Bilateral testicular infarction and orchiectomy as a complication of polyarteritis nodosa

We report an unusual case of a 28-year-old male with constitutional symptoms and bilateral testicular pain. After diagnosis of cytomegalovirus (CMV) hepatitis, his constitutional symptoms and testicular pain worsened despite treatment for epididymoorchitis. Ultrasound was concerning for infarction. Exploration in the operating room revealed bilateral testicular infarction requiring bilateral orchiectomy with subsequent androgen hormone replacement. Pathologic diagnosis was polyarteritis nodosa (PAN). PAN is a rare systemic vasculitis that affects multiple organs. There are no previous reports of PAN-induced vasculitis leading to bilateral testicular infarction and bilateral orchiectomy.     

Pancreaticoduodenal arterial rupture and hemoabdomen in ACI/SegHsd rats with polyarteritis nodosa

Many lesions associated with aging have been well-characterized in various strains of rats. Although documented in Sprague-Dawley and spontaneously hypertensive rats, polyarteritis nodosa has not previously been reported in ACI/SegHsd rats. ACII SegHsd rats were maintained on high-fat (40.5%), low-fat (11.6%), and high-fat to low-fat dietary protocols to examine the correlation between dietary fat and the regulation of prostate 5alpha-reductase gene expression and prostate cancer. Seven rats died unexpectedly with hemoabdomen and rupture of the pancreaticoduodenal artery secondary to polyarteritis nodosa (PAN). The purpose of this study was to analyze the pathologic findings in these and the remaining ACI/SegHsd rats and to correlate the level of dietary fat with the presence of PAN, arterial rupture, and hemoabdomen. Approximately 65% of the rats had evidence of PAN by histopathology, with a 24% incidence of arterial rupture. Additional lesions noted included an 88% incidence of chronic progressive nephropathy (CPN) and a 32% incidence of cartilaginous foci in the aortic valve. We found no association between the percentage of dietary fat and incidence of PAN, CPN, or cardiac cartilage. Although arterial rupture is a known complication of polyarteritis nodosa in humans, this case series is the first to document arterial rupture and hemoabdomen in rats with PAN.     

Analysis of vascular lesions in murine SLE. I. Association with serologic abnormalities

In murine SLE, two different vascular lesions can develop. A necrotizing polyarteritis (NPA), exclusively found in MRL/I mice, is characterized by a dense infiltration of PMN and fibrinoid necrosis of the arterial wall. The second, a degenerative vascular lesion, occurs in a low incidence in all SLE mice, except the (NZW X BXSB)F1 (WBF1) male, in which its incidence is 100%. This lesion shows subendothelial deposits of immunoglobulins with minimal or no inflammatory or proliferative reaction. This degenerative vascular disease (DVD) is predominantly localized in the coronary arteries and is highly correlated with myocardial infarction. Serologic analysis revealed that NPA in MRL/I mice was associated with relatively late development of high levels of autoantibodies and circulating immune complexes; DVD in WBF1 mice was associated with an early onset of autoantibody production of a low magnitude that gave rise to a persistent low level of circulating immune complexes. Characterization of circulating immune complexes in MRL/I mice showed these complexes were mainly of intermediate size (7S-19S) and contained predominantly anti-DNA antibodies. In WBF1 mice, complexes were barely detectable and contained mostly anti-gp70 antibodies. Elution of kidneys showed that the major antibody deposited in MRL/I mice has an anti-DNA specificity, whereas in WBF1 animals, the major antibody was anti-gp70. Furthermore, a 10 times greater amount of immunoglobulins could be eluted from WBF1 hearts with DVD than from MRL/I and BXSB hearts. Additionally, we found that the lack of an inflammatory reaction in DVD was not because of a preferential deposition of noncomplement-fixing IgG1 antibodies nor could it be related to a defective inflammatory response, because WBF1 mice had an undiminished reverse passive Arthus reaction throughout their lives. It is concluded that NPA develops secondary to high levels of autoantibodies with a concomitant rise in immune complexes, whereas DVD is associated with sustained low levels of circulating immune complexes.     

