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.

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.

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.

Invasive Breast Cancer: Recognition of Molecular Subtypes.

SUMMARY: Molecular profiling has fundamentally changed our understanding of breast cancer in the last 10 years, by creating a new taxonomy of breast cancers based on the expression patterns of so-called 'intrinsic genes'. Hierarchical clustering analyses performed on microarray-based gene expression profiles of breast cancers defined distinct breast cancer subgroups (luminal type A/B, HER2-enriched type, basal-like type). Since the initial landmark study by Perou et al., the concept of intrinsic breast cancer subtypes has been corroborated and expanded by several independent research groups. Further studies revealed individual properties of the intrinsic subgroups regarding the clinical course and the responsiveness to chemotherapy. The new gene expression profile-based taxonomy of breast cancer has been enthusiastically embraced by the scientific community and hailed as a major breakthrough on the way to individually tailored therapies. However, validation of the gene signatures in prospective studies is necessary before accepting these new technologies in daily clinical practice. In this review, the current data regarding the intrinsic subtypes and the associated clinical implications as well as the methodology of molecular profiling and possible use of immunohistochemistry in identifying intrinsic subtypes are discussed.

Ki67, chemotherapy response, and prognosis in breast cancer patients receiving neoadjuvant treatment.

BACKGROUND: The pathological complete response (pCR) after neoadjuvant chemotherapy is a surrogate marker for a favorable prognosis in breast cancer patients. Factors capable of predicting a pCR, such as the proliferation marker Ki67, may therefore help improve our understanding of the drug response and its effect on the prognosis. This study investigated the predictive and prognostic value of Ki67 in patients with invasive breast cancer receiving neoadjuvant treatment for breast cancer. METHODS: Ki67 was stained routinely from core biopsies in 552 patients directly after the fixation and embedding process. HER2/neu, estrogen and progesterone receptors, and grading were also assessed before treatment. These data were used to construct univariate and multivariate models for predicting pCR and prognosis. The tumors were also classified by molecular phenotype to identify subgroups in which predicting pCR and prognosis with Ki67 might be feasible. RESULTS: Using a cut-off value of > 13% positively stained cancer cells, Ki67 was found to be an independent predictor for pCR (OR 3.5; 95% CI, 1.4, 10.1) and for overall survival (HR 8.1; 95% CI, 3.3 to 20.4) and distant disease-free survival (HR 3.2; 95% CI, 1.8 to 5.9). The mean Ki67 value was 50.6 ± 23.4% in patients with pCR. Patients without a pCR had an average of 26.7 ± 22.9% positively stained cancer cells. CONCLUSIONS: Ki67 has predictive and prognostic value and is a feasible marker for clinical practice. It independently improved the prediction of treatment response and prognosis in a group of breast cancer patients receiving neoadjuvant treatment. As mean Ki67 values in patients with a pCR were very high, cut-off values in a high range above which the prognosis may be better than in patients with lower Ki67 values may be hypothesized. Larger studies will be needed in order to investigate these findings further.

Numerous IgG4-positive plasma cells are ubiquitous in diverse localised non-specific chronic inflammatory conditions and need to be distinguished from IgG4-related systemic disorders.

BACKGROUND: IgG4-related systemic fibrosclerosis is a recently defined disorder characterised by a diffuse or tumefactive inflammatory reaction rich in IgG4-positive plasma cells associated with sclerosis and obliterative phlebitis. Although characteristic histopathological features are essential for the diagnosis of these disorders, to date there exists no consensus regarding the cut-off values used to define a 'significant IgG4-positive plasma cell count,' and data regarding the distribution of IgG4-positive plasma cells under common (non-specific) inflammatory conditions are lacking. METHODS: The authors analysed 121 randomly selected histopathological specimens containing prominent lymphoplasmacytic infiltrates (11 obstructive sialadenitis, 27 inflammatory lesions of the oral cavity, 24 inflammatory gastrointestinal lesions, 15 rheumatoid synovitis, 15 non-specific synovitis, eight non-specific dermatitis and 21 primary carcinomas with a peritumoral inflammatory response). For comparison, seven cases of sclerosing sialadenitis (Küttner tumour) were examined. RESULTS: High counts of IgG4 plasma cells were found in sclerosing sialadenitis (mean 40/high-power field (hpf)), contrasting sharply with sialadenitis caused by sialolithiasis (mean 3/hpf). Greatly varied but generally high counts of IgG4-positive plasma cells were also seen in several of the other lesions, particularly in rheumatoid synovitis (mean 55/hpf), oral cavity lesions (mean 79/hpf) and carcinoma-associated inflammatory response (mean 24/hpf). The mean IgG4/IgG ratios for all lesions varied between 0 and 0.4. CONCLUSIONS: The results demonstrate the ubiquitous occurrence of variably high numbers of IgG4-positive plasma cells under diverse non-specific inflammatory conditions, indicating that high IgG4-positive plasma cell counts and high IgG4/IgG ratios per se do not reliably distinguish IgG4-associated systemic disease from non-specific conditions, and that the IgG4 counts must be cautiously interpreted in the context of appropriate clinical and histopathological features.

Diabetes and prognosis in a breast cancer cohort.

PURPOSE: Epidemiological studies indicated that type 2 diabetes mellitus may increase breast cancer risk and mortality. The aim of this retrospective cohort study was to examine the effect of diabetes on the clinical course and the prognosis of early stage breast cancer in relation to tumour and patient characteristics. METHODS: The cohort analyzed in this study consisted of 4,056 patients with invasive primary breast cancer. We compared overall survival, distant metastasis-free survival and local recurrence free survival between breast cancer patients with and without diabetes. RESULTS: In our cohort 276 breast cancer patients (6.8%) were affected by diabetes compared to 3,780 patients (93.2%) without diabetes. Women with diabetes were significantly older, had larger tumours, and a higher rate of lymph node involvement. After a follow-up period of 5 years, stratification for age and adjustment for other prognostic factors, overall mortality following breast cancer was significantly higher in diabetic breast cancer patients (hazard ratio, HR 1.92; 95% confidence interval, CI 1.49-2.48). We found no significant differences in distant metastasis-free survival and local recurrence free survival between the two groups, but we found a slightly significant higher rate of distant metastasis in the group of patients with diabetes and oestrogen receptor negative tumours (HR 2.28; CI 1.31-3.97). CONCLUSION: In this study, patients with diabetes and oestrogen receptor negative breast cancer had a more than 2-fold higher risk for distant metastasis compared to patients without diabetes. Diabetes was also associated with an almost 2-fold increase in mortality within the 5 years follow-up period.