Role of histological findings and pathologic diagnosis for detection of human papillomavirus infection in men.

Early HPV infection in males is difficult to detect clinically and pathologically. This study assessed histopathology in diagnosing male genital HPV. External genital lesions (n = 352) were biopsied, diagnosed by a dermatopathologist, and HPV genotyped. A subset (n = 167) was diagnosed independently by a second dermatopathologist and also re-evaluated in detail, tabulating the presence of a set of histopathologic characteristics related to HPV infection. Cases that received discrepant diagnoses or HPV-related diagnoses were evaluated by a third dermatopathologist (n = 163). Across dermatopathologists, three-way concordance was fair (k = 0.30). Pairwise concordance for condyloma was fair to good (k = 0.30-0.67) and poor to moderate for penile intraepithelial neoplasia (k = -0.05 to 0.42). Diagnoses were 44-47% sensitive and 65-72% specific for HPV 6/11-containing lesions, and 20-37% sensitive and 98-99% specific for HPV 16/18. Presence of HPV 6/11 was 75-79% sensitive and 35% specific for predicting pathologic diagnosis of condyloma. For diagnosis of penile intraepithelial neoplasia, HPV 16/18 was 95-96% specific but only 40-64% sensitive. Rounded papillomatosis, hypergranulosis, and dilated vessels were significantly (P < 0.05) associated with HPV 6/11. Dysplasia was significantly (P = 0.001) associated with HPV 16/18. Dermatopathologists' diagnoses of early male genital HPV-related lesions appear discordant with low sensitivity, while genotyping may overestimate clinically significant HPV-related disease. Rounded papillomatosis, hypergranulosis, and dilated vessels may help establish diagnosis of early condyloma.

STIM1- and Orai1-mediated Ca(2+) oscillation orchestrates invadopodium formation and melanoma invasion.

Ca(2+) signaling has been increasingly implicated in cancer invasion and metastasis, and yet, the underlying mechanisms remained largely unknown. In this paper, we report that STIM1- and Orai1-mediated Ca(2+) oscillations promote melanoma invasion by orchestrating invadopodium assembly and extracellular matrix (ECM) degradation. Ca(2+) oscillation signals facilitate invadopodial precursor assembly by activating Src. Disruption of Ca(2+) oscillations inhibited invadopodium assembly. Furthermore, STIM1 and Orai1 regulate the proteolysis activity of individual invadopodia. Mechanistically, Orai1 blockade inhibited the recycling of MT1-matrix metalloproteinase (MMP) to the plasma membrane and entrapped MT1-MMP in the endocytic compartment to inhibit ECM degradation. STIM1 knockdown significantly inhibited melanoma lung metastasis in a xenograft mouse model, implicating the importance of this pathway in metastatic dissemination. Our findings provide a novel mechanism for Ca(2+)-mediated cancer cell invasion and shed new light on the spatiotemporal organization of store-operated Ca(2+) signals during melanoma invasion and metastasis.

Senescent fibroblasts in melanoma initiation and progression: an integrated theoretical, experimental, and clinical approach.

We present an integrated study to understand the key role of senescent fibroblasts in driving melanoma progression. Based on the hybrid cellular automata paradigm, we developed an in silico model of normal skin. The model focuses on key cellular and microenvironmental variables that regulate interactions among keratinocytes, melanocytes, and fibroblasts, key components of the skin. The model recapitulates normal skin structure and is robust enough to withstand physical as well as biochemical perturbations. Furthermore, the model predicted the important role of the skin microenvironment in melanoma initiation and progression. Our in vitro experiments showed that dermal fibroblasts, which are an important source of growth factors in the skin, adopt a secretory phenotype that facilitates cancer cell growth and invasion when they become senescent. Our coculture experiments showed that the senescent fibroblasts promoted the growth of nontumorigenic melanoma cells and enhanced the invasion of advanced melanoma cells. Motivated by these experimental results, we incorporated senescent fibroblasts into our model and showed that senescent fibroblasts transform the skin microenvironment and subsequently change the skin architecture by enhancing the growth and invasion of normal melanocytes. The interaction between senescent fibroblasts and the early-stage melanoma cells leads to melanoma initiation and progression. Of microenvironmental factors that senescent fibroblasts produce, proteases are shown to be one of the key contributing factors that promoted melanoma development from our simulations. Although not a direct validation, we also observed increased proteolytic activity in stromal fields adjacent to melanoma lesions in human histology. This leads us to the conclusion that senescent fibroblasts may create a prooncogenic skin microenvironment that cooperates with mutant melanocytes to drive melanoma initiation and progression and should therefore be considered as a potential future therapeutic target. Interestingly, our simulations to test the effects of a stroma-targeting therapy that negates the influence of proteolytic activity showed that the treatment could be effective in delaying melanoma initiation and progression.

