Pathomechanisms of Paraneoplastic Myasthenia Gravis

Thymic T cell development is characterized by sequential selection processes to ensure generation of a self-tolerant, immuncompetent mature T cell repertoire. Malfunction of any of these selection processes may potentially result in either immunodeficiency or autoimmunity. Myasthenia gravis (MG) is a typical autoimmune manifestation of thymic epithelial tumors (thymomas) and is related to the capacity of these tumors to generate and export mature T cells. Analysis of the factors that lead to autoimmunization in thymomas will help to understand the mechanisms that prevent MG under physiological conditions in humans. In a comparison of MG(+) and MG(-) thymomas, we could show that only thymomas capable of generating mature CD45RA+CD4+ T cells are associated with MG (p< 0.0001), while terminal thymopoiesis was abrogated in MG(-) thymomas. In particular, acquisition of the CD27+CD45RA+ phenotype appears to be a critical checkpoint of late T cell development in the human thymus and may play an important role in the prevention of autoimmunity. Moreover, MG(-) thymomas were virtually depleted of regulatory (CD4+CD25+) T cells (regT), while regT were readily detectable in MG(+) thymomas, albeit at significantly reduced numbers compared to control thymuses. Thus, in MG(+) thymoma patients, thymectomy apparently also results in removal of a regulatory T cell pool and may explain the frequent temporary postoperative deterioration of MG in these patients

Paraneoplastic Autoimmunity in Thymus Tumors

Autoimmune phenomena are more frequent in thymic epithelial tumors (TET) than in any other human tumor. Mysthenia gravis (MG) is by far the most common autoimmune disease in thymoma patients. MG is characterized by muscle weakness due to autoantibodies against the acetylcholine receptor (AChR), and CD4 +AChR-specific T cells play a pivotal role for the production of these autoantibodies. About 10% of MG patients have a thymoma and, interestingly, only such thymomas exhibit an MG association that maintains thymuslike morphological and functional features with respect to the homing and differentiation of immature T cells. Since AChR protein is not expressed in thymomas, the specificity of the autoimmunity in thymoma-associated MG is thought to be determined by nonreceptor proteins with AChR epitopes. Such proteins are overexpressed in cortical-type MG-associated thymomas, and medullary thymomas express these proteins at barely detectable levels. Aside from this quantitative difference, the pathogenesis of anti-AChR autoimmunity might be qualitatively different in these thymoma subtypes. Our findings suggest that an antigen-specific abnormal Tcell selection by cortical-type TET may contribute to the pathogenesis of paraneoplastic MG. In contrast, an abnormal (intratumorous) activation of autoreactive T cells may be operative in medullary thymomas

Differential diagnosis of laryngeal spindle cell carcinoma and inflammatory myofibroblastic tumor – report of two cases with similar morphology

BACKGROUND: Spindle cell tumors of the larynx are rare. In some cases, the dignity is difficult to determine. We report two cases of laryngeal spindle cell tumors. CASE PRESENTATION: Case 1 is a spindle cell carcinoma (SPC) in a 55 year-old male patient and case 2 an inflammatory myofibroblastic tumor (IMT) in a 34 year-old female patient. A comprehensive morphological and immunohistochemical analysis was done. Both tumors arose at the vocal folds. Magnified laryngoscopy showed polypoid tumors. After resection, conventional histological investigation revealed spindle cell lesions with similar morphology. We found ulceration, mild atypia, and myxoid stroma. Before immunohistochemistry, the dignity was uncertain. Immunohistochemical investigations led to diagnosis of two distinct tumors with different biological behaviour. Both expressed vimentin. Furthermore, the SPC was positive for pan-cytokeratin AE1/3, CK5/6, and smooth-muscle actin, whereas the IMT reacted with antibodies against ALK-1, and EMA. The proliferation (Ki67) was up to 80% in SPC and 10% in IMT. Other stainings with antibodies against p53, p21, Cyclin D1, or Rb did not result in additional information. After resection, the patient with SPC is free of disease for seven months. The IMT recurred three months after first surgery, but no relapses were found eight months after resurgery. CONCLUSION: Differential diagnosis can be difficult without immunohistochemistry. Therefore, a comprehensive morphological and immunohistochemical analysis is necessary, but markers of cell cycle (apart from the assessment of proliferation) do not help

Expression of CD56 isoforms in primary and relapsed adult granulosa cell tumors of the ovary

