FOXA1 is an essential determinant of ERalpha expression and mammary ductal morphogenesis.

FOXA1, estrogen receptor alpha (ERalpha) and GATA3 independently predict favorable outcome in breast cancer patients, and their expression correlates with a differentiated, luminal tumor subtype. As transcription factors, each functions in the morphogenesis of various organs, with ERalpha and GATA3 being established regulators of mammary gland development. Interdependency between these three factors in breast cancer and normal mammary development has been suggested, but the specific role for FOXA1 is not known. Herein, we report that Foxa1 deficiency causes a defect in hormone-induced mammary ductal invasion associated with a loss of terminal end bud formation and ERalpha expression. By contrast, Foxa1 null glands maintain GATA3 expression. Unlike ERalpha and GATA3 deficiency, Foxa1 null glands form milk-producing alveoli, indicating that the defect is restricted to expansion of the ductal epithelium, further emphasizing the novel role for FOXA1 in mammary morphogenesis. Using breast cancer cell lines, we also demonstrate that FOXA1 regulates ERalpha expression, but not GATA3. These data reveal that FOXA1 is necessary for hormonal responsiveness in the developing mammary gland and ERalpha-positive breast cancers, at least in part, through its control of ERalpha expression.

Follicular center helper T-cell (TFH) marker positive mycosis fungoides/Sezary syndrome.

We identified 11 patients with CD10(+) cutaneous T-cell lymphoma by flow cytometry. All cases were CD4(+) and CD8(-). Three patients had extensive lymphadenopathy, systemic symptoms and an aggressive clinical course consistent with angioimmunoblastic T-cell lymphoma or peripheral T-cell lymphoma. However, 8 of the 11 patients had a prolonged disease course with gross morphology, histology and tumor cell phenotype indistinguishable from mycosis fungoides or Sezary syndrome. Immunohistochemical studies confirmed CD10 expression in seven of the eight cases and revealed the lymphoma cells were Bcl-6(+), PD-1(+), and EBV(-). Two had significant expression of CXCL-13(+). The findings indicate that lymphoma cells from mycosis fungoides or Sezary syndrome may express follicular center helper T-cell markers CD10, Bcl-6, and PD-1 and occasionally CXCL-13. The expression of these markers in some cases of mycosis fungoides/Sezary syndrome suggests follicular center helper T-cell differentiation and may lead to confusion in distinguishing mycosis fungoides/Sezary syndrome from other follicular center helper T-cell marker positive T-cell lymphomas with cutaneous manifestations.

Id-like reaction to BCG therapy for bladder cancer.

Id reaction, also known as autoeczematization, is the development of dermatitis that is distant to an initial site of infection or sensitization. Clinical findings typically include an acute, intensely pruritic maculopapular or papulovesicular eruption that most frequently involves the extremities. Histology typically reveals spongiotic dermatitis that often is vesicular, and eosinophils may be present in the infiltrate. Id reactions can result from inflammatory skin conditions such as stasis dermatitis as well as infectious entities including mycobacterial infections. BCG live therapy consists of an attenuated strain of Mycobacterium bovis that is utilized as a first-line treatment of superficial transitional cell carcinomas. We report the case of an id-like reaction in a 90-year-old man who developed an intensely pruritic, scaly, erythematous eruption on all 4 extremities 2 weeks after starting weekly intravesical use of BCG therapy for superficial transitional cell carcinoma. A representative biopsy demonstrated spongiotic dermatitis with overlying scaling and an eosinophilic infiltrate. The eruption resolved after discontinuation of BCG therapy and treatment with topical corticosteroids.

Treatment-refractory actinic keratoses successfully treated using simultaneous combination topical 5-fluorouracil cream and imiquimod cream: a case-control study.

BACKGROUND: Most actinic keratoses (AKs) respond to standard treatments, but a subset persist and require further intervention. We report a series of 10 patients with AKs that failed to respond to conventional treatment with cryotherapy and topical monotherapy but responded completely to simultaneous therapy with topical 5-fluorouracil (5-FU) and imiquimod creams. OBJECTIVE: To report the success of this combination therapy in refractory AKs and to determine whether any clinical or histologic features predict for treatment resistance. METHODS: Case-control study with two control groups matched to each patient according to lesion location and sex. RESULTS: Mean lesion diameter (p < .001), lesion diameter greater than 1 cm (p < .001), and the presence of pain (p = .01) were statistically associated with failure of cryotherapy and topical monotherapy. None of the histologic features evaluated were found to be statistically significant, although thicker epidermis was nearly so (p = .054). CONCLUSIONS: In patients who have failed standard therapy for AKs, combination treatment using topical 5-FU and imiquimod cream may be an effective alternative therapeutic strategy. Larger lesion diameter, specifically greater than 1 cm, and the presence of pain predict conventional treatment resistance.

