Ectopic pregnancy in noncommunicating horn of unicornuate uterus: 3D-ultrasound and primary laparoscopic management.

Unicornuate uterus with pregnancy in the noncommunicating rudimentary horn is extremely rare. Diagnosis requires awareness, high suspicion index, 3D ultrasound, and MRI. If missed, it can be catastrophic. Treatment varies across literature. We present a case where detection was done by 3D ultrasound and primary laparoscopic surgery done for treatment.

Localized immunoglobulin light chain amyloidosis: Novel insights including prognostic factors for local progression.

In localized light chain amyloidosis (locAL), amyloidogenic light chains (aLC) are produced and deposited locally by a B-cell clone. We present 293 patients with immunohistochemically confirmed locAL. Lung (nodular pulmonary) with 63 patients was the most involved organ. The aLC was λ in 217 cases (κ:λ ratio 1:3). A local B-cell clone was identified in 30% of cases. Sixty-one (21%) had a concomitant autoimmune disorder (cAD). A monoclonal component (MC) were present in 101 (34%) patients and were more frequent in subjects with cAD (51% vs 34%; P = .03). Cigarette smoking was more prevalent in lung locAL (54% vs 37%; P = .018). After a median follow-up of 44 months, 16 patients died and 5- and 10-years locAL progression-free survival (PFS) were 62% and 44%. Interestingly, locAL-PFS was shorter among patients with an identified clonal infiltrate at amyloid deposition site (40 vs 109 months; P = .02) and multinuclear giant cells and/or an inflammatory infiltrate resulted in longer locAL-PFS in lung involvement (65 vs 42 months; P = .01). However, no differences in locAL PFS were observed in patients with cAD, a MC and involved organ site. Treatment was administered in 163 (54%) patients and was surgical in 135 (46%). Median locAL-PFS after first treatment was 56 months. Responders had longer locAL-PFS (78 vs 17 months; P < .001). Three patients with lung locAL and a MC were diagnosed as systemic AL amyloidosis at follow-up. In summary, locAL pathogenesis seems to be heterogeneous and the clonal infiltrate leads local progression.

AL amyloidosis with a localized B cell neoplasia.

Immunoglobulin light chain-derived (AL) amyloidosis may occur as a systemic disease usually with dismal prognosis and a localized variant with favorable outcome. We report 29 patients with AL amyloidosis and associated lymphoplasmacytic infiltrate spatially related to amyloid deposits. In 17 cases, the amyloid deposits were classified as ALλ and 12 as ALκ Histopathology in all cases showed relatively sparse plasma cells and B cells without tumor or sheet formation by the lymphoplasmacytic infiltrate. The B cells predominantly showed an immunophenotype of the marginal zone. In situ, hybridization revealed 17 cases with λ- and 10 with κ light chain restricted plasma cells, which was concordant with the AL subtype in each case. Clonal immunoglobulin heavy variable gene (IGHV) or κ light chain rearrangement was found in 23/29 interpretable cases. A single case harbored a MYD88L265P-mutation. Taken together, we detected 27 (93%) cases of AL amyloidosis with an associated light chain restricted and predominantly molecularly clonal plasma cell population. Clinical data were available in 18 patients. Five patients suffered from systemic lymphoma and two from systemic AL amyloidosis. The remaining cases were classified as localized with regard to both, the AL amyloidosis and the light chain restricted plasma cell population. To the best of our knowledge, we herein present the largest cohort of AL amyloidosis associated with a light chain restricted and predominantly molecularly clonal plasma cell population, which we designate as a distinct disease entity: "AL amyloidosis with a localized B cell neoplasia of undetermined significance".

Local vs. systemic pulmonary amyloidosis-impact on diagnostics and clinical management.

Immunoglobulin-derived light-chain (AL) amyloidosis of lungs and bronchi can appear as a systemic and a local form. While systemic AL amyloidosis may need haemato-oncological care, the localised form can be treated restrained. We re-evaluated 207 specimens of lungs and bronchi sent in for amyloid diagnostics. Amyloid was diagnosed by polarization microscopy using Congo red-stained tissue specimens and classified immunohistochemically. Histoanatomical amyloid distribution patterns were documented as well as additional histological findings. For 118 patients with AL amyloidosis, we retrieved clinical data. CT scan results were available from 59 patients. AL amyloidosis was the most common type (183 cases). ALλ was found in 141 and of ALκ in 27 cases. Fifteen cases were AL amyloid not otherwise specified. Twenty cases harboured transthyretin and three serum amyloid A derived amyloid. By correlation of histoanatomy, radiological and clinical data, amyloid was rarely in the initial differential diagnosis. Local AL amyloidosis often presented with a nodular pattern on CT scan and showed a significantly better disease-specific 10-year survival compared with systemic AL amyloidosis (96.0 vs. 51.9%). Localised and systemic pulmonary and bronchial AL amyloidosis are having a completely different prognosis. While CT scan might be indicative, histological and clinical assessment are mandatory to reach a proper diagnosis and guide patient care.

