Concordance rate of vulvoscopic findings in detecting early vulvar neoplasia.

PURPOSE: Colposcopy-guided punch biopsy is a cornerstone method for diagnosing vulvar diseases. The aim of this study was to evaluate the concordance rate of clinical findings in vulvar diseases during examinations, in comparison with colposcopy-directed punch biopsy. We also developed a new classification to simplify the categorization of vulvoscopic findings. METHODS: The concordance rate of the clinical findings was compared with the final histology results from punch biopsies. The data were collected between January 2014 and May 2017 at the Erlangen University Hospital. RESULTS: A total of 482 colposcopy-directed punch biopsies of the vulva were obtained in 420 women. The overall concordance rate of the clinical findings in comparison with the histological vulvar punch-biopsy findings was 53.9% for all entities - benign lesions, lichen, low- and high-grade squamous intraepithelial lesions (LSIL/HSILs), and vulvar carcinoma. The concordance rate for detecting LSILs was 64.3% (45/70). The concordance rate for detecting HSILs was 62.3% and for Vulvar carcinoma 65.2%. CONCLUSIONS: Punch biopsy of suspicious lesions continues to be a cornerstone in diagnosing HSILs and carcinoma of the vulva. Careful work-up of the vulva is recommended when patients have symptoms such as pruritus or pain. The new classification is more specific for diagnosing lesions in the vulva.

Accuracy of colposcopic findings in detecting vaginal intraepithelial neoplasia: a retrospective study.

PURPOSE: Malignancies of the vagina are rare, but colposcopy-directed biopsies play a major role in detecting vaginal intraepithelial lesions. Data of accuracy in detecting neoplasia of the vagina are very rare compared to accuracy in detecting cervical neoplasia. The aim of this study was to evaluate the accuracy of colposcopy-directed biopsy in comparison with clinical findings of the examiner. METHODS: The accuracy of colposcopy-directed biopsy was compared with the clinical finding in relation to the patient's age and the examiner's level of training. This was done in combination with PAP-smear, HPV-test results, and the history of other malignancies of the lower genital tract. The data were collected between January 2014 and February 2018 at the certified Dysplasia Unit of the University Hospital Erlangen. RESULTS: In total, 253 biopsies from 253 women from the vagina were obtained. The overall accuracy of biopsy in comparison with clinical finding was 52.17% for all entities-benign lesions, low-grade squamous intraepithelial lesions (LSILs), high-grade squamous intraepithelial lesions (HSILs), and vaginal carcinoma. The accuracy for detecting HSIL was 82.46% (47/57), with an underdiagnosis rate of 15.79% and an overdiagnosis rate of 1.79%. CONCLUSION: With a sensitivity of over 80%, colposcopy-directed biopsy plays an important role in detecting vaginal-HSIL. A highly experienced practitioner is increasing the sensitivity in detecting vaginal-HSIL. Careful examination is required in women with a history of HSIL of the lower genital tract or with simultaneous neoplasia because they are of greater risk of developing vaginal malignancies. The combination of careful clinical work up, PAP-smear, HPV-testing, and colposcopy-guided biopsy is crucial in detecting vaginal-HSIL.

Correlation between referral cytology and in-house colposcopy-guided cytology for detecting early cervical neoplasia.