Identification of HBsAg determinants in immune complexes from hepatitis B virus-associated vasculitis

Circulating immune complexes were characterized from 25 sera obtained from five patients with polyarteritis nodosa and three with cutaneous venulitis associated with hepatitis B virus infection. Complexes were isolated by polyethylene glycol and conglutinin-anticonglutinin precipitation methods and were analyzed for HBsAg and anti-HBsAg. Low pH was used to dissociate the complexes, and components were separated into antigen and antibody fractions by using immobilized protein A. In this study, three observations were significant: 1) complexes were frequent and quantitatively more in cutaneous venulitis than in polyarteritis; 2) the levels of HBsAg in the antigen fractions of polyarteritis were greater and correlated with the clinical improvement of the disease; the serum levels of HbsAg remained the same throughout the course of the disease; and 3) complexes from polyarteritis were not completely dissociable at pH 2.6 compared with those from patients with cutaneous venulitis and chronic active hepatitis. The antigen fractions electrophoresed in polyacrylamide gel with SDS demonstrated 6 to 10 protein bands with m.w. ranging between 17,000 and 120,000 daltons. To precisely define the polypeptide antigen moiety involved in the immune complex formation, a transfer blotting technique was used employing human anti-HBsAg globulin as probe. Polypeptides with m.w. 97,000, 49,000, and 23,000 were found to form complexes in both groups of patients.     

Detection of the G17V RHOA Mutation in Angioimmunoblastic T-Cell Lymphoma and Related Lymphomas Using Quantitative Allele-Specific PCR

Angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) are subtypes of T-cell lymphoma. Due to low tumor cell content and substantial reactive cell infiltration, these lymphomas are sometimes mistaken for other types of lymphomas or even non-neoplastic diseases. In addition, a significant proportion of PTCL-NOS cases reportedly exhibit features of AITL (AITL-like PTCL-NOS). Thus disagreement is common in distinguishing between AITL and PTCL-NOS. Using whole-exome and subsequent targeted sequencing, we recently identified G17V RHOA mutations in 60–70% of AITL and AITL-like PTCL-NOS cases but not in other hematologic cancers, including other T-cell malignancies. Here, we establish a sensitive detection method for the G17V RHOA mutation using a quantitative allele-specific polymerase chain reaction (qAS-PCR) assay. Mutated allele frequencies deduced from this approach were highly correlated with those determined by deep sequencing. This method could serve as a novel diagnostic tool for 60–70% of AITL and AITL-like PTCL-NOS.     

Circulating CD4+ T lymphocytes with intracellular but no surface CD3 antigen in five of seven patients consecutively diagnosed with angioimmunoblastic T-cell lymphoma

Angioimmunoblastic T-cell lymphoma (AITL) accounts for less than 1% of all lymphatic malignancies. Oligoclonality or monoclonality for any of the T-cell receptor (TCR) chain genes can be demonstrated in the majority of the cases. During systematic screening for the presence of circulating lymphocytes with atypical coexpression of differentiation antigens in patients with T-cell lymphomas, we have discovered a minor population (accounting for 0.2% to 10.% of all lymphocytes) of atypical lymphocytes in the blood of five of seven patients consecutively diagnosed in 1997/1998 by lymph node histology to have AITL. The major distinguishing feature of these cells consists of the lack of the surface expression of the CD3 antigen, but not of the intracellular expression. These cells express the T-cell antigens CD2 and CD5 on their surface, but not CD7, and they express CD4 and CD45 at numbers of molecules per cell typical for T lymphocytes. Gene scan analyses for the TCR gamma chain revealed oligoclonality of these flow-sorted cells in one patient and monoclonality in two patients, the same patterns of TCR gamma chain gene as determined processing the respective diagnostic lymph nodes. Circulating CD4-expressing T lymphocytes with exclusively cytoplasmic expression of CD3 appear to represent the malignant population in patients with histologically diagnosed AITL.     

Spontaneous retroperitoneal hemorrhage caused by segmental arterial mediolysis

Spontaneous retroperitoneal hemorrhage is a rare clinical entity; signs and symptoms include pain, hematuria, and shock. Spontaneous retroperitoneal hemorrhage can be caused by tumors, such as renal cell carcinoma and angiomyolipoma; polyarteritis nodosa; and nephritis. The least common cause is segmental arterial mediolysis. Although computed tomography is used for the diagnosis of spontaneous retroperitoneal hemorrhage, it can miss segmental arterial mediolysis as the cause of the hemorrhage. The diagnosis of segmental arterial mediolysis as a cause of spontaneous retroperitoneal hemorrhage requires angiography, with pathologic confirmation for a definitive diagnosis.     

