Marianna Shvartsbeyn

Epothilones in development for non--small-cell lung cancer: novel anti-tubulin agents with the potential to overcome taxane resistance.

Progress in the treatment of non-small-cell lung cancer (NSCLC) will require the introduction of new agents as well as better use of existing therapies. Targeted therapies are likely to have a profound effect on the treatment of NSCLC after identification of patients who are most likely to benefit. The epothilones are novel anti-tubulin agents derived from Sorangium cellulosum. β III tubulin overexpression has been implicated as a mechanism of anti-tubulin resistance that can be overcome by epothilones. Several epothilones have advanced to clinical trials; ixabepilone (BMS247550, aza-epothilone B, Bristol-Myers Squibb, New York, NY), patupilone (EPO906, Novartis, Basel, Switzerland) and sagopilone (ZK-EPO, ZK-219477, Schering AG, Berlin-Wedding, Germany) are currently in active development. Several of the epothilones, most notably ixabepilone, have demonstrated activity in lung cancer in phase I and II trials, including taxane-resistant patients. Although a phase II study failed to show superior outcome in patients with β III tubulin overexpression, other aspects of the epothilones argue for their continued development.

Dermal changes in superficial basal cell carcinoma, melanoma in situ and actinic keratosis and their implications

Basal cell carcinoma (BCC) has a characteristic stroma, but less is known about the dermal characteristics associated with melanoma in situ (MIS) and actinic keratosis (AK).

Perifollicular fibroma in Birt–Hogg–Dubé syndrome: an association revisited

Background: Mutation in the folliculin gene in Birt–Hogg–Dubé (BHD) syndrome leads to a spectrum of benign tumors of the hair follicle, classically including both fibrofolliculoma and trichodiscoma. In addition, lesions clinically indistinguishable from fibrofolliculoma/ trichodiscoma may show histopathologic findings of perifollicular fibroma or angiofibroma. Although some consider perifollicular fibroma to be a variant of angiofibroma, the specific histopathologic findings of perifollicular fibroma are uncommon.

Melanocytic tumor with GNA11 p.Q209L mutation mimicking a foramen magnum meningioma

Melanocytic tumors of the central nervous system arise from elanocytes normally found in the leptomeninges. They most comonly present as intradural-extramedullary lesions of the posterior ossa and cervical spine, but may occur throughout the neuraxis 1]. This group includes diffuse leptomeningeal melanocytosis and ocal tumors ranging from benign melanocytomas to malignant rimary CNS melanomas. Few tumors of intermediate grade (“atypcal” melanocytic tumors) have been reported [1]. Here we report n unusual intermediate-grade melanocytic tumor arising from he dura of the craniocervical junction. Its radiographic and gross ppearance were suggestive of a foramen magnum meningioma. Our ability to grade and treat CNS melanocytic tumors is limted by our poor understanding of their molecular derangements. here is some evidence that their pathogenesis resembles that of ther melanocytic neoplasms. In particular, uveal melanomas have een found to harbor frequent mutations of GNAQ [2] and GNA11 3], which encode components of two related G proteins. A recent

Silicon-associated subcutaneous lesion presenting as a mass: a confounding histopathologic correlation.

Liquid silicon used for soft tissue augmentation can produce different histologic patterns when implanted into the dermis or subcutis, depending on the degree of purification and the injected volume. The pure medical-grade silicon implanted in miniscule amounts in a controlled manner results in minimal fibroplasia without significant inflammation. The industrial-grade silicon contaminated by additives may remain dormant for years and eventually cause formation of extensive granulomas and disfiguring nodules. We report a case of a 35-year-old transsexual woman who presented with bilateral buttock masses. Histologic evaluation revealed collections of cells with lipid-containing cytoplasmic vacuoles resembling lipoblasts. This pattern can be clinically and histologically confusing for a neoplastic process, particularly when this adverse effect of adulterated silicon develops years after the injection.

Transformation of porokeratosis ptychotropica into invasive squamous cell carcinoma

