a rare association.

Myasthenia gravis (MG) is an autoimmune neuromuscular junction disease. An association between thymic epithelial neoplasms and MG is well known. However, it is rarely associated with hematologic malignancies. In particular, very few cases of lymphoblastic lymphoma involving the thymus and MG have been reported. Here we report a case T-cell lymphoblastic lymphoma involving the thymus who developed MG after the initial diagnosis. The patient initially presented with a mediastinal mass which was diagnosed as lymphoblastic lymphoma. MG was diagnosed during leukemic relapse in this patient and was based on clinical presentation and neurophysiologic studies including single fiber electromyography (EMG) and repetitive nerve stimulation tests. In contrast to the other cases with such an association, the myasthenic symptoms presented nine months after the diagnosis of lymphoma by thymectomy. The patient had a highly aggressive clinical course and was resistant to various chemotherapy regimens.

CD56+ lymphoma presenting as a testicular tumor.

A case of an unusual lymphoma type, CD56 (+) T/NK lymphoma, presenting as a testicular tumor is described. A 35 year old man who presented with right testicular swelling, underwent right inguinal orchiectomy, with a presumptive diagnosis of abscess or malignancy. Histopathology showed a diffuse mixed large and small cell lymphoma with a focal angiocentric growth pattern. Immunohistochemically CD45RO and CD56 were found to be positive in the neoplastic cells. In situ hybridization assay for EBV showed the presence of EBV related small ribonucleic acid sequences (EBER) within the tumor cells. Despite systemic chemotherapy, the patient had an aggressive clinical course with two skin and left testicular recurrences in the first year of his disease.

Characteristics of auto anti-idiotypic antibodies reactive with antibodies expressing the pathogenic idiotype, IdLNF1, in the (NZB x SWR)F1 model for lupus nephritis and its parental strains.

The F1 cross between SWR and NZB mice, SNF1, develops severe immune complex glomerulonephritis, in a similar manner to humans with systemic lupus erythematosus (SLE). Our previous data indicate that the idiotypically-related family of antibodies, IdLNF1 may play a role in the pathogenesis of this nephritis. The sera of SNF1 mice, but not NZB or SWR, contained high titers of IdLNF1+ IgG antibodies, which peaked at 22-24 weeks, coinciding with an increase in the CD4 to CD8 ratio of IdLNF1-reactive T cells and IdLNF1 Ig (IgG + IgM) deposition in the kidney glomerulus. Here, auto anti-IdLNF1 antibody levels were quantitated as the mice aged and were found to be significantly different in the three strains, particularly after 20 weeks of age. Moreover, auto anti-IdLNF1 antibody levels were decreased only in SNF1 mice at 20-24 weeks of age. Auto anti-IdLNF1 antibodies were purified by affinity chromatography; anti-IdLNF1 antibodies derived from SNF1 appeared to be of the Ab2 beta or gamma type, while those from SWR mice were Ab2 alpha. Thus, differences in the specificity of auto anti-idiotypic antibodies may be critical in the regulation of the IdLNF1 idiotype in SWR and SNF1 mice, and the development of nephritis in SNF1 mice.

Large granular lymphocyte leukaemia occurring after renal transplantation.

Post-transplantation lymphoproliferative disorders (PTLD) are a clinicopathologically heterogeneous group of lymphoid proliferations. The majority are of B-cell origin and associated with Epstein-Barr virus (EBV) infection. In contrast, the development of T-cell PTLD is much less common and EBV does not appear to be involved in pathogenesis. In this report we describe three patients who developed large granular lymphocyte (LGL) leukaemia after renal transplantation. These patients had clonal expansion of CD3+, CD8+, CD57+, CD56- LGL. We were unable to detect CMV antigen or find evidence for EBV or human T-cell leukaemia/lymphoma virus genome in the LGL from these patients. These data show that LGL leukaemia should be included as one of the types of T-cell proliferations which can occur post transplant.

Bronchiolitis obliterans-organizing pneumonia (BOOP)-like variant of Wegener's granulomatosis. A clinicopathologic study of 16 cases.

The classic histologic features of Wegener's granulomatosis (WG) in lung include necrotizing granulomatous inflammation and necrotizing vasculitis. Recently, several histologic variants have been recognized, including cases characterized by bronchocentric inflammation, a marked eosinophil infiltrate, alveolar hemorrhage, and capillaritis or interstitial fibrosis. We report 16 cases of another variant in which bronchiolitis obliterans-organizing pneumonia (BOOP)-like fibrosis represents the main histologic finding. The extensive geographic necrosis characteristic of Wegener's granulomatosis was absent in all cases, although small suppurative granulomas, minute foci of bland necrosis, and microabscesses were common. All cases showed the typical necrotizing vasculitis of Wegener's granulomatosis. Other frequent findings included darkly staining multinucleated giant cells, prominent acute inflammation, aggregates of epithelioid histiocytes, hemosiderin-filled macrophages, and areas of nonspecific parenchymal fibrosis. The clinical and radiographic features of this variant of Wegener's granulomatosis appear to be indistinguishable from the classic type. Pathologists need to be aware that Wegener's granulomatosis can occasionally manifest histologic changes suggestive of BOOP. The diagnosis will not be overlooked if additional features, especially vasculitis, suppurative granulomas, tiny necrotic zones, microabscesses, and multinucleated giant cells, are appreciated.