<p>Abstract</p> <p>Background</p> <p>Adult granulosa cell tumors of the ovary (GCTs) are sex cord stromal tumors of unpredictable behaviour. Up to now, the prediction of the relapsing/malignant potential remains difficult. CD56 (NCAM) in GCTs was previously described in only two studies. However, the expression of its isoforms was not examined.</p> <p>Methods</p> <p>30 GCTs (16 primaries, 14 relapses) were investigated immunohistochemically with antibodies against Pan-CD56 (CD56^Pan) and the isoform with 140/180 kDa length (CD56^{140/180 kDa}). The reaction was assessed with respect to percentage of positive cells and intensity of staining.</p> <p>Results</p> <p>In all GCTs, CD56^Panwas expressed, but differences were found between primaries and relapses. The percentage of CD56^Panpositive tumor cells was lower in relapses, whereas CD56^{140/180 kDa}showed a higher staining intensity in the latter.</p> <p>Conclusion</p> <p>Expression of CD56 is an additional sensitive and helpful immunohistochemical tool for histopathologists diagnosing a GCT. It does not seem possible to provide a validly individual risk assessement. However, the different expression of CD56 isoforms might indicate important changes in the course to a more malignant behaviour.</p

A Striational Muscle Antigen and Myasthenia Gravis-Associated Thymomas Share an Acetylcholine-Receptor Epitope

The coincidence of autoantibodies against the acetylcholine receptor (AChR) and muscle striational antigens (SA) is a characteristic finding in thymoma-associated myasthenia gravis (MG), but their origins are still unresolved. Some common muscle antigens that were shown to be targets of anti-SA autoantibodies in thymoma-associated MG have also been detected in normal or neoplastic thymic epithelial cells, suggesting that the release of (eventually altered) antigens from the thymic tumors could elicit SA autoimmunity. In contrast to this model, we report here that titin, which is a recently reported target of SA autoimmunity, is not expressed in thymomas. In addition, we show that skeletal muscle type-II fibers exhibit a striational immunoreactivity with monoclonal antibody mAb155, which was previously identified to label a very immunogenic cytoplasmic epitope of the AChR and neoplastic epithelial cells of MGassociated thymomas. We conclude from these findings that titin autoimmunity in thymoma-associated MG is either due to a molecular mimicry mechanism involving tumor antigens (other than titin) or is a secondary phenomenon following release of titin from muscle. Based on the common immunoreactivity of the AChR, a striational antigen and thymoma, we suggest as the pathogenetic mechanism of thymoma-associated MGa "circulus vitiosus" in which SA autoimmunity could help maintain the AChR autoimmunity that is primarily elicited by the thymomas

Lethal pneumatosis coli in a 12-month-old child caused by acute intestinal gas gangrene after prolonged artificial nutrition: a case report

<p>Abstract</p> <p>Introduction</p> <p>Pneumatosis coli is a rare disease with heterogeneous symptoms which can be detected in the course of various acute and chronic intestinal diseases in children, such as necrotizing enterocolitis, intestinal obstruction and intestinal bacteriological infections.</p> <p>Case presentation</p> <p>We report the case of a 12-month-old boy who died of pneumatosis coli caused by an acute intestinal gas gangrene after prolonged artificial alimentation.</p> <p>Conclusion</p> <p>While intestinal gas gangrene is a highly uncommon cause of pneumatosis coli, it is important to consider it as a differential diagnosis, especially in patients receiving a prolonged artificial food supply. These patients may develop intestinal gas gangrene due to a dysfunctional intestinal barrier.</p

Lymphangiosis carcinomatosa in squamous cell carcinomas of larynx and hypopharynx – value of conventional evaluation and additional immunohistochemical staining of D2-40

<p>Abstract</p> <p>Background</p> <p>Recent studies revealed a predictive value of lymphatic vessel invasion (L1) for the nodal metastasizing and poor prognosis in malignant tumors at different sites. The monoclonal antibody D2-40 (podoplanin) stains specifically endothelial cells of lymphatic vessels and improves the search for L1. However, the importance of this immunohistochemical staining was not investigated in squamous cell carcinomas (SCC) of larynx and hypopharynx.</p> <p>Aim</p> <p>This study was performed to compare the diagnostic potential of convential and immunohistochemical determination of L1 in SCC of larynx and hypopharynx with special respect to the predictive value for nodal metastasizing and prognosis.</p> <p>Methods</p> <p>119 SCCs of the larynx (n = 70) respectively hypopharynx (n = 49) were investigated. The lymphatic vessel invasion was assessed by conventional method (HE stain) and immunohistochemical staining with an antibody against D2-40 (DAKO, Germany). Immunohistochemistry was performed in accordance with manufacturer's protocol. L1 was searched microscopically in a standardized magnification (×200) in serial sections of tumor samples (1 section per cm tumor diameter).</p> <p>Results</p> <p>The immunohistochemical investigation did not show significant advantages for the prediction of regional nodal metastases. Despite a low sensitivity (< 50%) in both methods, the specifity can reach 80%. The negative predictive value in both methods seems acceptable (up to 80%), whereas the positive predictive value is not higher than 64%. Cases with L1 detected either conventionally or immunohistochemically did not show a significant shorter survival than cases with L0. However, a non-significant shorter survival was found. Only in SCC of hypopharynx, a combination of both methods revealed patients with a significant worse prognosis.</p> <p>Conclusion</p> <p>The status of lymphatic vessel invasion should be documented in standardized tumor reports. A benefit of an additional immunohistochemical investigation was not found, for the daily routine HE-stain seems sufficient.</p