Islet cell antibodies, circulating immune complexes and antinuclear antibodies in diabetes mellitus

Serum samples of patients suffering from diabetes mellitus were tested for complement-fixing and non complement-fixing islet cell antibodies, antinuclear antibodies and circulating immune complexes. There was no correlation between circulating immune complexes or antinuclear antibodies and secondary diabetic complications. A close relationship was found between the ICA titer and complement fixation of ICA. The incidence of ICA at the onset of the disease was higher in the patients under the age of 10 (85%) and decreased with increasing age up to 45% in patients with onset above age 20. In five patients being positive and four patients being negative for ICA at onset of disease, changes and fluctuations in antibody titers were observed over 38 months. Since manifestation of diabetes mellitus is believed to be an endpoint of a long lasting autoimmune process, our observations indicate that the autoimmune phenomena are merely indicators of ongoing autoimmune reactions not necessarily reflecting the state of autoaggression or islet cell destruction.     

Non-Hodgkin¿s Lymphoma of the synovium discovered in total knee arthroplasty: a case report

ABSTRACT: BACKGROUND: Musculoskeletal involvement occurs in 25% of patients with non-Hodgkin's lymphoma (NHL). Primary lymphoma in the joint is rare. It can present as a bone lesion or as atypical soft tissue proliferation. NHL has an increased incidence in patients with autoimmune rheumatic diseases. CASE PRESENTATION: We present a case in which non-Hodgkin's lymphoma was found coincidentally in the synovium during knee joint replacement surgery in a 69-year old woman with rheumatoid arthritis. Pigmented, vitreous tissue was resected, which turned out to be a diffuse large B-cell lymphoma after histological examination. The coincidental intraoperative finding of intra-articular non-Hodgkin's lymphoma was reported twice before, presenting as synovial proliferation in elbow and shoulder surgery. In a few other cases non-Hodgkin's lymphoma presented most often in the knee, as a bone lesion or, when soft tissue was involved, as arthritis. CONCLUSION: Non-Hodgkin's lymphoma should be considered in patients with autoimmune rheumatic diseases. In case of persistent arthritis, non-respondent to anti-inflammatory drugs, a biopsy might be warranted. Moreover, when arthroscopy or arthrotomy is planned, any atypical tissue should be sent for histological analysis. Early diagnosis of NHL can contribute to improved outcome of its rapidly developing treatment options.     

Expression of the significance of silent information regulator type-1 in Angioimmunoblastic T-cell lymphoma is greater association with tumorigenesis and has strong implications for adverse prognosis

Silent information regulator type-1 (SIRT1) is the best-studied member of the Sirtuin (Sir2) family of nicotinamide dinucleotide (NAD)-dependent class III histone deacetylases (HDACs). Rrecently, it is suggested that SIRT1 may be involved in the development of malignant tumors including mouse lymphoma, but has not yet been explored in Angioimmunoblastic T-cell lymphoma (AITL). Therefore, we investigated the prevalence and the prognostic impact of SIRT1 expression in AITL. Immunohistochemical expression of SIRT1, p53 were evaluated by using a 2 mm core from 45 AITL patients. Positive expression of SIRT1 was seen in 71.11% (32 of 45) of patients and p53 expression were seen in 53.33% (24 of 45). SIRT1 and p53 expression were significantly associated with shorter PFS by univariate analysis (P=0.009 and P < 0.001, respectively), multivariate analysis also shows that SIRT1 expression relate to worse prognosis. We also suggest inferior survival in AITL with the combined expression of SIRT1 and clinical characteristics of high IPI scores, high clinical stage, increased serum LDH, decreased HGB and increased γ-Globulin. In conclusion, our results indicate that SIRT1 is strongly expressed in AITL and it act as a clinically significant prognostic indicator for AITL patients, may also serve as a therapeutic target in AITL.     

Renal sinus pseudolymphoma in a patient with multiple carcinomas: a case report and a brief review of the literature

The term pseudolymphoma refers to a heterogeneous group of benign reactive T-cell or B-cell lymphoproliferative processes of diverse causes that simulate lymphoma clinically and histologically but usually undergo spontaneous remission. Its pathogenesis is still unclear. The prognosis is good although some evidence suggests that pseudolymphoma may progress to lymphoma. Pseudolymphoma of the urinary tract is extremely rare. We herein report a case of pseudolymphoma of the renal sinus in a 70-year-old man, associated with a high grade urothelial carcinoma of the bladder and to a prostatic adenocarcinoma (Gleason score 6). A brief review of the literature is included. The kidney showed a well-defined, whitish soft mass which involved the renal sinus. Microscopically, the lesion of the renal sinus consisted of a proliferation of small to medium size lymphocytes (CD20 positive and Bcl-2 negative) sometimes arranged in hyperplastic follicular structures. The diagnosis was confirmed by molecular studies which showed an oligopolyclonal IgH rearrangement. To the best of our knowledge, this is the second case of pseudolymphoma with a complete molecular characterization ever described in the renal sinus and the first one associated with multiple urogenital carcinomas.     