A 70-year-old woman presented with a pruritic perianal eruption of 6 years’ duration. Her medical history included microscopic colitis and cervical carcinoma 30 years prior for which she underwent total abdominal hysterectomy, bilateral salpingooophorectomy, and cobalt-60 external beam radiotherapy. Physical examination revealed a pink, butterfly-shaped plaque with a raised, hyperkeratotic border involving the gluteal cleft and bilateral medial buttocks. A shave biopsy was performed, and clinicopathologic correlation led to the diagnosis of porokeratosis ptychotropica (PP) (Fig. 1). During intermittent follow-up over the next 9 years, the PP lesion expanded centrifugally and developed mild-to-moderate keratinocytic atypia as detected by three surveillance biopsies. Treatment with numerous topical and intralesional corticosteroids had minimal effect. During this time, the patient also developed a chronic ulcer overlying the coccyx. Eighteen years after initial presentation, a scaly, pink papule was noted within the PP lesion on the left medial buttock (Fig. 2a). A shave biopsy revealed invasive squamous cell carcinoma (ISCC) with overlying porokeratosis (Fig. 2b), which a surgical oncologist then excised. After Institutional Review Board approval, the PP/ISCC specimen was tested for human papillomaviruses (HPV) 6, 11, 16, and 18 by in situ hybridization. In addition, immunohistochemistry was performed using anti-p53, p16, and cyclin D1 antibodies (prediluted, Ventana/Roche, Ventana Medical Systems, Tucson, AZ, USA) with a Benchmark Ultra immunostainer (Ventana/Roche). Whereas the areas of PP expressed p16, those of ISCC lacked p16 expression (Fig. 2c). The specimen was negative for HPV and diffusely positive for p53 and cyclin D1.

Dysregulation of the microvasculature in nonlesional non-sun-exposed skin of patients with lupus nephritis.

Objective. Membrane endothelial protein C receptor (mEPCR) is highly expressed in peritubular capillaries of kidneys from patients with active and poorly responsive lupus nephritis (LN). We investigated the hypothesis that changes in the microvasculature are widespread with extension to the dermal vasculature. Methods. Skin biopsies from uninvolved skin (buttocks) were performed in 27 patients with LN and 5 healthy controls. Sections were stained with specific antibodies reactive with mEPCR, adiponectin, intercellular adhesion molecule-1 (ICAM-1), and CD31; then assessed by enumeration of stained blood vessels (percentage positive blood vessels) blinded to knowledge of clinical information. Results. There was a significant increase in the prevalence of blood vessels that stained for mEPCR and ICAM-1 in patients compared to controls [94% vs 59% (p = 0.045) and 81% vs 67% (p = 0.037), respectively]. Adiponectin staining and CD31 staining were similar between the groups (45% vs 43% and 98% vs 92%). Dermal staining for mEPCR was greater in patients with proliferative glomerulonephritis than in those with membranous disease (96% vs 60%; p = 0.029). A composite of poor prognostic renal markers and death was significantly associated with greater expression of mEPCR staining. Conclusion. These data are consistent with the notion that in patients with LN, activation of the microvasculature extends beyond the clinically targeted organ. The insidious expression of this widespread vasculopathy may be a contributor to longterm comorbidities.

Cocaine-induced intracerebral hemorrhage in a patient with cerebral amyloid angiopathy.

Abstract:  Intracerebral hemorrhage (ICH) is a well‐recognized complication of recreational cocaine use. The precise mechanism of the cocaine‐induced hemorrhagic event is unclear, although multiple factors have been implicated. We report a case of a 62‐year‐old woman who suffered left parieto‐occipital ICH with herniation and death, following a cocaine binge. Microscopic examination also revealed extensive cerebral amyloid angiopathy (CAA) in the vicinity of the hemorrhage. We additionally studied brain tissue in eight subjects between ages of 60 and 80 who were positive for cocaine metabolites at autopsy; of these, none had vascular amyloid‐β deposits by immunohistochemistry. Whereas we found no evidence that chronic cocaine use is a risk factor for CAA, given the age‐associated nature of CAA and the aging population using cocaine, CAA‐induced hemorrhage in the setting of cocaine use may be more common than recognized. This is the first reported case of CAA‐associated ICH precipitated by cocaine.

Pseudocystic dermatofibrosarcoma protuberans: report of two cases and demonstration of COL1A1-PDGFB rearrangement.

We report two unique cases of dermatofibrosarcoma protuberans (DFSP) that included a pseudocystic component. Molecular analysis of one of the cases showed a characteristic COL1A1‐PDGFB rearrangement in both the main tumor and also in the cells lining the pseudocystic portion of the tumor, confirming the diagnosis and indicating that the lining represented a component of the proliferation. It is important to raise awareness of this rare variant within the varied spectrum of DFSP.

Trisomy 8 in myeloid leukemia cutis confirmed by fluorescence in situ hybridization analysis

We present a case of a 64‐year‐old man with refractory acute myeloid leukemia and trisomy 8 who developed leukemia cutis. Interphase fluorescence in situ hybridization (FISH) was performed on a paraffin‐embedded skin section. FISH confirmed a population of cells with trisomy 8 in the blastic infiltrates involving the skin. This case illustrates a novel application of interphase FISH to confirm the diagnosis of leukemia cutis.