IdLNF1-specific T cell clones accelerate the production of IdLNF1 + IgG and nephritis in SNF1 mice.

We have shown that antibodies bearing a nephritogenic idiotype (IdLNF1) are important in the pathogenesis of autoimmune glomerulonephritis in the (NZB x SWR)F1 hybrid, SNF1. A significant shift in the ratio of CD4+ to CD8+ IdLNF1-specific T lymphocytes, in favour of CD4+ IdLNF1-specific T cells, occurred at 22-24 weeks of age in the SNF1 and correlated with an increase in serum IdLNF1 + IgG and its deposition in the kidney. Recently, we reported the characteristics of six IdLNF1-specific T cell clones (CD3+CD4+CD8-V beta 17a+) derived from 22-week-old SNF1 mice which proliferated in response to IdLNF1 + Ig and augmented IdLNF1 + IgG production when mixed with SNF1 B cells in vitro. No increase in the production of anti-DNA antibodies was seen. Here we report results of the adoptive transfer of three of these clones, A1, B6 and D2, into 6-8-week-old SNF1 mice. Serum immunoglobulin (Ig) (IgG and IgM) levels did not differ from those of age-matched unmanipulated SNF1 up to and including 35 days post-injection. Similarly, total IdLNF1 + Ig levels did not vary significantly among the groups until 28 days post-injection. However, elevated levels of IdLNF1 + IgG were observed as early as 7 days post-injection in mice receiving clone B6 and 21 days post-injection in mice receiving clone D2. This was in sharp contrast with the results obtained in mice treated with clone A1 or unmanipulated SNF1 mice, which did not express IdLNF1 + IgG during this period. Digital image analysis of the kidney glomeruli of mice receiving T cell clones B6 or D2 demonstrated a significantly (P < 0.05) higher level of IdLNF1 + Ig deposition and glomerulonephritis than age-matched unmanipulated SNF1 mice or mice which had received clone A1. Interestingly, there was no statistically significant difference in the production of anti-ssDNA or dsDNA antibodies with the treatments. Mean survival for mice treated with T cell clones B6 and D2 was significantly (P < or = 1 x 10(-6)) shorter compared to unmanipulated SNF1 mice, while that of mice which had received T cell clone A1 was significantly (P < or = 3 x 10(-6)) longer, as determined by chi-squared analysis. The overall survival of mice treated with clones B6 and D2 did not differ from that of unmanipulated mice; however, mice treated with clone A1 survived significantly (P < or = 0.05) longer.(ABSTRACT TRUNCATED AT 400 WORDS)

CD3+, CD56+ aggressive variant of large granular lymphocyte leukemia.

Clonal expansions of CD3+ large granular lymphocytes (LGL) have been classified as T-LGL leukemia. The majority of patients with T-LGL leukemia have a chronic disease (years) manifested often by severe neutropenia, rheumatoid arthritis, and mild-to-moderate splenomegaly. The characteristic phenotype of the leukemic LGL is CD3+, CD8+, CD16+, CD57+, and CD56-. In this report we describe an aggressive variant of T-LGL leukemia in which leukemic LGL also expressed CD56, as identified by two-color flow-cytometry analysis. In contrast to the chronic nature typical of T-LGL leukemia, these patients presented with a severe systemic illness that was rapidly progressive and resistant to treatment. Atypical clinical features included rapidly increasing spleen size to massive proportions, extensive lymphadenopathy, and the presence of B symptoms (fever, nightsweats, weight loss). Hematologic and pathologic features were also unusual for T-LGL leukemia. These patients had very high LGL counts at diagnosis (range 11,692 to 26,312 microL), which increased rapidly despite treatment. Histopathologic examination of splenic sections showed extensive infiltration of red pulp cords and sinuses by leukemic cells with atrophy of the white pulp. These clinicopathologic features are similar to those described for patients with natural killer cell (NK)-LGL leukemia, whose cells are also CD56+. However, unlike NK-LGL leukemia, we could not show a direct pathogenic role for Epstein-Barr virus (EBV), as Southern-blot analyses using an EBV-joined termini probe were negative in these patients. Our findings suggest that CD3+, CD56+ LGL leukemia is a distinct clinicopathologic entity separate from the usual CD3+, CD56- T-LGL leukemia. The expression on leukemic LGL of CD56, an adhesion molecule, may determine the aggressive biologic nature of this newly described disease.

Applications of in situ hybridization in the study of hematologic malignancies.