In Europe expression of EBNA2 is associated with poor survival in EBV-positive diffuse large B-cell lymphoma of the elderly.

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) of the elderly occurs by definition in patients above the age of 50 years without any known underlying immunodeficiency. We investigated the incidence and clinical relevance of this subtype in Europe with special attention to the EBV-latency type. Among the 598 DLBCL, 15 EBV-positive lymphomas fulfilling the criteria of EBV-positive DLBCL of the elderly were identified (2.5%). Patients with EBV-positive DLBCL expressing EBNA2 showed a significantly poorer overall survival than patients with EBNA2-negative EBV-positive DLBCL (p = 0.0156). The incidence of EBV-positive DLBCL of the elderly in Europe is much lower than in Asian countries (2.5% of all cases of DLBCL). Interestingly, the likelihood of EBV positivity did not increase with age in patient above 50 years. Among EBV-positive DLBCL of the elderly a subgroup with EBV-latency type III expressing EBNA2 can be identified, which shows a poor outcome.

Epstein-Barr virus-negative diffuse large B-cell lymphoma hosts intra- and peritumoral B-cells with activated Epstein-Barr virus.

Although the vast majority of diffuse large B-cell lymphomas (DLBCL) are negative for the Epstein-Barr virus (EBV), a subset of DLBCL in immunocompetent patients carries EBV in the lymphoma cells and expresses EBV-encoded RNA and/or proteins. EBV-positive DLBCL are rare and represent either pyothorax associated DLBCL or EBV-positive DLBCL of the elderly. In all cases of EBV-positive DLBCL, EBV is detectable in virtually all lymphoma cells, indicating that EBV was present at an initial phase of lymphomagenesis. We identified four lymphomas with an unusual EBV expression pattern. The majority of B-cell blasts were EBV-negative, but accompanied by a small number (less than 10 % of all B-cells) of EBV-positive B-cells with blastic morphology. The median age of the patients was 56.5 years, and no clinically evident immunosuppression was reported. In one patient EBV-positive blasts occurred in the gastric mucosa which resembled an EBV-positive mucocutaneous ulcer. In all cases EBV-positive B-cells occurred in small loose clusters within or adjacent to an EBV-negative DLBCL. In one case we were able to study immunoglobulin gene rearrangement in microdissected EBV-positive B-cells and the EBV-negative lymphoma compartment. This revealed different rearrangement patterns in EBV-negative DLBCL than in EBV-positive peritumoral B-cells, without clonal relationship between these B-cell populations. Despite the molecular data being limited to one patient, we suggest that in close proximity to EBV-negative DLBCL intra- and peritumoral EBV-positive B-cells may occur, possibly due to local immune escape mechanisms. This represents a diagnostic pitfall.

Reproducibility of Her2/neu scoring in gastric cancer and assessment of the 10% cut-off rule.

The application of Trastuzumab on gastric cancer patients is based on Her2/neu immunostaining. The testing method relies on visual estimation of both membranous staining intensity, and positive tumor ratio with respect to a 10% cutoff. We evaluated the effect of inter- and intraobserver variations of both factors on therapeutic decision, especially if the positive tumor ratio hovers around the 10% cutoff. Ten pathologists scored 12 Her2/neu immunohistologically stained whole sections of gastric cancer. Applying the common rules for Her2/neu testing for gastric cancer, they separately noted the strongest identifiable staining intensity and the corresponding positive tumor ratio. Scoring was done repeatedly using the microscope, plain virtual microscopy, and virtual microscopy with a manual outline drawing function. Agreements on the strongest identified staining intensities were moderate. Overall concordance correlation coefficients of positive tumor ratios ranged from 0.55 to 0.81. Reproducibility was not improved by virtual microscopy. Pathologists have a good ability to estimate ratios of clearly demarcated areas, but gradients in staining intensities hinder reproducible visual demarcation of positive tumor areas. When hovering around the 10% positive tumor ratio cutoff there is a risk of misinterpretation of the staining results. This could lead to a denial of Trastuzumab therapy. Assessment of Her2/neu expression should be carried out by experienced pathologists because they can more reproducibly rate membranous staining intensities. The low reproducibility of positive tumor ratio is inherent in the testing method and cannot be improved by virtual microscopy. Therefore, we propose to reconsider the 10% cut-off limit.