Epstein-Barr virus-associated lymphoproliferative disorders

Epstein-Barr virus (EBV) is a ubiquitous member of the herpesvirus family that is associated with a variety of lymphomas and lymphoproliferative diseases. It encodes a multitude of genes that drive proliferation or confer resistance to cell death. Among these are two key viral proteins which mimic the effects of the activated cellular signaling proteins. EBV-associated lymphomas include Burkitt's lymphoma; natural killer (NK)/T-cell lymphoma, lymphoma and lymphoproliferative diseases in immunocompromized populations, and Hodgkin's lymphoma. The character of the viral association differs among these entities with some consistently associated with EBV in all populations and all parts of the world, and others associated with the virus only in particular circumstances. An example of the former is nasal NK/T-cell lymphoma, while an example of the latter is Burkitt's lymphoma. The pattern of viral gene expression also varies among tumor types with different viral genes playing key roles in different tumors and conferring sensitivity to immune surveillance. Thus some of the post-transplant lymphoproliferative diseases are exquisitely sensitive to CD8 T-cell immunosurveillance, while other tumors such as Burkitt's lymphoma may be nearly impervious to such surveillance. Knowledge of the EBV association is not only important for understanding the pathogenesis of these tumors, but is increasingly important for diagnosis, monitoring and treatment.     

Antineutrophil cytoplasmic autoantibody in renal disease

ANCA are an important marker for identifying pauci-immune necrotizing and crescentic glomerulonephritis and systemic vasculitis. Patients with ANCA-associated renal disease have a spectrum of illness ranging from renal-limited disease to widespread vasculitis, including the clinicopathologic syndromes of polyarteritis nodosa and Wegener's granulomatosis. ANCA may be directly involved in the pathogenesis of pauci-immune glomerulonephritis and necrotizing systemic vasculitis.     

Elimination of immune complex deposits from the kidneys of autoimmune NZB/N mice administered a xeno-spleen perfusate

54 autoimmune NZB/N mice, 6 and 10 months of age, were intravenously injected 0.2 ml solution prepared during perfusion of the isolated sheep spleen with a buffer solution. Perfusion solution was injected 8 times with 2-3-day intervals. The control group of 43 mice received intravenously 0.2 ml of a buffer solution in the similar manner. After the treatment the levels of anti-DNA antibodies and circulating immune complexes were significantly decreased in the sera of mice which received the perfusion solution, as compared with the levels of control groups. Immunofluorescent studies showed a marked decrease in the number of glomerular immune complexes deposits in mice treated with perfusion solution. Six- and ten-month old mice exhibited a similar effect. The perfusion solution may be capable of eliminating the immune complexes from the blood and kidneys of autoimmune mice.     

Immunologic reconstitution, autoimmunity, and T-cell immune deficiencies.

A 17-month-old female with combined immunodeficiency, a proliferative response to allogeneic cells in MLC, and circulating B lymphocytes (50%, all with surface immunoglobulin M) was treated with transfer factor (TF). After six doses of transfer factor, serum levels of IgG increased from 234 mg/dl to 1071 mg/dl and a lymphocyte proliferative response was detected to pokeweed mitogen. However, no change in T-cell function was observed. Clinically, she did well, but after the eighth dose of transfer factor, she developed the nephrotic syndrome. Renal biopsy suggested immune complex glomerulonephritis. Subsequently following treatment for Pneumocystis carinii, a 20-day cultured thymus was transplanted intraperitoneally. Two weeks after thymus transplant, the patient started to develop delayed skin reactivity and in vitro mitogen responsiveness. Six weeks posttransplant, the PHA and pokeweed mitogen responses were approximately 60% of normal, but the Concanavalin A response had disappeared. Subsequently she developed a Coombs positive hemolytic anemia, a cutaneous vasculitis, and thrombocytopenia. There was no evidence of GVH disease. Multiple autoimmune manifestations developed in association with transfer factor therapy and transplantation of cultured thymus tissue. T-Cell deficiencies are predisposed to autoimmune diseases because of imbalances of regulatory T-cell function. These imbalances of regulatory T-cell function may occur especially following partial immune reconstitution. The changes in B-cell function during transfer factor therapy may have resulted from enhanced T-cell-B-cell interaction. This immunopotentiation effect of transfer factor together with partial T-cell reconstitution may have led to B-cell hyperresponsiveness and autoimmune disease.     

