Painful scrotal dermatitis secondary to topical 5-fluorouracil.

5-Fluorouracil (5-FU) is an antineoplastic agent that is used topically to treat actinic keratoses. Although topical 5-FU frequently causes irritant contact dermatitis at the site of application, distant skin reactions are rare and could relate to accidental transfer or systemic absorption of the drug. We present a patient who developed a painful scrotal dermatitis after applying the topical cream to actinic keratoses on his chest. Upon discontinuation of topical 5-FU, the reaction resolved over a four-week period with oral prednisone and topical betamethasone ointment. The patient was re-challenged with topical 5-FU one year later and again developed scrotal pain and erythema similar to the initial reaction. Scrotal dermatitis is a rare adverse effect of topical 5-FU therapy that can be associated with significant distress and disruption of daily activities.

A Distinctive Histological Form of Squamous Cell Carcinoma With Perineural Invasion.

A modest proportion of individuals diagnosed with squamous cell carcinoma (SCC) display perineural invasion (PNI), the neoplastic invasion of one or more nerves. It is associated with a marked increase in mortality in patients with SCC and is oftentimes only diagnosed after a significant invasion occurs. An 84-year-old male, otherwise in good health, presented to us with a fast-growing, 3-cm nodule on his right malar region associated with paresthesia and radiating pain. Biopsy of the lesion revealed moderately differentiated infiltrative squamous cell carcinoma, which was later discovered to involve the perineural fascia of the trigeminal nerve. Excision of the infraorbital nerve and maxillary bone was performed to remove the tumor, with the resulting defect later reconstructed. Here, we present findings of SCC with unique histological features predictive of potential PNI. These features include a rim of cuboidal cells which quickly transition into a well-differentiated, eosinophilic parakeratotic core, reminiscent of a "fried egg" appearance. Awareness of these histological findings may allow clinicians to detect PNI in patients with SCC before widespread and irreversible involvement.

Injury-induced innate immune response in human skin mediated by transactivation of the epidermal growth factor receptor.

We found that sterile wounding of human skin induced epidermal expression of the antimicrobial (poly)peptides human beta-defensin-3, neutrophil gelatinase-associated lipocalin, and secretory leukocyte protease inhibitor through activation of the epidermal growth factor receptor. After skin wounding, the receptor was activated by heparin-binding epidermal growth factor that was released by a metalloprotease-dependent mechanism. Activation of the epidermal growth factor receptor generated antimicrobial concentrations of human beta-defensin-3 and increased the activity of organotypic epidermal cultures against Staphylococcus aureus. These data demonstrate that sterile wounding initiates an innate immune response that increases resistance to overt infection and microbial colonization.

Differential regulation of beta-defensin expression in human skin by microbial stimuli.

In response to infection, epithelia mount an innate immune response that includes the production of antimicrobial peptides. However, the pathways that connect infection and inflammation with the induction of antimicrobial peptides in epithelia are not understood. We analyzed the molecular links between infection and the expression of three antimicrobial peptides of the beta-defensin family, human beta-defensin (hBD)-1, hBD-2, and hBD-3 in the human epidermis. After exposure to microbe-derived molecules, both monocytes and lymphocytes stimulated the epidermal expression of hBD-1, hBD-2, and hBD-3. The induced expression of hBD-3 was mediated by transactivation of the epidermal growth factor receptor. The mechanisms of induction of hBD-1 and hBD-3 were distinct from each other and from the IL-1-dependent induction of hBD-2 expression. Thus during inflammation, epidermal expression of beta-defensins is mediated by at least three different mechanisms.

Pathologic analysis of sentinel lymph nodes in melanoma patients: current and future trends.

Sentinel lymph node dissection (SLND) has become the standard of care for the staging of clinically-node negative melanomas and breast cancers. A large literature documents the efficacy of SLND in the staging of melanoma and breast cancer. The SLND has lower associated patient morbidity in comparison to elective node dissections that remove the closest regional-draining node group. SLND has improved accuracy over traditional regional node dissection for the staging of melanoma. Currently, several multicenter trials are evaluating the prognostic significance of melanoma micrometastases in SLN detected by immunohistochemical and molecular methods. Pending trial outcome analysis, SLND has no proven effect on mortality. However, given the current oncologic emphasis on detection and removal of nodal tumor metastases, the technique has an important role in minimizing the invasiveness of tumor staging for melanoma and breast cancer. As long as lymph node metastases are used for staging solid malignancies, surgical pathologists are likely to encounter SLN excisional biopsies as a part of their routine practice.

The place of lymphatic mapping and sentinel node biopsy in oncology.

The techniques of sentinel lymphatic mapping (LM) and sentinel lymph node biopsy (SLNB) have become almost routine for the staging of clinically node-negative patients with high-risk cutaneous melanoma. The techniques are also widely applied to staging of the axilla in breast cancer. Investigations of the use of LM and SLNB for other solid malignancies have also shown promise. LM/SLNB requires a multidisciplinary effort involving experienced surgeons, nuclear medicine physicians, and surgical pathologists. The techniques require a learning curve for all involved personnel, requiring experience with at least 30 cases followed by complete nodal dissection after SLNB to achieve full competency. Surgical pathologists play a pivotal role in determining optimum sentinel node analysis. The techniques have lower morbidity and greater accuracy than traditional complete regional node dissection. Pathologists are receiving increasing numbers of SLN specimens and are expected to evaluate the results of the application of the LM/SLNB techniques to a range of solid tumors. We have reviewed LM/SLNB in regard to melanoma and breast cancer and other types of malignancies. The techniques have much to offer, but despite their seeming simplicity, need considerable technical skill and clinical judgment if they are to be effectively applied. They also provide unique opportunities for basic and translational research.