PURPOSE: The current cervical cancer screening program in Germany recommends that the results showing suspected HPV infection should be further examined in specialized colposcopy units. This study aimed to correlate externally documented Pap smear results with in-house colposcopy-guided Pap cytology results and compare colposcopy-guided biopsy and postoperative histopathology results. METHODS: Clinical data were analyzed from 3627 examinations in 2844 patients who visited a university certified dysplasia unit from 2014 to 2017; 2212 patients underwent complete assessments, including Pap smear, colposcopy, HPV testing, colposcopy-guided biopsy, and/or surgery. The results were analyzed descriptively. RESULTS: External and in-house Pap results were consistent in 1054 ofthe 2212 patients (47.65%). Referral cytology showed a higher grade than in-house in 456 (20.61%) and a lower grade in 702 (31.74%). Using the histopathological findings as the gold standard, overdiagnosis in the referral cytology was noted in 180 patients (13.19%), underdiagnosis in 263 (19.27%), and concordant findings in 922 (67.55%). For in-house cytology, overdiagnosis was found in 133 patients (10.74%), underdiagnosis in 192 (15.51%), and accurate diagnosis with congruent cytology and histopathology findings in 913 (73.75%). CONCLUSIONS: The rate of detection of cervical abnormalities differs significantly depending on whether the examination is performed routinely or in specialized units. Colposcopy-guided Pap smears correlate significantly better with histology than referral cytology results without colposcopic guidance. More severe lesions were also detected more accurately.

Characterization of Molecular Subtypes of Paget Disease of the Breast Using Immunohistochemistry and In Situ Hybridization.

CONTEXT.­: Paget disease of the breast, in most cases, represents intraepidermal spread of ductal carcinoma in situ. Molecular subtypes of invasive carcinoma of the breast have prognostic and therapeutic significance and show characteristic distribution. Little is known about the distribution of molecular subtypes in Paget disease of the breast. OBJECTIVES.­: To examine the distribution of molecular subtypes in Paget disease of the breast and to compare them to concurrent invasive carcinoma of the breast, if present. DESIGN.­: We examined 48 cases of Paget disease of the breast with immunohistochemistry and antibodies against estrogen and progesterone receptors, human epidermal growth factor receptor 2 (HER2), and Ki-67, as well as HER2 chromogenic in situ hybridization, to classify the cases into molecular subtypes. Then, we compared the results to the molecular subtypes of associated invasive carcinoma of the breast, if present. RESULTS.­: The HER2 subtype was the most common found in Paget disease of the breast, followed by the luminal B subtype and 2 cases of the triple-negative subtype. The associated invasive carcinoma cases were most often of the luminal B subtype, followed by the HER2 subtype and the triple-negative subtype. The molecular subtype of Paget disease and invasive carcinoma was congruent in most of the cases. CONCLUSIONS.­: Molecular subtypes of invasive carcinoma of the breast can already be detected in Paget disease. The distribution of molecular subtypes of Paget disease and of Paget disease-associated invasive carcinoma differs from invasive carcinoma without associated Paget disease, with the HER2 subtype overrepresented in Paget disease and associated invasive carcinoma and the luminal and triple-negative subtypes underrepresented.

Digital pathology imaging and computer-aided diagnostics as a novel tool for standardization of evaluation of aganglionic megacolon (Hirschsprung disease) histopathology.

Based on a recently introduced immunohistochemical panel (Bachmann et al. 2015) for aganglionic megacolon (AM), also known as Hirschsprung disease, histopathological diagnosis, we evaluated whether the use of digital pathology and 'machine learning' could help to obtain a reliable diagnosis. Slides were obtained from 31 specimens of 27 patients immunohistochemically stained for MAP2, calretinin, S100ß and GLUT1. Slides were digitized by whole slide scanning. We used a Definiens Developer Tissue Studios as software for analysis. We configured necessary parameters in combination with 'machine learning' to identify pathological aberrations. A significant difference between AM- and non-AM-affected tissues was found for calretinin (AM 0.55% vs. non-AM 1.44%) and MAP2 (AM 0.004% vs. non-AM 0.07%) staining measurements and software-based evaluations. In contrast, S100ß and GLUT1 staining measurements and software-based evaluations showed no significant differences between AM- and non-AM-affected tissues. However, no difference was found in comparison of suction biopsies with resections. Applying machine learning via an ensemble voting classifier, we achieved an accuracy of 87.5% on the test set. Automated diagnosis of AM by applying digital pathology on immunohistochemical panels was successful for calretinin and MAP2, whereas S100ß and GLUT1 were not effective in diagnosis. Our method suggests that software-based approaches are capable of diagnosing AM. Our future challenge will be the improvement of efficiency by reduction of the time-consuming need for large pre-labelled training data. With increasing technical improvement, especially in unsupervised training procedures, this method could be helpful in the future.

