Whitney A. High

Imatinib mesylate treatment of nephrogenic systemic fibrosis

OBJECTIVE To examine the effectiveness of imatinib mesylate in the treatment of nephrogenic systemic fibrosis (NSF). METHODS Two patients with stage 5 chronic kidney disease and NSF were treated with oral imatinib mesylate at a dosage of 400 mg/day. Skin thickening and tethering were assessed using the modified Rodnan skin thickness score (MRSS), and knee joint flexion contractures were measured with a goniometer. RESULTS Each patient displayed progressive reduction of skin thickening and tethering, with a steady decrease in the MRSS, following the initiation of imatinib mesylate treatment. The patient who had knee joint contractures achieved increased knee extension with passive range-of-motion exercises once his skin thickening and tethering had begun to decrease. Within weeks of stopping imatinib mesylate, the skin changes recurred in each patient. Recurrent skin thickening and tethering again improved in the patient who resumed taking imatinib mesylate for longer than 2 weeks. Skin biopsies performed both before and after initial dosing of that patient revealed less fibrosis and less staining for type I procollagen after imatinib mesylate treatment, but essentially unchanged tissue gadolinium content. CONCLUSION Imatinib mesylate treatment decreases fibrosis and results in the relatively rapid and steady improvement of skin changes and knee joint contractures in patients with stage 5 chronic kidney disease and NSF, despite the persistence of gadolinium in the tissues. Because skin changes recurred after discontinuation of imatinib mesylate, the duration for which treatment may be required is undetermined.

Secondary syphilis: a histologic and immunohistochemical evaluation

Abstract:  The usual method for detecting spirochetes in tissue sections is the silver stain; however, they are often difficult to detect due to marked background staining commonly seen with this technique. In certain clinical settings, such as neurosyphilis, congenital syphilis, and immunosuppressive conditions including human immunodeficiency virus (HIV) infection, a better method of detecting spirochetes in tissue sections is needed. We compare immunohistochemistry (IHC) with a monoclonal antibody to Treponema pallidum to silver staining in 19 biopsies from 17 patients with serologic evidence of secondary syphilis. IHC demonstrated a sensitivity of 71%, which was superior to the 41% sensitivity of the silver stain (p = 0.084). Furthermore, specificity was improved with IHC, as background artifacts were markedly reduced. Dermal spirochetes were visualized in all 12 positive cases, while epidermal organisms were seen in only eight cases. This finding lies contrary to accepted teaching that organisms are most commonly seen at the dermal epidermal junction. Of interest, perineural plasmacellular infiltrates were frequently seen in our cases (74%). Spirochetes were not seen in any of 14 control cases with similar histopathologic patterns. Although serologic studies remain the gold standard, IHC is more sensitive and specific than silver stain for detecting T. pallidum in biopsies of secondary syphilis.

Nephrogenic Systemic Fibrosis after Gadopentetate Dimeglumine Exposure: Case Series of 36 Patients

PURPOSE To retrospectively assess the association between gadopentetate dimeglumine exposure at magnetic resonance imaging and the development of nephrogenic systemic fibrosis (NSF). MATERIALS AND METHODS This HIPAA-compliant study had institutional review board approval. Informed consent was waived. A search of medical and pathologic records was performed to identify patients with NSF that was diagnosed between January 1998 and December 2007. Patients with known exposure to gadolinium-based contrast agents other than gadopentetate dimeglumine were excluded. Medical records were then reviewed for gadopentetate dimeglumine exposure, renal status, concomitant diseases, timing of NSF symptom onset, date of NSF diagnosis, and clinical outcome. Skin gadolinium deposition was assessed for those patients with adequate available tissue. Spearman rank correlations were estimated to assess the relationship between the dose of gadopentetate dimeglumine and the time to onset of NSF. RESULTS Thirty-six patients (mean age, 62.6 years; range, 30-83 years) had been exposed to gadopentetate dimeglumine prior to NSF onset. All had stage 5 chronic kidney disease and all but one were undergoing dialysis at the time of exposure. NSF developed within 3 months after the last gadopentetate dimeglumine exposure (range, 1-59 months) in 21 (66%) of 32 patients. The patients had been exposed to median cumulative gadopentetate dimeglumine volumes of 35, 40, 85, and 117.5 mL over the 3, 12, and 24 months and up to 11 years preceding the onset of NSF, respectively. Patients who received higher cumulative and total gadopentetate dimeglumine doses had a higher risk of developing NSF than did those who received lower doses (odds ratio = 1.2). Twenty (56%) of 36 patients died, with a median interval of 18 months between NSF symptom onset and death. CONCLUSION NSF develops in patients with renal impairment after exposure to gadopentetate dimeglumine in a dose- and time-dependent manner. SUPPLEMENTAL MATERIAL http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.2531082160/-/DC1.