By IL-1 signaling, monocyte-derived cells dramatically enhance the epidermal antimicrobial response to lipopolysaccharide.

Epithelia react to microbial pathogens by mounting a defensive response that includes the production of antimicrobial peptides. In this study, we show that, in human epidermal cultures, Escherichia coli LPS was a very weak direct inducer of human beta-defensin (HBD)-2 mRNA and peptide, but the induction was greatly amplified when monocyte-derived cells (MoDeC) acted as intermediaries between LPS and the epidermis. IL-1R antagonist largely reversed the effect of MoDeC on epidermal HBD-2, indicating that, from among the many products of MoDeC, IL-1 was the dominant inducer of HBD-2 synthesis. In normal fresh human skin, which contains Langerhans cells and other myeloid cell types, in addition to keratinocytes, LPS also induced HBD-2 in an IL-1-dependent manner. In DNA microarray expression studies, HBD-2 was one of the most abundant mRNAs induced in epidermis by LPS-treated MoDeC, and its induction was reversed by IL-1Ra. Thus, epidermal response to LPS is potently amplified by MoDeC through IL-1-mediated signaling, leading to a selective increase in the synthesis of the antimicrobial peptide HBD-2. This pattern of responses establishes a key role for both IL-1 and HBD-2 in the host defense reaction of the epidermis.

Pseudomyxoma peritonei is a disease of MUC2-expressing goblet cells.

Pseudomyxoma peritonei, a syndrome first described by Karl F. Rokitansky in 1842, is an enigmatic, often fatal intra-abdominal disease characterized by dissecting gelatinous ascites and multifocal peritoneal epithelial implants secreting copious globules of extracellular mucin. Although past interest in the syndrome has focused on the questions of the site of origin (appendix versus ovary), mechanisms of peritoneal spread (multicentricity, redistribution phenomenon, or metastasis), and the degree of malignant transformation present (adenoma, borderline tumor, or carcinoma), another important question is the mechanism behind the accumulation of extracellular mucin, the real cause of the disease's morbidity and mortality irrespective of the site of origin, mechanism of peritoneal spread, or transformed status of its epithelium. Taking advantage of the recently cloned human mucin genes, we decided to investigate this question. Our studies revealed that pseudomyxoma peritonei is a disease of MUC2-expressing goblet cells. These cells also express MUC5AC but the latter mucin is not specific for pseudomyxoma peritonei. MUC2 expression accounts for the voluminous deposits of extracellular mucin (mucin:cell ratios exceeding 10:1) and distinguishes pseudomyxoma peritonei secondarily involving the ovary from primary ovarian mucinous tumors with peritoneal implants. Because mucinous tumors of the appendix similarly express MUC2, the MUC2 expression profile also supports an appendiceal rather than ovarian origin for pseudomyxoma peritonei. Increased steady-state mRNA is observed in pooled cases of pseudomyxoma peritonei but does not occur on the basis of gene rearrangement or gene amplification. Primary epithelial cell cultures obtained from pseudomyxoma peritonei express MUC2 whose levels can be epigenetically regulated. These lines up-regulate MUC2 expression in response to both methylation inhibition by 5-azacytidine and exposure to Pseudomonas aeruginosa lipopolysaccharide, both of whose effects can be suppressed by genistein pretreatment. Both immunocytochemical as well as in situ hybridization studies with ancillary digital image analysis reveal that MUC2 expression in cases of pseudomyxoma peritonei is independent of the degrees of malignant transformation that are present and, in fact, reflects the constitutive levels of expression observed in normal goblet cells of the appendix. Extracellular mucin accumulates dramatically in pseudomyxoma peritonei because the number of MUC2-secreting cells dramatically increase and because this MUC2 has no place to drain. These studies suggest that pseudomyxoma peritonei should be regarded as a disease of MUC2-expressing goblet cells whose MUC2 expression might be susceptible to pharmacological targeting.

Galectin-1-mediated apoptosis in mycosis fungoides: the roles of CD7 and cell surface glycosylation.

Sezary cells, the malignant T cells in mycosis fungoides/Sezary syndrome, resist a variety of apoptosis-inducing agents, a feature that contributes to the poor response to therapy in mycosis fungoides. Galectin-1 is a mammalian lectin that triggers T cell apoptosis. For T cells to be susceptible to galectin-1-induced apoptosis, the T cells must express specific glycoprotein receptors, such as CD7, that bear the specific oligosaccharides recognized by galectin-1. Because Sezary cells are characteristically CD7(-), lack of CD7 expression has been proposed to render Sezary cells resistant to galectin-1-induced death. However, the role played by aberrant cell surface glycosylation in resistance of Sezary cells to galectin-1 has not been examined. In this study, we demonstrated abundant galectin-1 in mycosis fungoides skin lesions, indicating that Sezary cells are exposed to galectin-1 in vivo. To determine specific characteristics of Sezary cells that contribute to galectin-1 resistance, we assessed CD7 expression and cell surface glycosylation of Sezary cells in mycosis fungoides lesions and of four Sezary T cell lines. Sezary cells in primary lesions and Sezary T cell lines demonstrated a characteristic "glycotype" with sialylated core 1 O-glycans that promote galectin-1 resistance. Expression of CD7 was necessary but not sufficient for galectin-1-induced death of Sezary cell lines. In addition, CD7(-) Sezary cell lines, and Sezary cells within mycosis fungoides lesions, expressed galectin-1, whereas CD7-positive Sezary cell lines did not express galectin-1. We propose that both loss of CD7 expression and altered cellular glycosylation contribute to apoptosis resistance of malignant T cells in mycosis fungoides.