Introducing a novel highly prognostic grading scheme based on tumour budding and cell nest size for squamous cell carcinoma of the uterine cervix.

A novel histopathological grading system based on tumour budding and cell nest size has recently been shown to outperform conventional (WHO-based) grading algorithms in several tumour entities such as lung, oral, and oesophageal squamous cell carcinoma (SCC) in terms of prognostic patient stratification. Here, we tested the prognostic value of this innovative grading approach in two completely independent cohorts of SCC of the uterine cervix. To improve morphology-based grading, we investigated tumour budding activity and cell nest size as well as several other histomorphological factors (e.g., keratinization, nuclear size, mitotic activity) in a test cohort (n = 125) and an independent validation cohort (n = 122) of cervical SCC. All parameters were correlated with clinicopathological factors and patient outcome. Small cell nest size and high tumour budding activity were strongly associated with a dismal patient prognosis (p < 0.001 for overall survival [OS], disease-specific survival, and disease-free survival; test cohort) in both cohorts of cervical SCC. A novel grading algorithm combining these two parameters proved to be a highly effective, stage-independent prognosticator in both cohorts (OS: p < 0.001, test cohort; p = 0.001, validation cohort). In the test cohort, multivariate statistical analysis of the novel grade revealed that the hazard ratio (HR) for OS was 2.3 for G2 and 5.1 for G3 tumours compared to G1 neoplasms (p = 0.010). In the validation cohort, HR for OS was 3.0 for G2 and 7.2 for G3 tumours (p = 0.012). In conclusion, our novel grading algorithm incorporating cell nest size and tumour budding allows strongly prognostic histopathological grading of cervical SCC superior to WHO-based grading. Therefore, our data can be regarded as a cross-organ validation of previous results demonstrated for oesophageal, lung, and oral SCC. We suggest this grading algorithm as an additional morphology-based parameter for the routine diagnostic assessment of this tumour entity.

Calbindin D28k-Immunoreactivity in Human Enteric Neurons.

Calbindin (CALB) is well established as immunohistochemical marker for intrinsic primary afferent neurons in the guinea pig gut. Its expression by numerous human enteric neurons has been demonstrated but little is known about particular types of neurons immunoreactive for CALB. Here we investigated small and large intestinal wholemount sets of 26 tumor patients in order to evaluate (1) the proportion of CALB⁺ neurons in the total neuron population, (2) the colocalization of CALB with calretinin (CALR), somatostatin (SOM) and vasoactive intestinal peptide (VIP) and (3) the morphology of CALB+ neurons. CALB+ neurons represented a minority of myenteric neurons (small intestine: 31%; large intestine: 25%) and the majority of submucosal neurons (between 72 and 95%). In the submucosa, most CALB⁺ neurons co-stained for CALR and VIP (between 69 and 80%) or for SOM (between 20 and 3%). In the myenteric plexus, 85% of CALB+ neurons did not co-stain with the other markers investigated. An unequivocal correlation between CALB reactivity and neuronal morphology was found for myenteric type III neurons in the small intestine: uniaxonal neurons with long, slender and branched dendrites were generally positive for CALB. Since also other neurons displayed occasional CALB reactivity, this protein is not suited as an exclusive marker for type III neurons.

Endometriosis as a risk factor for ovarian or endometrial cancer - results of a hospital-based case-control study.

