Faculty Bibliography

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare premature aging disorder caused by a de novo heterozygous point mutation G608G (GGC>GGT) within exon 11 of LMNA gene encoding A-type nuclear lamins. This mutation elicits an internal deletion of 50 amino acids in the carboxyl-terminus of prelamin A. The truncated protein, progerin, retains a farnesylated cysteine at its carboxyl terminus, a modification involved in HGPS pathogenesis. Inhibition of protein farnesylation has been shown to improve abnormal nuclear morphology and phenotype in cellular and animal models of HGPS. We analyzed global gene expression changes in fibroblasts from human subjects with HGPS and found that a lamin A-Rb signaling network is a major defective regulatory axis. Treatment of fibroblasts with a protein farnesyltransferase inhibitor reversed the gene expression defects. Our study identifies Rb as a key factor in HGPS pathogenesis and suggests that its modulation could ameliorate premature aging and possibly complications of physiological aging.

CD200 (OX-2) is a cell surface glycoprotein that imparts immune privileges by suppressing alloimmune and autoimmune responses through its receptor, CD200R, expressed primarily on myeloid cells. The ability of CD200 to suppress myeloid cell activation is critical for maintaining normal tissue homeostasis but may also enhance the survival of migratory neoplastic cells. We show that CD200 expression is largely absent in well-differentiated primary squamous cell carcinoma (SCC) of the skin, but is highly induced in SCC metastases to the lymph node and other solid tissues. CD200 does not influence the proliferative or invasive capacity of SCC cells or their ability to reconstitute primary skin tumors. However, loss of CD200 impairs the ability of SCC cells to metastasize and seed secondary tumors, indicating that the survival of CD200(+) SCC cells may depend on their ability to interact with CD200R(+) immune cells. The predominant population of CD200R(+) stromal cells was CD11b(+)Gr-1(+) myeloid-derived suppressor cells, which release elevated levels of granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor when in the presence of SCC cells in a CD200-dependent manner. Collectively, our findings implicate CD200 as a hallmark of SCC metastasis and suggest that the ability of CD200(+) SCC keratinocytes to directly engage and modulate CD200R(+) myeloid-derived suppressor cells is essential to metastatic survival.

BACKGROUND:Dermatofibrosarcoma protuberans (DFSP) is an unusual soft-tissue tumor with a propensity for subclinical extension and local recurrence. Surgical excision, even with tissue-sparing techniques, may cause significant deformity or disability because of the infiltrative nature of DFSP. In this study, we evaluate retrospective data obtained from 4 patients with locally advanced or recurrent DFSP who received neoadjuvant imatinib mesylate therapy before undergoing Mohs micrographic surgery. OBSERVATIONS/METHODS:Patients treated with neoadjuvant imatinib therapy had an average tumor size reduction of 36.9%. This clinical response was paralleled by histopathologic changes, including decreased cellularity in 100% of the total area as well as significant hyalinization. Imatinib therapy for DFSP before Mohs micrographic surgery was associated with 100% local control at a maximum follow-up of 4 years. CONCLUSIONS:Neoadjuvant imatinib therapy is a well-tolerated, novel approach to DFSP that reduces tumor burden and facilitates resection. Larger prospective studies are needed to confirm and expand on these results.

The risk of invasion and destruction of cranium, underlying dura, and cranial nerves by basal cell carcinoma (BCC) is extremely low, with an estimated incidence of 0.03%. Intracranial BCC invasion by direct extension is rare, and orbital spread from a nasal lesion has not been reported in the literature. We describe a case of intracranial invasion of a multiply recurrent nasal BCC, which caused progressive bilateral blindness from optic nerve compression, with spinal canal involvement causing subsequent lower extremity weakness and paralysis. This case underscores the importance of early and appropriate treatment of high risk BCC, and aggressive treatment of recurrent lesions as early as possible.

Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare disorder characterized by accelerated aging and early death, frequently from stroke or coronary artery disease. 90% of HGPS cases carry the LMNA G608G (GGC>GGT) mutation within exon 11 of LMNA, activating a splice donor site that results in production of a dominant negative form of lamin A protein, denoted progerin. Screening 150 skin biopsies from unaffected individuals (newborn to 97 years) showed that a similar splicing event occurs in vivo at a low level in the skin at all ages. While progerin mRNA remains low, the protein accumulates in the skin with age in a subset of dermal fibroblasts and in a few terminally differentiated keratinocytes. Progerin-positive fibroblasts localize near the basement membrane and in the papillary dermis of young adult skin; however, their numbers increase and their distribution reaches the deep reticular dermis in elderly skin. Our findings demonstrate that progerin expression is a biomarker of normal cellular aging and may potentially be linked to terminal differentiation and senescence in elderly individuals.

As transplant medicine advances, new immunosuppressive regimens are increasing the long-term survival of solid organ transplant recipients (SOTRs). This growing population is at significantly increased risk for developing cutaneous malignancies, particularly squamous cell carcinoma (SCC), as a result of chronic immunosuppression. Conventional risk factors for the development of skin cancer, including fair skin type, advanced age, sun exposure, and genetic predisposition, also play a crucial role in the initiation and progression of SCC in SOTRs. Immunosuppressed patients develop more aggressive and more numerous SCCs than immunocompetent individuals, however. It is important to understand the mechanisms underlying immunosuppression-mediated SCC development to identify prognostic markers and to develop effective prevention and treatment strategies. This article addresses the fundamental differences between SCC in SOTRs and those in the general population, focusing on the role that immunosuppression plays in the pathogenesis of this malignancy.

BACKGROUND:The purpose of this study was to analyze available datasets to assess the degree of asymmetry typically associated with DFSP, and to study the optimal surgical approach for extirpating these tumors by clearing lateral margins. METHODS:MEDLINE (1994-2004) was searched for English-language multi-patient series concerning DFSP. Case series were included if complete information could be obtained for: (a) two-dimensional preoperative tumor size as measured on the skin surface before removal; (b) postoperative tumor size, as estimated by the dimensions of the final wound defect. Four case series met these criteria, and the authors were contacted directly for unpublished raw data. RESULTS:For each of 98 included tumors we computed: (1) the tumor index, a measure of clinically apparent tumor surface area; (2) clearance margin, or the theoretical best and worst-case surgical margins that would have been required for tumor clearance. We used this information to (a) assess the relationship between clinically apparent tumor size and final surgical margin; (b) determine the proportion of tumors of a given size that would be cleared by a margin of given width. We found that standard wide excision margin of 4 cm was predicted to provide a tumor clearance rate of 95% for tumors of preoperative size less than or equal to 3 cm x 3 cm. CONCLUSIONS:There is a weak relationship between preoperative tumor size and the width of the final defect after clearance. Based on our calculations, very wide local excision is necessary for clearance of most DFSPs.