Intralesional agents in the management of cutaneous malignancy: A review

Intralesional agents have a role in the management of cutaneous malignancies. In this article, the efficacy, side effects, strengths, limitations, costs, and practical considerations regarding the use of intralesional agents to treat basal cell carcinoma, squamous cell carcinoma, selected cutaneous lymphomas, and even metastatic melanoma are reviewed. Intralesional administration of 5-fluorouracil, interferon, interleukin-2, bleomycin with electrochemotherapy, and aminolevulinic acid with photodynamic therapy are discussed as treatment modalities in basal cell carcinoma. Interferon (∼1.5 M IU, 3 times weekly × 3 weeks) is perhaps the most widely used regimen for basal cell carcinoma. With regard to squamous cell carcinoma, treatment with 5-fluorouracil, methotrexate, interferon, and bleomycin are reviewed. Methotrexate (∼0.3-2.0 mL of 12.5 or 25 mg/mL, two injections ∼2 weeks apart) was perhaps the most widely used agent. Interferon (3 M IU × 3 times weekly for ∼8.5 weeks) and rituximab (10-30 mg per lesion, 3 times weekly for 1 week, possibly repeated 4 weeks later) are sometimes used in the management of primary cutaneous B-cell lymphomas, whereas in primary cutaneous CD30(+) lymphoma intralesional methotrexate (0.4-0.5 mL of 50 mg/mL weekly for 2 weeks) has been used. Finally, the roles of BCG vaccine, cidofovir, rose bengal, and bleomycin with electrochemotherapy for the palliation of metastatic melanoma are reviewed. Intralesional management appears most useful when surgical intervention is not a viable option, for cases in which the cosmetic outcome may be superior, or for situations in which the side effects from systemic chemotherapeutic agents are to be minimized.

Microcystic adnexal carcinoma : an immunohistochemical reappraisal

Even though immunohistochemical comparisons of microcystic adnexal carcinoma vs infiltrative basal cell carcinoma and desmoplastic trichoepithelioma exist, they are mostly restricted to the use of a single stain. In addition, a comparison with squamous cell carcinoma has not been reported previously. In this study, we compare the expression of cytokeratin (CK) 15, CK7, CK20, CK903, carcinoembryonic antigen (CEA), CD10, CD15 and BerEP4 in 13 microcystic adnexal carcinoma, eight desmoplastic trichoepithelioma, 10 infiltrative basal cell carcinoma, and eight squamous cell carcinoma of which five exhibited ductal differentiation. We found that the majority of microcystic adnexal carcinoma (92%) and desmoplastic trichoepithelioma (100%) cases expressed CK15 while the infiltrative basal cell carcinoma and squamous cell carcinoma cases were all negative. Forty percent of infiltrative basal cell carcinoma expressed CK7; while only two microcystic adnexal carcinoma cases (15%) and one squamous cell carcinoma with ductal differentiation (12%) expressed CK7 in the remaining three tumor categories. None of the desmoplastic trichoepithelioma expressed CK7. All tumors were strongly positive for CK903. While the neoplastic cells were negative, luminal staining of ductal structures was noted for CK7, CD15 and CEA in some of the microcystic adnexal carcinoma, desmoplastic trichoepithelioma and squamous cell carcinoma with ductal differentiation cases. Sixty percent of infiltrative basal cell carcinoma, 31% of microcystic adnexal carcinoma, and 25% of squamous cell carcinoma express CD10. BerEP4 expression was noted in 38% of microcystic adnexal carcinoma, 57% of desmoplastic trichoepithelioma, 100% of infiltrative basal cell carcinoma, and 38% of squamous cell carcinoma. In conclusion, we found CK15 to be a useful marker in distinguishing microcystic adnexal carcinoma from infiltrative basal cell carcinoma and squamous cell carcinoma with ductal differentiation. Our experience indicates that microcystic adnexal carcinoma and desmoplastic trichoepithelioma have a similar immunohistochemical profile that is, CK15+ and BerEP4+/−; thus, additional studies are needed to separate these two entities.

Quantification of gadolinium in nephrogenic systemic fibrosis: re-examination of a reported cohort with analysis of clinical factors.

BACKGROUND Nephrogenic systemic fibrosis (NSF) has been associated with exposure to gadolinium-based contrast agent (GdCA) used in medical imaging. OBJECTIVE We sought to quantify levels of gadolinium in affected skin of patients with NSF and correlate the levels to clinical and laboratory parameters. METHODS Skin biopsy specimens were analyzed using inductively coupled plasma mass spectroscopy (ICP-MS) and the micrograms of gadolinium per gram (microg/g) of dry tissue were determined. Clinical and laboratory data were obtained through retrospective chart review. Pearson correlation coefficients were used to correlate tissue gadolinium levels with various parameters. RESULTS Six patients from a prior cohort were analyzed for gadolinium in affected skin. The mean amount of gadolinium in affected skin of NSF patients was 320.1 microg/g. No gadolinium was found in limited control tissue from patients unexposed to GdCA or in patients exposed to such agents, but without disease. Higher levels of gadolinium in skin correlated with younger age, lower body weight, lower corrected serum calcium levels, and lower erythropoietin dosing. LIMITATIONS The study was limited by the small number of cases and by the retrospective nature of the data and skin samples. CONCLUSION Gadolinium is present in substantial amounts within the skin of patients with NSF. Quantification of gadolinium in tissue using ICP-MS may facilitate our understanding of the disease.