BACKGROUND: No screening programs are available for ovarian or endometrial cancer. One reason for this is the low incidence of the conditions, resulting in low positive predictive values for tests, which are not very specific. One way of addressing this problem might be to use risk factors to define subpopulations with a higher incidence. The aim of this study was to investigate the extent to which a medical history of endometriosis can serve as a risk factor for ovarian or endometrial cancer. METHODS: In a hospital-based case-control analysis, the cases represented patients with endometrial or ovarian cancer who were participating in studies aimed at assessing the risk for these diseases. The controls were women between the age of 40 and 85 who were invited to take part via a newspaper advertisement. A total of 289 cases and 1016 controls were included. Using logistic regression models, it was tested whether self-reported endometriosis is a predictor of case-control status in addition to age, body mass index (BMI), number of pregnancies and previous oral contraceptive (OC) use. RESULTS: Endometriosis was reported in 2.1 % of the controls (n = 21) and 4.8 % of the cases (n = 14). Endometriosis was a relevant predictor for case-control status in addition to other predictive factors (OR 2.63; 95 % CI, 1.28 to 5.41). CONCLUSION: This case-control study found that self-reported endometriosis may be a risk factor for endometrial or ovarian cancer in women between 40 and 85 years. There have been very few studies addressing this issue, and incorporating it into a clinical prediction model would require a more precise characterization of the risk factor of endometriosis.

Pattern of SMARCB1 (INI1) and SMARCA4 (BRG1) in poorly differentiated endometrioid adenocarcinoma of the uterus: analysis of a series with emphasis on a novel SMARCA4-deficient dedifferentiated rhabdoid variant.

The role of the switch/sucrose nonfermenting chromatin remodeling complex in the initiation and progression of cancer is emerging. In the female genital tract, only ovarian small cell carcinoma, hypercalcemic type harbors recurrent inactivating SMARCA4 mutations. Otherwise, only rare case reports documented SMARCB1 involvement in endometrial cancer. We analyzed 24 grade 3 uterine endometrioid adenocarcinomas and 2 undifferentiated carcinomas for immunohistochemical expression of SMARCB1 and SMARCA4. All tumors showed high-grade nuclear features with a predominance of solid growth pattern. All cases showed intact nuclear SMARCB1 expression in all tumor cells. However, 1 case of a 78-year-old woman showed complete loss of SMARCA4 in 90% of the tumor with retained expression in 10% of the tumor. The SMARCA4-intact component was a moderate-to-poorly differentiated endometrioid adenocarcinoma. The SMARCA4-deficient dominating component showed solid growth of highly anaplastic undifferentiated large cells with prominent rhabdoid features. None of the 25 SMARCA4-intact cases showed rhabdoid cell morphology. To our knowledge, this is the first systematic study of SMARCB1 and SMARCA4 expression in endometrioid adenocarcinoma of uterus and the first description of a novel SMARCA4-deficient variant of dedifferentiated/undifferentiated endometrial carcinoma. The presence of a differentiated SMARCA4-intact endometrioid component points to a novel pathway of dedifferentiation in endometrioid adenocarcinoma as a consequence of a "second hit." This case further underlines the close link between the "rhabdoid phenotype" and the SWI/SNF pathway.

Association of molecular subtypes with breast cancer risk factors: a case-only analysis.

As breast cancer (BC) screening identifies many BCs with a good prognosis, which might be overdiagnosed and therefore overtreated, the identification of subgroups with a high risk for aggressive subtypes might be helpful. The aim of this case-case analysis was to investigate the association between epidemiological risk factors and molecular subtypes in a cohort of BC patients. Epidemiological risk factors for 2587 BC patients were obtained using a structured questionnaire and from the patients' charts. The histopathological information (estrogen and progesterone receptor, HER2 and Ki-67) used in the analysis was retrieved from the original pathology reports. Analyses using conditional inference regression trees were carried out on these data. The strongest influence factor on the distribution of the molecular subtypes was age at first diagnosis of BC. An influence of BMI was also identified in patients aged either more than 42 years or 49.6 years or less. Older patients aged more than 49.6 years and perimenopausal women with a BMI of 32.4 kg/m or less were most likely to develop luminal A-like BC. Young patients aged 42 years or less and perimenopausal patients with a BMI more than 32.4 kg/m more often developed triple-negative BC. The study confirmed that age at diagnosis is an important factor influencing the distribution of molecular subtypes. In the perimenopausal group, it may be postulated that BMI plays a critical role in the pathogenesis of BC, defining a subgroup that is more likely to develop triple-negative BC or luminal B-like disease and another group in which there is a more postmenopausal distribution pattern.

