Low-affinity nerve growth factor receptor (P75 NGFR) as a marker of perineural invasion in malignant melanomas.

BACKGROUND: Perineural invasion (PNI) is a well-recognized route of tumor extension in cutaneous neoplasms. Despite an established association with increased local recurrences and metastases, the mechanisms responsible for PNI have yet to be elucidated. We hypothesize that P75 NGFR, a nerve growth factor receptor, may be implicated in the pathogenesis of PNI in these tumors. METHODS: P75 NGFR immunohistochemical staining was performed on 47 skin tumors with PNI including invasive squamous cell carcinomas (SCCs = 29), basal cell carcinomas (BCCs = 8) and malignant melanomas (MMs = 10). These were compared with similar lesions without PNI (SCCs = 7, BCCs = 7 and MMs = 9). RESULTS: P75 NGFR staining was absent in all invasive SCCs irrespective of the presence of PNI (n = 0/36). Two BCCs with PNI (n = 2/8) and three without PNI (n = 3/7) showed focal P75 NGFR staining. Interestingly, 8 of 10 invasive MMs with PNI had positive P75 NGFR expression (80%), in contrast to only 1 of 9 without PNI (11%). CONCLUSIONS: P75 NGFR may play a mechanistic role in invasive MMs demonstrating PNI. Furthermore, its expression may serve as a marker of PNI in those tumors that lack histological evidence of nerve involvement at the time of excision.

Melanocytic nevi in pregnancy: histologic features and Ki-67 proliferation index.

BACKGROUND: Changes in the clinical appearance of benign dermal nevi during pregnancy may be concerning for malignant transformation. Because the hormonal milieu of pregnancy has not proven to alter their banal behavior, histologic characterization is needed to prevent over-diagnosis and unnecessary treatment. METHODS: Dermal nevi excised from pregnant women (n = 16) were compared with nevi from location- and aged-matched control patients (n = 15). Histologic features and Ki-67 proliferation index were evaluated. RESULTS: Nevi in pregnancy were more likely to have dermal mitotic figures (62.5% vs. 13.3%, p = 0.028) and higher mitotic rates (1.44 vs. 0.20 mitoses/mm(2), p = 0.0027) than control nevi. A distinctive histologic entity, termed superficial micronodules of pregnancy (SMOPs), was observed more frequently in the nevi of pregnancy (81.3% vs. 26.7%, p = 0.040), and showed consistent immunoreactivity for HMB45. There was a trend toward higher Ki-67 proliferation index in the nevi of pregnancy (3.0% vs. 1.0%, p = 0.073). Prominent multinucleated melanocytes were seen only in controls. There was no significant difference in pigmentation or irritation changes between groups. CONCLUSIONS: Dermal nevi removed during pregnancy show characteristic histologic features including increased dermal mitoses, superficial micronodules of pregnancy (SMOPs), and trend toward increased Ki-67 proliferation index.

Autologous Graft Thickness Affects Scar Contraction and Quality in a Porcine Excisional Wound Model.

BACKGROUND: Texture, color, and durability are important characteristics to consider for skin replacement in conspicuous and/or mobile regions of the body such as the face, neck, and hands. Although autograft thickness is a known determinant of skin quality, few studies have correlated the subjective and objective characters of skin graft healing with their associated morphologic and cellular profiles. Defining these relationships may help guide development and evaluation of future skin replacement strategies. METHODS: Six-centimeter-diameter full-thickness wounds were created on the back of female Yorkshire pigs and covered by autografts of variable thicknesses. Skin quality was assessed on day 120 using an observer scar assessment score and objective determinations for scar contraction, erythema, pigmentation, and surface irregularities. Histological, histochemical, and immunohistochemical assessments were performed. RESULTS: Thick grafts demonstrated lower observer scar assessment score (better quality) and decreased erythema, pigmentation, and surface irregularities. Histologically, thin grafts resulted in scar-like collagen proliferation while thick grafts preserves the dermal architecture. Increased vascularity and prolonged and increased cellular infiltration were observed among thin grafts. In addition, thin grafts contained predominately dense collagen fibers, whereas thick grafts had loosely arranged collagen. α-Smooth muscle actin staining for myofibroblasts was observed earlier and persisted longer among thinner grafts. CONCLUSIONS: Graft thickness is an important determinant of skin quality. High-quality skin replacements are associated with preserved collagen architecture, decreased neovascularization, and decreased inflammatory cellular infiltration. This model, using autologous skin as a metric of quality, may give a more informative analysis of emerging skin replacement strategies.