Allogeneic MHC antigen requirements for lupus-like autoantibody production and nephritis in murine graft-vs-host disease

A graft-vs-host (GVH) reaction of parental T cells in allogeneic F1 mice can lead to an autoimmune disease resembling human SLE. We analyzed the contribution of MHC genes to the development of IgG antinuclear antibody production and immune complex glomerulonephritis in MHC-congenic F1 recipients. DBA/2 T cells elicited IgG antibodies to histone, ssDNA, and dsDNA in all histoincompatible F1 recipients that were studied. The anti-DNA antibody responses were quantitatively similar among the F1 combinations and displayed comparable IgG2a subclass and cationic charge characteristics. In contrast, severe renal disease was manifested only in F1 mice that expressed H-2b encoded class II gene products. Disease susceptibility was associated with a decrease in circulating anti-DNA antibodies and a characteristic localization of immune complexes in the glomeruli. The data suggest that the production of potentially pathogenic IgG anti-nuclear antibodies is not sufficient for the development of renal disease in GVH-induced lupus. Thus, another event separate from autoantibody production is MHC dependent and appears to be critical for the formation and/or deposition of pathologic immune complexes.     

Role of infection in the pathogenesis of rheumatic diseases

Advanced immunological technology has revealed immunological abnormalities not only in some chronic and autoimmune connective tissue disorders but also in conditions like infective arthritis where infection apparently seems to play the only role. On the other hand role of infection in the pathogenesis of some connective tissue disorders has recently gained much importance from the observation of clinical, pathological and immunological similarities between these diseases and certain infectious diseases occurring in animal models. Meanwhile, knowledge gained into human leucocyte-A system and its association with certain diseases opens another angle in etiopathogenesis of certain rheumatic diseases. It has been postulated that adaptive mechanism of a microbe or the binding between the human leucocyte-A molecule and carbohydrate moiety of a microbe may set up an autoimmune reaction and in the presence of some triggering factors in the environment may lead on to disease manifestations. An attempt has been made to discuss the role of infection in the outcome of rheumatic diseases such as septic arthritis, polyarteritis nodosa, rheumatic fever, enteropathic arthritis, ankylosing spondylitis, rheumatoid arthritis and systemic lupus erythematoses in genetically susceptible individuals producing immunological abnormalities.     

T cell-lymphoma in the eyelid of a 9-year-old English Setter

Background

Eyelid tumours are frequently found in dogs, most of these being benign. In case of an ulcerating eyelid tumour, malignancy must be considered. We report a unique case of a low-grade peripheral T-cell lymphoma in the eyelid of a 9-year-old English Setter.

Case presentation

A 9-year-old Setter presented with a 6-month history of an eyelid ulcer. A malignant eyelid neoplasm was suspected, and the lesion was surgically excised. No other treatment was applied, and 19 months after excision the dog was still well. Histopathology revealed a diffuse lymphocytic infiltrate in the eyelid skin. Ulceration of the epithelium was seen, and the underlying tumour was composed of round and poorly demarcated pleomorphic tumour cells. The cytoplasm was pale and the nuclei heterogeneous. Numerous mitoses were present. The tumour cells stained strongly for CD3. The final diagnosis was a peripheral T-cell lymphoma not otherwise specified (NOS).

Conclusions

This is the first described case of a solitary T-cell lymphoma NOS in the haired eyelid skin in a dog. Lymphoma should be considered in case of a persistent eyelid ulcer and a biopsy should be performed. T-cell lymphoma is generally an aggressive disease; however, indolent cases are well known, and as this case shows, complete excision of a solitary T-cell lymphoma can be curable. Canine cutaneous epitheliotropic T-cell lymphoma is an important differential diagnosis, which must be recognized as the prognosis is very poor and systemic treatment is mandatory. The sub-classification of canine lymphoma is not complete, and further studies are needed to identify lymphoma subgroups and provide treatment guidelines.