Detection of EBV in reactive and neoplastic lymphoproliferations in adults-when and how?

Lymphoproliferations associated with Epstein-Barr Virus (EBV) in adult patients pose a diagnostic challenge for pathologists for several reasons. First, the EBV lymphoproliferations represent a clinically and histologically very broad spectrum ranging from self-limiting lymphoproliferations to manifest malignant lymphomas. Second, the classification of these diseases is not solely based on histopathology but rather requires a synopsis of clinical as well as pathological features. And third, a resource-efficient diagnostic procedure demands a deliberate strategy for selecting the tissue specimens that are to be tested for EBV. We describe how the clinical context and histological features may indicate to histopathologists which lymphatic tissues should be tested for the presence of EBV and how these features guide the classification. We provide recommendations as to which biopsy specimens should be investigated for EBV and which methods for detecting viral association are appropriate.

HHV-8-encoded viral IL-6 collaborates with mouse IL-6 in the development of multicentric Castleman disease in mice.

Human herpes virus 8 (HHV-8) or Kaposi sarcoma-associated herpes virus is the etiologic agent of Kaposi sarcoma, primary effusion lymphoma, and plasma cell-type multicentric Castleman disease (MCD). HHV-8 encodes a viral homolog of human IL-6, called viral IL-6 (vIL-6), which does not require the cellular IL-6 receptor for binding to the ubiquitously expressed gp130 receptor subunit and subsequent JAK-STAT signaling. Thus, in contrast to IL-6, vIL-6 can stimulate virtually all cells in the body. To elucidate the mechanism by which vIL-6 drives human diseases, we generated transgenic mice that constitutively express vIL-6 under control of the MHC class I promoter. The mice were found to exhibit vIL-6 serum levels comparable with those observed in HHV-8-infected patients, to contain elevated amounts of phosphorylated STAT3 in spleen and lymph nodes, where vIL-6 was produced, and to spontaneously develop key features of human plasma cell-type MCD, including splenomegaly, multifocal lymphadenopathy, hypergammaglobulinemia, and plasmacytosis. Transfer of the vIL-6 transgene onto an IL-6-deficient genetic background abrogated MCD-like phenotypes, indicating that endogenous mouse IL-6 is a crucial cofactor in the natural history of the disease. Our results in mice suggest that human IL-6 plays an important role in the pathogenesis of HHV-8-associated MCD.

Organ-preserving management of ovarian pregnancies by laparoscopic approach.

This article discusses the possible etiology and the preoperative, operative, and postoperative management of five ovarian pregnancies based on the initial nonspecific signs and symptoms and the high risk of hemoperitoneum and/or hypovolemic shock of a ruptured ovarian pregnancy with the associated diagnostic problems. The advances made in transvaginal ultrasonography and monitoring of serum ß-hCG levels in blood samples, as well as the substantial progress made in diagnostic pelviscopy and operative laparoscopy, have led to an early minimal invasive surgical management with the main emphasis on an organ-preserving procedure, i.e., a simple enucleation of the gestational sac with the utmost protection of the surrounding ovarian tissue.

Forced dimerization of gp130 leads to constitutive STAT3 activation, cytokine-independent growth, and blockade of differentiation of embryonic stem cells.

The mode of activation of glycoprotein 130 kDa (gp130) and the transmission of the activation status through the plasma membrane are incompletely understood. In particular, the molecular function of the three juxtamembrane fibronectin III-like domains of gp130 in signal transmission remains unclear. To ask whether forced dimerization of gp130 is sufficient for receptor activation, we replaced the entire extracellular portion of gp130 with the c-jun leucine zipper region in the chimeric receptor protein L-gp130. On expression in cells, L-gp130 stimulates ligand-independent signal transducer and activator of transcription (STAT) 3 and extracellular signal-regulated kinase 1/2 phosphorylation. gp130 activation could be abrogated by the addition of a competing peptide comprising the leucine zipper region of c-fos. When stably expressed in the interleukin-3-dependent Ba/F3 murine pre-B-cells, these cells showed constitutive STAT3 activation and cytokine-independent growth over several months. Because gp130 stimulation completely suppressed differentiation of murine embryonic stem cells in vitro, we also stably expressed L-gp130 in these cells, which completely blocked their differentiation in the absence of cytokine stimulation and was consistent with high constitutive expression levels of the stem cell factor OCT-4. Thus, L-gp130 can be used in vitro and in vivo to mimic constitutive and ligand-independent activation of gp130 and STAT3, the latter of which is frequently observed in neoplastic diseases.