Effective treatment of rumination with Nissen fundoplication.

Rumination is a syndrome characterized by the effortless regurgitation of recently ingested food. It has been linked to severe medical and psychosocial conditions including malnutrition, aspiration pneumonia, and complete social withdrawal. Psychotherapy, the current treatment modality for rumination, may improve symptoms but requires significant motivation and is rarely curative. We hypothesized that a complete fundoplication would eliminate, or at least impair, the ability to regurgitate gastric contents through the esophagogastric junction. We performed a Nissen fundoplication in five patients with a classic history of rumination. In all cases, symptoms had been resistant to medical and psychiatric intervention prior to fundoplication. Formal preoperative testing included esophageal manometry, 24-hour pH monitoring, endoscopy, and upper gastrointestinal barium swallow studies. All patients reported their primary symptom to be effortless recurrent postprandial regurgitation for 1 to 2 hours after meals consistent with rumination. Four (80%) of the five patients had low resting lower esophageal sphincter pressures with evidence of gastroesophageal reflux disease on 24-hour pH monitoring. All patients reported complete cessation of ruminating behavior after Nissen fundoplication. We report, for the first time, complete elimination of rumination symptoms after a Nissen fundoplication. Although further trials are needed to confirm our results, we recommend considering a Nissen fundoplication for treatment of rumination refractory to behavioral and medical interventions.

Serial transplantation of NMU-induced rat mammary tumors: a model of human breast cancer progression.

Human breast cancer is a heterogeneous disease that appears to progress from an in situ tumor to invasive cancer. Little is known about the molecular events driving this progression. Although microarray technology has helped us understand the genetic heterogeneity of breast cancer, its application to studying the transition from in situ to invasive disease is limited by the inability to follow the progression of a single patient's tumor. We previously used rat specific microarrays to show that N-methyl-N-nitrosourea induced tumors are similar to low-grade estrogen-receptor positive human breast cancer. Here, we transplanted these tumors through 5 generations of syngeneic hosts, and studied 65 resulting tumors. Most transplanted tumors gradually progressed from a noninvasive, low-grade cancer to a higher-grade invasive disease, losing p63 localization and basement membrane integrity. Invasive cancers frequently demonstrated a more mesenchymal phenotype with increased vimentin expression. Additionally, a unique transplant series is described with a phenotype similar to human basal-like breast cancer. Rat-specific Affymetrix gene arrays containing 15,866 gene probes identified genes that differentiated highly invasive tumors from those of low invasive potential. A linear regression analysis was used to find genes whose change in expression paralleled increasing invasive features independent of the transplant lineage of origin. Genes identified were assigned membership in cell adhesion, signal transduction, cell cycle and extracellular matrix groups, among others. This animal model overcomes the difficulty in studying human breast cancer progression. Our data support a gradual and continuous alteration in programs of gene expression during breast cancer invasion.

Gene expression profiling of NMU-induced rat mammary tumors: cross species comparison with human breast cancer.

Breast cancer is a complex genetic disease characterized by the accumulation of multiple molecular alterations. The NMU breast cancer model induced in the rat is used for the study of mammary carcinogenesis because it closely mimics human breast disease. To assess the validity of this model from a more global molecular perspective, and also to devise a general technique to compare animal profiles with human microarray studies, we have characterized 25 NMU-induced mammary tumors and 11 normal glands using a combination of immunohistochemical and microarray analyses. The rat mammary carcinomas were classified as non-invasive, ER-positive ductal carcinomas with a composition of differentiated epithelial and myoepithelial cell lineages. Gene expression profiles generated using rat Affymetrix arrays containing 15,866 genes demonstrated that the rat mammary tumors are homogeneous and that H-ras mutations did not confer a unique molecular signature. We compared the resulting rat profiles with those obtained from a human dataset by merging the raw microarray data, using an approach that involves a combination of cross-species and cross-platform analysis. Using this novel strategy, we demonstrate the ability of 2305 rat orthologs to recapitulate the classification of human tumors derived from human Affymetrix arrays. The gene expression profiles of the NMU-induced primary tumors were most similar to ER-positive, low to intermediate grade breast cancer. Our technique provides a means to correlate gene expression data from animal models of cancer to human cancer and disease states.