In situ hybridization is a molecular technique that can be useful in the study of hematologic malignancies. Thus far, the most extensive uses have been in the detection of viral sequences and in the detection of chromosomal alterations. Other applications such as the identification of various cellular gene products are more limited, but with improvements in the sensitivity and reliability of methods for ISH, their use will become more widespread. Information provided by ISH contributes to our understanding of the pathophysiology and etiology of hematologic malignancies. In the future, ISH may be used routinely in the evaluation of leukemias and lymphomas.

Treatment with antibody reactive with the nephritogenic idiotype, IdLNF1, suppresses its production and leads to prolonged survival of (NZB x SWR)F1 mice.

The F1 progeny of the cross between SWR and NZB mice (SNF1) develop severe immune complex glomerulonephritis, similar to that seen in human SLE. An idiotypically-related family of nephritic antibodies (IdLNF1) has been shown to be important in the pathogenesis of autoimmune glomerulonephritis in these mice. Interestingly, the majority of IdLNF1+ antibodies do not bind DNA. Here, we sought to examine whether regulation of the expression of this idiotype was important in the development of lupus nephritis and to identify the mechanisms regulating its expression. In the present study, biweekly injections of SNF1 mice with 100 micrograms of rabbit anti-IdLNF1 antibodies, beginning at 8 to 10 weeks of age, resulted in significant P < or = 0.05) suppression of IdLNF1+ Ig(G+M) and IgG production. The decrease appeared to be mediated via significant (P < or = 0.05) decreases in the percentage of IdLNF1-expressing B cells and CD4+ IdLNF1-specific T cells in the treated SNF1 mice compared to the controls. This was accompanied by a significant (P < or = 0.005) increase in survival with delayed onset of glomerulonephritis. Surprisingly, there was no difference in the incidence of anti-DNA antibody production between the treated and control SNF1 mice. These results support the hypothesis that dysregulation of pathogenic idiotypes, not confined to anti-DNA antibody idiotypes as had been shown in previous studies, may contribute to the development of SLE.

Characterization of IdLNF1-specific T cell clones from the (NZB x SWR)F1 murine model for systemic lupus erythematosus.

A family of nephritogenic antibodies bearing an idiotype, IdLNF1, has been shown to be important in the pathogenesis of autoimmune glomerulonephritis in the (NZB x SWR)F1 hybrid, SNF1. Previously, we have reported that a significant shift in the ratio of CD4+ to CD8+ IdLNF1-specific T lymphocytes, in favor of CD4+ IdLNF1-specific T cells, occurred at 20 to 24 weeks of age in the SNF1 and correlated with an increase in serum IdLNF1+ IgG and deposition of IdLNF1 Ig in the kidney glomeruli. Six IdLNF1-specific CD3+CD4+CD8- T cells clones have been derived from 22-week-old SNF1 mice. All six proliferated in response to Con A and anti-CD3. Three of the clones reacted with monoclonal antibody for V beta 8.1,8.2: B3, B5, and TA5 and proliferated specifically in response to IdLNF1 Ig in an Ia-restricted manner. The other three clones, A1, B6, and D2, reacted with anti-V beta 17a+ monoclonal antibody and appeared to be not Ia-restricted. T cell clones B6, D2, and TA5 promoted the production of very high levels of IdLNF1+ IgG by SNF1 B cells in vitro, while B3 and B5 induced the production of only low levels. Interestingly, clone A1 did not induce any IdLNF1+ Ig production. Furthermore, these T cell clones did not induce the production of anti-DNA antibody by SNF1 B cells.

The onset of nephritis in the (NZB x SWR)F1 murine model for systemic lupus erythematosus correlates with an increase in the ratio of CD4 to CD8 T lymphocytes specific for the nephritogenic idiotype (IdLNF1).

An idiotypically related family of nephritogenic antibodies (IdLNF1) has been shown to be important in the pathogenesis of autoimmune glomerulonephritis in the (NZB x SWR)F1 hybrid, SNF1. Idiotype-specific T lymphocytes which modulate expression of antibody bearing that idiotype may be important in the pathogenesis of systemic lupus erythematosus (SLE). Here, IdLNF1-reactive T lymphocytes were not only found to be present in the NZB, SWR, and SNF1, but a significantly (P < or = 0.05) greater number of IdLNF1-reactive Thy 1.2+ splenic lymphocytes were observed as early as 12 weeks of age in the SNF1. Further, a significant shift in the ratio of CD4+ to CD8+ IdLNF1-reactive T lymphocytes in favor of CD4+ IdLNF1-reactive T cells was observed at 20 to 24 weeks of age only in the SNF1. This shift correlated with an increase in IdLNF1+IgG, and deposition of IdLNF1 bearing immunoglobulin in the kidney glomeruli. These observations suggest a role for idiotype-specific T lymphocytes in the induction of glomerulonephritis in this murine model of SLE.