HPV16-L1-specific antibody response is associated with clinical remission of high-risk HPV-positive early dysplastic lesions.

BACKGROUND/AIM: The present study was aimed at clarifying if use of a rapid human papillomavirus type 16 L1-specific antibody test could be used to improve clinical management of high-risk HPV-positive low-grade squamous intraepithelial lesion (LSIL)/high-grade squamous intraepithelial lesion (HSIL). PATIENTS AND METHODS: The study was nested within a prospective study of 801 patients with early dysplastic high-risk HPV-positive lesions to examine the prognostic significance of HPV-L1 protein detection. Serum samples of 87 patients were tested with a rapid HPV16-L1-specific antibody test. The results were correlated with the clinical outcome during 66 months of follow-up. RESULTS: A combined analysis of the 22 antibody-positive women showed that 17 were also L1 protein-positive, and 5 were L1 capsid protein-negative. An HPV-specific immune competence strongly correlates with clinical remission of low-grade squamous intraepithelial lesion (76.6%). For L1 antigen and HPV16-L1 antibody double-positive women, the risk of progression to cervical intraepithelial neoplasia grade 3 was low (5.8%). CONCLUSION: The rapid anti-HPV16-L1 test could be a promising tool to improve risk assessment and appropriate clinical management of high-risk HPV-positive early dysplastic lesions.

Immunohistochemical expression of IMP3 and p53 in inflammatory lesions and neoplastic lesions of the gastric mucosa.

AIM: Expression of the oncofetal protein insulin like growth factor II messenger ribonucleic acid binding protein 3 (IMP3) has been shown to differentiate between benign and malignant lesions in several tissues. Our aim was to assess the immunohistochemical expression of IMP3 in inflammatory and neoplastic lesions of the gastric mucosa and to determine whether IMP3, alone or in combination with p53, could be used for identifying neoplasia of the gastric mucosa. METHODS: IMP3 and p53 immunohistochemistry was performed on 57 cases of gastritis, 28 cases of dysplasia of the gastric mucosa and 63 cases of gastric carcinomas. Focal IMP3 positivity was detected in 86% of non-neoplastic lesions of the gastric mucosa. Using a simple product score (PS), 96% of non-neoplastic lesions of the gastric mucosa were assessed as IMP3(PS) negative. None of the low-grade dysplasia but 83% of high-grade dysplasia were IMP3(PS) positive. Gastric carcinomas showed IMP3(PS) positivity in 65%. Adding p53 to the diagnostic panel increased sensitivity significantly. CONCLUSION: High-grade dysplasia and gastric carcinomas can be distinguished from low-grade dysplasia and inflammatory lesions of the gastric mucosa with a high specificity and good sensitivity using a combination of the immunohistochemical markers IMP3 and p53.

Correlation of histological and macroscopic findings in peritoneal endometriosis.

CONTEXT: In the last two decades, a color based concept of disease activity in peritoneal endometriosis has been in use in the clinical context, with red lesions being considered active and black or white lesions being interpreted as less active or dormant. OBJECTIVE: Our aim was to analyze 4 main color categories of peritoneal endometriosis (black, white, red and brown) in one single patient group using histomorphological and immunohistochemical methods. DESIGN: 65 endometriosis lesions (30 black, 17 white, 11 brown, 7 red) were resected from 47 premenopausal, nulliparous women which had not received exogenous hormones for at least six months prior to the operation. Specimen workup, histomorphological analysis and immunohistochemical analysis were performed in a standardized manner. RESULTS: The color categories showed a broad overlap in proliferative activity and hormone receptor expression. Differences were found in lesion morphology. Adjacent stromal reaction in particular showed a marked increase from red through brown and black to white lesions. Differences were also seen in gland pattern and gland content. CONCLUSIONS: Lesion colors in peritoneal endometriosis seem to be determined by gland content and a varying adjacent stromal reaction and more likely reflect an aging process than different levels of disease activity.