Non-bullous neutrophilic dermatosis within neonatal lupus erythematosus

To the Editor We read with interest the article by Gleason et al. detailing the occurrence of a non-bullous neutrophilic dermatoses as a dermatologic manifestation of lupus. In our own practice, we recently observed two cases of neonatal lupus erythematosus (NLE) that presented chiefly with a neutrophilic infiltrate and nuclear debris confined to the upper dermis, and wish to suggest that this may also be a dermatologic manifestation within this subcategory of disease.

Nephrogenic Systemic Fibrosis in Rats Treated with Erythropoietin and Intravenous Iron

PURPOSE To use a rat model for nephrogenic systemic fibrosis (NSF) that was administered high-dose gadodiamide to determine whether the co-administration of erythropoietin (Epo) and intravenous iron potentiated development of skin lesions that are thought to be a marker for the development of NSF. MATERIALS AND METHODS The local committee for animal research approved this study. High-dose gadodiamide was administered, 2.5 mmol per kilogram of body weight for 20 days, or 500 times the U.S. Food and Drug Administration-approved dose, to four groups of Hannover-Wistar rats: group A, gadodiamide only; B, gadodiamide and Epo; C, gadodiamide and intravenous iron; and D, gadodiamide, Epo, and intravenous iron. The animals were sacrificed 7 days after final injection, and the authors examined dermal histologic findings from each animal and measured metal deposition by using inductively coupled plasma mass spectrometry. To compare the effect of metal deposition and cellularity, a linear mixed effects model was used to fit the data within PROC MIXED modeled with rat-specific random effects, and subsequently a Dunnett adjustment was performed. RESULTS Rats treated with gadodiamide and both Epo and intravenous iron (group D) had significantly worse skin lesions at gross and histologic analysis (P = .004) compared with the rate treated with gadodiamide only (group A). Group D also had increased levels of deposited gadolinium as measured by means of mass spectrometry (P = .012). CONCLUSION With a rat model similar to those already existing in the literature, skin changes were more marked in animals exposed to gadodiamide, Epo, and intravenous iron, as opposed to those animals exposed to gadodiamide alone; this experiment suggests that great caution may be warranted when prescribing gadolinium-based contrast agents to patients receiving Epo and intravenous iron.

Gadolinium deposition in nephrogenic systemic fibrosis: An examination of tissue using synchrotron x-ray fluorescence spectroscopy

BACKGROUND Nephrogenic systemic fibrosis is a fibrosing disorder associated with gadolinium (Gd)-based contrast agents dosed during renal insufficiency. OBJECTIVE In two patients, Gd deposition in tissue affected by nephrogenic systemic fibrosis was quantified using inductively coupled plasma mass spectrometry. The presence of Gd was confirmed and mapped using synchrotron x-ray fluorescence spectroscopy. RESULTS Affected skin and soft tissue from the lower extremity demonstrated 89 and 209 ppm (microg/g, dry weight, formalin fixed) in cases 1 and 2, respectively. In case 2, the same skin and soft tissue was retested after paraffin embedding, with the fat content removed by xylene washes, and this resulted in a measured value of 189 ppm (microg/g, dry weight, paraffin embedded). Synchrotron x-ray fluorescence spectroscopy confirmed Gd in the affected tissue of both cases, and provided high-sensitivity and high-resolution spatial mapping of Gd deposition. A gradient of Gd deposition in tissue correlated with fibrosis and cellularity. Gd deposited in periadnexal locations within the skin, including hair and eccrine ducts, where it colocalized to areas of high calcium and zinc content. LIMITATIONS Because of the difficulty in obtaining synchrotron x-ray fluorescence spectroscopy scans, tissue from only two patients were mapped. A single control with kidney disease and gadolinium-based contrast agent exposure did not contain Gd. CONCLUSIONS Gd content on a gravimetric basis was impacted by processing that removed fat and altered the dry weight of the specimens. Gradients of Gd deposition in tissue corresponded to fibrosis and cellularity. Adnexal deposition of Gd correlated with areas of high calcium and zinc content.

Malpractice in Dermatopathology—Principles, Risk Mitigation, and Opportunities for Improved Care for the Histologic Diagnosis of Melanoma and Pigmented Lesions

Melanoma represents a substantial source of risk within dermatology and dermatopathology. This article seeks to provide general pathologists, dermatologists and dermatopathologists with an overview of the basics principles of medical malpractice litigation, a review of the essentials of reporting and the importance of expert consultation for melanoma and pigmented lesions, and suggestions to improve quality care and reduce medicolegal risk associated with melanoma and pigmented lesions.