HER2/ErbB2-induced breast cancer cell migration and invasion require p120 catenin activation of Rac1 and Cdc42.

Breast cancers that overexpress the receptor tyrosine kinase ErbB2/HER2/Neu result in poor patient outcome because of extensive metastatic progression. Herein, we delineate a molecular mechanism that may govern this malignant phenotype. ErbB2 induction of migration requires activation of the small GTPases Rac1 and Cdc42. The ability of ErbB2 to activate these small GTPases necessitated expression of p120 catenin, which is itself up-regulated by signaling through ErbB2 and the tyrosine kinase Src. Silencing p120 in ErbB2-dependent breast cancer cell lines dramatically inhibited migration and invasion as well as activation of Rac1 and Cdc42. In contrast, overexpression of constitutively active mutants of these GTPases reversed the effects of p120 silencing. Lastly, ectopic expression of p120 promoted migration and invasion and potentiated metastatic progression of a weakly metastatic, ErbB2-dependent breast cancer cell line. These results suggest that p120 acts as an obligate intermediate between ErbB2 and Rac1/Cdc42 to modulate the metastatic potential of breast cancer cells.

Aberrant expression of LMO4 induces centrosome amplification and mitotic spindle abnormalities in breast cancer cells.

The LIM-only protein, LMO4, is a transcriptional modulator overexpressed in breast cancer. It is oncogenic in murine mammary epithelium and is required for G2/M progression of ErbB2-dependent cells as well as growth and invasion of other breast cancer cell types. However, the mechanisms underlying the oncogenic activity of LMO4 remain unclear. Herein, we show that LMO4 is expressed in all breast cancer subtypes examined and its expression level correlates with the degree of proliferation of such tumours. In addition, we have determined that LMO4 silencing induces G2/M arrest in cells from various breast cancer subtypes, suggesting that LMO4 action in the cell cycle is not restricted to a single breast cancer subtype. This arrest was accompanied by increased cell death, amplification of centrosomes, and formation of abnormal mitotic spindles. Consistent with its ability to positively and negatively regulate the formation of active transcription complexes, overexpression of LMO4 also resulted in an increase in centrosome number. Centrosome amplification has been shown to prolong the G2/M phase of the cell cycle and induce apoptosis; thus, we conclude that supernumerary centrosomes mediate the G2/M arrest and cell death in LMO4-deficient cells. Furthermore, the correlation of centrosome amplification with genomic instability suggests that the impact of dysregulated LMO4 on the centrosome cycle may promote LMO4-induced tumour formation.

Pagetoid reticulosis in a 5-year-old boy.

We present a rare case of pagetoid reticulosis arising in a 5-year-old white boy. He had a history of a large chronic erythematous, scaly patch on his left buttock that had shown intermittent partial response to a topical antifungal medication. A punch biopsy specimen revealed dramatic epidermal hyperplasia, with parakeratosis and prominent exocytosis of single and clustered mononuclear cells (Pautrier's microabscesses) into the epidermis. Some of these exhibited hyperchromatic nuclei with irregular contours. They stained prominently for CD3, CD4, and CD8, with a predominance of CD8(+) cells. T-cell receptor gene rearrangement by polymerase chain reaction was negative for a clonal process on a second biopsy specimen that was nondiagnostic on routine sections. Pagetoid reticulosis is an indolent, unilesional variant of mycosis fungoides, in which the atypical T cells may express a CD4(-)/CD8(+) phenotype. This is in contrast to primary cutaneous epidermotropic CD8(+) cytotoxic T-cell lymphoma, which is often very aggressive with a poor outcome. Pagetoid reticulosis is exceedingly rare in children and adolescents. Two features predict a benign course in this 5-year-old child: the unilesional clinical presentation and the CD8 predominance of the epidermal lymphocytes.

MUC1 is expressed at high frequency in early-stage basal-like triple-negative breast cancer.