What neurons hide behind calretinin immunoreactivity in the human gut?

Calretinin (CALR) is often used as an immunohistochemical marker for the histopathological diagnosis of human intestinal neuropathies. However, little is known about its distribution pattern with respect to specific human enteric neuron types. Prior studies revealed CALR in both myenteric and submucosal neurons, most of which colabel with choline acetyl transferase (ChAT). Here, we specified the chemical code of CALR-positive neurons in small and large intestinal wholemounts in a series of 28 patients. Besides other markers, we evaluated the labeling pattern of CALR in combination with vasoactive intestinal peptide (VIP). In colonic submucosa, CALR and VIP were almost completely colocalized in about three-quarters of all submucosal neurons. In the small intestinal submucosa, both the colocalization rate of CALR and VIP as well as the proportion of these neurons were lower (about one-third). In the myenteric plexus of both small intestine and colon, CALR amounted to 11 and 10 %, respectively, whereas VIP to 5 and 4 % of the whole neuron population, respectively. Colocalization of both markers was found in only 2 and 3 % of myenteric neurons, respectively. In section specimens, nerve fibers coreactive for CALR and VIP were found in the mucosa but not in the muscle coat. Summarizing the present and earlier results, CALR was found in at least one submucosal and two myenteric neuron populations. Submucosal CALR+/VIP+/ChAT± neurons innervate mucosal structures. Furthermore, CALR immunoreactivity in the myenteric plexus was observed in morphological type II (supposed primary afferent) and spiny type I (supposed inter- or motor-) neurons.

Spontaneous Pneumothorax due to Ectopic Deciduosis: A Case Report.

This report presents a 20-week pregnant 38-year-old woman with right-sided pneumothorax due to pulmonary deciduosis. Initial pleural drainage was ineffective. Video-assisted thoracoscopy revealed areas of consolidation within the lung parenchyma. A wedge resection with partial pleurectomy was performed. Histopathological examination showed subpleural decidual implants. The patient made a full recovery and was discharged on day 5. Videoscopic inspection of the lung parenchyma and pleura with resection of decidual foci is the recommended treatment for pneumothorax in pregnant women with pleuropulmonary deciduosis in whom classical pleural drainage is ineffective.

Hormone replacement therapy and prognosis in ovarian cancer patients.

Estrogen exposure has at least a moderate effect on the risk for ovarian cancer, and antiestrogen therapy may be helpful in treating the disease. It is known from breast cancer that previous hormone replacement therapy (HRT) may influence the molecular profile and prognostic behavior of these tumors. The aim of this study was therefore to investigate the influence of previous HRT on the prognosis in a cohort of patients with invasive epithelial ovarian cancer. Among 547 patients who were treated for ovarian malignancies at a single institution from 1995 to 2008, a total of 244 postmenopausal patients with epithelial cancer and under the age of 75 were identified for whom information about HRT before the onset of the disease was available. HRT was correlated with tumor and patient characteristics. Analyses of overall survival and progression-free survival were carried out using Cox proportional hazards models. Age, tumor stage, and resection status correlated significantly with HRT in the univariate analysis. Patients with previous HRT were more likely to have a lower stage, to be younger, and to have optimal debulking. With regard to survival, HRT had a positive effect on overall survival, specifically in the subgroup of patients with optimal debulking. No correlation was seen in relation to progression-free survival. Sex hormone exposure through HRT may influence the behavior of ovarian cancers after the onset of the disease. This study supports the hypothesis that ovarian cancer is a hormonally influenced tumor.