GSK3ß inhibition blocks melanoma cell/host interactions by downregulating N-cadherin expression and decreasing FAK phosphorylation.

This study addresses the role of glycogen synthase kinase (GSK)-3ß signaling in the tumorigenic behavior of melanoma. Immunohistochemical staining revealed GSK3ß to be focally expressed in the invasive portions of 12 and 33% of primary and metastatic melanomas, respectively. GSK3 inhibitors and small interfering RNA (siRNA) knockdown of GSK3ß were found to inhibit the motile behavior of melanoma cells in scratch wound, three-dimensional collagen-implanted spheroid, and modified Boyden chamber assays. Functionally, inhibition of GSK3ß signaling was found to suppress N-cadherin expression at the messenger RNA and protein levels, and was associated with decreased expression of the transcription factor Slug. Pharmacological and genetic ablation of GSK3ß signaling inhibited the adhesion of melanoma cells to both endothelial cells and fibroblasts and prevented transendothelial migration, an effect rescued by the forced overexpression of N-cadherin. A further role for GSK3ß signaling in invasion was suggested by the ability of GSK3ß inhibitors and siRNA knockdown to block phosphorylation of focal adhesion kinase (FAK) and increase the size of focal adhesions. In summary, we have, to our knowledge, demonstrated a previously unreported role for GSK3ß in modulating the motile and invasive behavior of melanoma cells through N-cadherin and FAK. These studies suggest the potential therapeutic utility of inhibiting GSK3ß in defined subsets of melanoma.

Recent advances in pathologic evaluation and reporting of melanoma.

Recent changes to the staging of melanoma, coupled with advances in surgical and medical treatment, have resulted in new methods for diagnostic evaluation and reporting of melanocytic lesions by pathologists. This review provides an update on recent changes in evaluation and reporting of primary melanoma, evaluation of regional lymph nodes, especially sentinel nodes, and the workup of distant metastatic melanoma specimens. A brief summary of commercially available molecular diagnostic techniques and their application to practice is included.

CD4/CD8 dual-positive mycosis fungoides: a previously unrecognized variant.

Mycosis fungoides (MF) is a primary cutaneous lymphoma characterized by atypical T-lymphocytes that usually presents as patches and plaques on photoprotected areas of the body, such as the groin and buttocks. Classically, the atypical lymphocytes in MF are CD3/CD4 positive with loss of CD7 and less often loss of CD5. In a minority of cases, the atypical infiltrate is CD8 positive. We report a case of biopsy-proven MF in an elderly woman who presented with sclerodermoid lesions on her abdomen and thigh. Immunohistochemical studies revealed coexpression of CD4 and CD8 in a subset of atypical T-lymphocytes, and this was confirmed with flow cytometry. To our knowledge, this is the first report of a CD4/CD8 dual-positive MF.

Cutaneous manifestations in CMML: Indication of disease acceleration or transformation to AML and review of the literature.

Our retrospective analysis explored the role of leukemia cutis (LC) in disease progression of chronic myelomonocytic leukemia (CMML). Of 108 patients with CMML, 11 patients (10.2%) had LC including its equivalent (2 patients). Four of these patients developed acute myeloid leukemia (AML) within 0-4 months. The remaining 7 patients demonstrated increased monocytes (<20% blasts), with 3 demonstrating extramedullary involvement. Overall survival from LC to disease progression was 7.8 months. Overall survival from diagnosis to the last follow-up in patients with LC was 28.2 months, shorter than patients without LC (44 months). LC and its equivalent could predict disease progression to AML.

Expression of alpha-methylacyl-CoA racemase (P504S) in sebaceous neoplasms.