Triple-negative breast cancer comprises 10% to 15% of newly diagnosed breast cancer and lacks expression of the estrogen, progesterone, and human epidermal growth factor receptor 2/neu receptors. Many such tumors are basal like, a molecular intrinsic subtype of breast cancer associated with poor clinical outcomes. Patients with early-stage basal-like triple-negative breast cancer are at a high risk for relapse and may, therefore, benefit from novel therapies, including immunotherapy. MUC1 is a tumor antigen expressed on adenocarcinomas and represents an ideal target for MUC1-based vaccination. We evaluated 52 cases of early-stage basal-like triple-negative breast cancer for MUC1 expression by immunohistochemistry. The intensity of staining was graded according to the intensity (negative [0], positive [1], or strongly positive [2]) and percentage (0%-100%) of tumor cells staining for MUC1. An overall score of 0 to 2.0 was calculated for each case by multiplying the intensity of staining by the percentage of tumor cells staining positively. Four staining patterns for MUC1 were identified: apical, cytoplasmic, membranous, and combination. Of the 52 cases of basal-like triple-negative breast cancers, 49 (94%) were positive for MUC1 expression. The mean score was 0.90 (range, 0-1.9). Cases were evenly distributed over this range, where most (67%) exhibited moderate to strong MUC1 expression (score, 0.5-1.90), 27% demonstrated weak MUC1 expression, and 6% lacked MUC1 expression. There was a significant difference in MUC1 score and percent MUC1+ cells in favor of the combination pattern. This study indicates that a large proportion of early-stage basal-like triple-negative breast cancer expresses MUC1 and provides a rationale for MUC1-based immunotherapy in this high-risk patient cohort.

Glandular cells in vaginal cytology Papanicolaou tests in patients with hysterectomy for endometrial adenocarcinoma.

The vaginal apex is the most common site of recurrence in patients with endometrial cancer. Although studies demonstrate that <1% of asymptomatic vaginal recurrences are detected by routine vaginal cytology alone, many practitioners still include it as part of the routine surveillance in these patients after hysterectomy. To further evaluate the effectiveness of vaginal cytology as a surveillance tool, we assessed the subsequent findings in patients reported to have benign and atypical glandular cells on vaginal cytology after hysterectomy performed for endometrial cancer.

Marginal zone B cell lymphomas with extensive plasmacytic differentiation are neoplasms of precursor plasma cells.

Occasional marginal zone lymphomas have extensive plasmacytic differentiation (P-MZL). We present an argument based on our data and previous published observations that P-MZL represent neoplasms of precursor plasma cells. Five P-MZL were analyzed by flow cytometry and the phenotype was compared with conventional MZL, plasma cell myeloma (PCM), reactive plasmacytoses (RP), and normal marrow plasma cells. The clonal cells in four of five P-MZL were CD19+, CD20(dim/⁻), CD38(bright), CD45++, CD56⁻, CD138⁻, and surface light chain(dim/⁻). One case was CD56+, CD138+, and CD19⁻. A separate clonal mature B cell population [CD20+, CD79b+] was not detected in any of these tumors. Hierarchical clustering demonstrated similarity between the neoplastic cells in four of the five P-MZL with plasma cells in RP comprised of precursor plasma cells. Analysis of normal bone marrow plasma cells revealed a CD45++CD38(bright)CD19+CD138⁻/+ precursor plasma cell population similar to the plasma cells in RP and P-MZL and a very small population of mature CD45+/⁻CD38(bright)CD138+CD19⁻ plasma cellsresembling the neoplastic cells in PCM. The findings suggest that P-MZL represents a malignancy of a plasma cell stage of differentiation distinct from the plasma cell stage corresponding to PCM. We propose the term precursor plasma cell neoplasm for these tumors.

Unusual and recently described cutaneous atrophic disorders.

Cutaneous atrophic conditions are typically caused by changes in the dermis or subcutaneous tissue, sometimes consisting of the loss of a single fiber type. Since a significant decrease of subepidermal tissue is necessary for these lesions to be macroscopically atrophic, many conditions may not be appreciated as atrophy in the clinical setting. Clinicians should be familiar with the common or classic disorders causing cutaneous atrophy; however, there are a few new or rarely described atrophic conditions which are more difficult to identify and may not be atrophic clinically. This paper serves to describe the salient clinical and histological features of these new or rare disorders.

Inflammatory pseudotumor of the spleen: review of clinical presentation and diagnostic methods.

We describe a 91-year-old woman with a clinical history of invasive ductal carcinoma of the breast diagnosed in 1991 who was admitted because of dizziness, poor appetite, and some swelling and tenderness over her cheeks. The patient's initial work up revealed a 5-cm well-demarcated hypodense solid lesion in her spleen with abnormally intense uptake on PET/CT scan raising suspicion for malignancy i.e. breast metastasis versus lymphoma. Further review demonstrated the presence of this splenic lesion, though slightly smaller, on a CT scan from ten years earlier (2000). An ultrasonographic guided core needle splenic biopsy was performed and the pathology result revealed histological findings compatible with inflammatory pseudotumor of the spleen. As a result, unnecessary splenectomy was avoided.