Juvenile xanthogranuloma developing after treatment of Langerhans cell histiocytosis: case report and literature review.

The synchronous or metachronous development of Langerhans cell histiocytosis and non-Langerhans cell histiocytosis in the same patient is rare. To date, only seven cases of xanthogranulomas developing in young patients with a history of Langerhans cell histiocytosis and systemic therapy have been reported in the literature. As of yet, the pathogenesis and the clinical significance of this phenomenon are unclear. We report the case of a 3 year old boy who developed juvenile Xanthogranulomas on the forehead and right upper eye lid 1.5 years after systemic therapy for monosystemic Langerhans cell histiocytosis of the bone and complete disease remission.

HIV-associated hypertrophic herpes simplex genitalis with concomitant early invasive squamous cell carcinoma mimicking advanced genital cancer: case report and literature review.

Hypertrophic herpes simplex genitalis (HHSG) is an uncommon anogenital manifestation of herpes simplex virus (HSV) infection in immunocompromised patients. To date, 24 cases of HHSG have been reported; 23 of them were affected human immune deficiency virus (HIV) type 1-positive patients. We describe the case of a 44-year-old African HIV-1-positive woman who presented with painful ulcerated nodular lesions of the vulva and perianal area measuring up to 7 cm in diameter. Macroscopically, the lesions were highly suspicious of widely invasive cancer. The histologic workup of the resection specimen revealed patchy high-grade vulvar intraepithelial neoplasia Grade 3 (VIN 3) and 2 microscopic foci of superficially invasive squamous cell carcinoma. The nodular lesions were caused by massive tumefactive plasma cell-rich inflammatory infiltrates extending into the subcutis. Multinucleated herpes simplex virus 1 and herpes simplex virus 2-positive epithelial cells with glassy intranuclear inclusions were detected at the borders of the ulcerations, consistent with HHSG. Despite repeated surgery and medical treatment, the patient had 3 recurrences of HHSG within 18 months. The presence of intraepithelial neoplasia in HHSG lesions is relatively rare and has been described in 6 of 18 resected HHSG lesions in the literature so far. With regard to invasive malignancy, the present case is the first report of a superficially invasive squamous cell carcinoma associated with HHSG. Awareness of this condition is necessary to avoid misinterpretation of HHSG as widely invasive squamous cell carcinoma with the hazard of surgical and oncological overtreatment.

IgG4 immune response in Churg-Strauss syndrome.

OBJECTIVE: T-helper type 2 responses are crucial in Churg-Strauss syndrome (CSS) and may enhance the production of IgG4 antibodies. The authors assessed the IgG4 immune response in CSS patients. METHODS: The authors included 46 consecutive patients with CSS (24 with active and 22 with quiescent disease), 26 with granulomatosis with polyangiitis (GPA, Wegener's), 25 with atopic asthma and 20 healthy controls and determined serum IgG, IgM, IgA, IgE and IgG subclass levels. Tissue infiltration by IgG4 plasma cells was assessed in nine patients with CSS, 10 with GPA, 22 with chronic sinusitis (11 with and 11 without eosinophilia). RESULTS: IgG4 levels were markedly higher in active CSS patients than in controls (p<0.001 vs all control groups). Serum IgG4 correlated with the number of disease manifestations (r=0.52, p=0.01) and the Birmingham vasculitis activity score (r=0.64, p=0.001). Longitudinal analysis in 12 CSS cases showed that both the IgG4 level and IgG4/IgG ratio dropped during disease remission (p=3×10(-5) and p=6×10(-4), respectively). Tissue analysis did not show an increased IgG4 plasma cell infiltration in CSS biopsies compared with control groups. CONCLUSIONS: Serum IgG4 levels are markedly elevated in active CSS and correlate with the number of organ manifestations and disease activity.