BACKGROUND: Alpha-methylacyl-CoA racemase (AMACR), also known as P504S, is a protein that plays an important role in mitochondrial and peroxisomal beta-oxidation of branched-chain fatty acid and bile acid intermediates. AMACR has been established as a valuable diagnostic marker for prostate cancer and has recently been shown to be useful in the diagnosis of colorectal carcinoma. Despite the importance of lipid metabolism in sebum production by sebaceous glands of the skin, there are no studies evaluating the expression of AMACR in sebaceous neoplasms. METHODS: Five samples of normal sebaceous glands as well as five cases each of sebaceous hyperplasia (SH), sebaceous adenoma (SA), basal cell carcinoma (BCC) with sebaceous differentiation and extraocular sebaceous carcinoma (SC) were evaluated for immunohistochemical (IHC) expression of AMACR. Each case was reviewed by a single dermatopathologist and graded using a semi-objective grading schema. RESULTS: Normal sebaceous glands showed strong (4+) expression of AMACR. Among sebaceous neoplasms, SH showed the highest expression (4+), SA and BCC with sebaceous differentiation showed varied expression (2+ and 1+, respectively), and extraocular SC showed no expression of AMACR. CONCLUSIONS: The expression of AMACR is increased in benign sebaceous glands and SH; with decreasing AMACR expression in tumors with less sebaceous differentiation (i.e. SA and SC). These findings provide insight into the potential pathogenesis of sebaceous neoplasms while assisting in the microscopic distinction of SA from SC.

Discordant omphalocele-exstrophy-imperforate anus-spinal defects (OEIS) complex and cardiac malformations in monochorionic twins.

The omphalocele-exstrophy-imperforate anus-spinal defects (OEIS) complex was first described by Carey et al. in 1978. It constitutes a specific combination of malformations. There are very few case reports of discordant OEIS in monozygotic twins and very few reports of OEIS in association with both hypoplastic left heart and ventricular septal defect. Our case represents the fifth reported case of cardiac malformations in a fetus with OEIS complex.

Bif-1 and Bax expression in cutaneous Merkel cell carcinoma.

BACKGROUND: Bax-interacting factor-1 (Bif-1) binds to Bax, which in turn activates this proapoptotic protein. In the absence of Bif-1, the ability to induce apoptosis through the intrinsic pathway is greatly reduced. Merkel cell carcinoma (MCC) classically shows an aggressive behavior and lack of response to chemotherapy, which remains unexplained. Previous studies have documented the presence of Bax in MCC, but Bif-1 expression has not been evaluated. Herein, the expression of Bif-1 and Bax in cutaneous MCC is examined. MATERIALS AND METHODS: The immunohistochemical expression of Bif-1 and Bax protein was examined in nine cases of MCC. Both positive and negative controls were conducted. All the cases were reviewed by a single dermatopathologist. RESULTS: Bif-1 was detected in nine cases (100%), and Bax was expressed in six cases (66%). The percent positive cells for Bif-1 in MCC ranged from 85% to 98% positive (mean 93.9%). At the same time, decreased Bax expression was shown with 0-8% positive cells (mean 3.45%). CONCLUSION: The increased expression of Bif-1 in MCC is associated with low levels of Bax staining. These findings suggest that the upregulation of Bif-1 could in part be responsible for tumorigenesis in cutaneous MCC. As shown, Bax and Bif-1 expression are not exclusively antithetical; therefore, future studies evaluating the expression of both proteins should be conducted.

CD117 immunoreactivity in atypical fibroxanthoma.

Atypical fibroxanthoma (AFX) is a spindle cell neoplasm of the skin seen typically on sun-damaged skin of the elderly. Though described as a benign entity, local recurrence and distant metastasis have been reported. This study aims to investigate the potential pathogenic role of CD117, the c-kit receptor in AFX. CD117 was detected in 15 of the 16 cases (94%). The percentage of positive cells for CD117 expression among all tumors was approximately 30%. CD117 proved to be a very sensitive marker of AFX. This antibody may be a useful diagnostic adjunct in AFX.

Purple penile papules.

Molluscum contagiosum may present in a variety of clinical and pathologic guises. We present the clinicopathologic features of an unusual case that initially was misinterpreted as bowenoid papulosis. The relevant histologic attributes of this case include the presence of a violaceous hyperplastic squamous epithelium adjacent to the infected keratinocytes. The presence of this violaceous cytoplasmic staining should prompt a search for molluscum in the appropriate clinical context.

Dermal atypical lipomatous tumor/well-differentiated liposarcoma obfuscated by epidermal inclusion cyst: a wolf in sheep's clothing?

Epidermal inclusion cysts are an exceedingly common entity seldom seen in association with a malignant tumor. Herein, we report a unique case of an epithelial inclusion cyst seen in association with an atypical lipomatous tumor/well-differentiated liposarcoma. The epidermal inclusion cyst was delimited to the dermis and circumferentially enveloped by an atypical adipocyte tumor containing myxoid foci and comprised of lipoblasts. This case underscores the importance of scrutinizing the entirety of cysts and other ostensibly trivial dermal entities to avoid the pitfall of misdiagnosing a potentially serious tumor.