Brigitte Coras

Ultrastructural Evidence of Dermal Gadolinium Deposits in a Patient with Nephrogenic Systemic Fibrosis and End-Stage Renal Disease

BACKGROUND AND OBJECTIVESnThe pathogenesis of acquired nephrogenic systemic fibrosis recently described for patients with renal insufficiency and a history of exposition to gadolinium-based magnetic resonance contrast agents is not completely understood. A role for circulating fibroblasts in the fibrosing tissue is hypothetical, and the mechanism of the assumed trigger function of gadolinium remains elusive.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnA skin lesion on a 76-yr-old man with symptoms of nephrogenic systemic fibrosis lasting 5 mo was studied at the ultrastructural level. After confirmation of he diagnosis by histopathologic methods, the presence and distribution of gadolinium, iron, calcium, and magnesium by energy filtering transmission electron microscopy was also examined.nnnRESULTSnThe performed electron spectroscopic imaging and electron energy loss spectroscopic analyses on deparaffinized samples revealed deposition of gadolinium in irregular small aggregates that adhered to cell profiles and collagen fibers of the connective tissue, forming a perivascular gadolinium-deposit zone in the skin. Traces of iron signal were demonstrated in singular gadolinium-positive deposits, and iron presence was found in adjacent connective tissue. The ultrastructural cell analysis of the lesion showed among numerous poorly differentiated fibrocytes also higher differentiated cells with myofibroblastic characteristics, including bundles of intermediate filaments and attachment plaques in the cell periphery, indicating an ability of lesional fibroblasts to differentiate into myofibroblastic cells.nnnCONCLUSIONSnThese findings support the pivotal role of gadolinium chelates in the development of nephrogenic systemic fibrosis.

Targeted combined anti-inflammatory and angiostatic therapy in advanced melanoma: a randomized phase II trial.

An angiostatic approach was used to assess the impact of anti-inflammatory therapy in combination with metronomic low-dose chemotherapy. A randomized multi-institutional phase II trial was designed to select metronomic chemotherapy (arm A: trofosfamide 50u2009mg orally three times daily, day 1+) or combined anti-inflammatory/angiostatic treatment (arm B: trofosfamide as above mentioned plus rofecoxib 25u2009mg orally, day 1+, and pioglitazone 60u2009mg orally, day 1+) for further evaluation. A total of 76 patients, mostly (>60%) refractory to at least one previous chemotherapy with maximum tolerated doses, and progression of metastatic melanoma were included. The estimated progression-free survival (PFS) rates at one year were 0% for metronomic chemotherapy (A), but 9% for additional anti-inflammatory therapy (B). Vice versa the hazard ratio for the intent-to-treat analysis of A versus B was 1.9 (P=0.008). By Cox analysis, the impact of anti-inflammatory therapy on PFS achieved significance (P=0.016) as well as C-reactive protein response on overall survival (P=0.045). WHO grade 3 (no grade 4) toxicities were reported in arm A/B in 19 and 28%, respectively. In conclusion, control of tumour-associated inflammatory processes (C-reactive protein response) is associated with longer PFS than achieved with metronomic chemotherapy alone in metastatic melanoma.

Cowpox and a cat.

In August, 2001, three people, a boy aged 14 years, awoman aged 20, and a man aged 54, living in neigh-bouring households in Schirnding, Germany, werescratched while playing with a cat. 2 days later, the 20-year-old woman had an itchy nodule, surrounded byerythema, on her right forearm where she had beenscratched. She also had malaise, night sweats, andpainful right axillary lymph nodes. The next day, furtherlesions developed on her right arm and in her left groin.She was admitted to the Department of Dermatology,University of Regensburg. While she was there, thenodule on her forearm increased to 4 2·5 cm (figure)with a necrotic black eschar in the centre with a raisedrim by day 20. The other two people had similar lesions,but these remained localised and neither had anymalaise. The 54-year-old had a history of smallpoxvaccination in childhood. The cat had an ulceratednodule on its right ear.Histopathology of a skin biopsy specimen and electron-microscopy of scab tissue showed vacuolar degenerationof keratinocytes, eosinophilic cytoplasmic inclusions, andbrick-shaped 200 300 nm orthopoxvirus particles.Confluent African green monkey kidney MA 104 cells(ATCC No. CRL-2378) were used for propagation ofviruses, and extracted DNA was subjected to PCR withprimers targeting the vaccinia virus gene of the 14 kDaprotein (A27L) and the acidophilic inclusion protein gene(A-type inclusion body, ATI).

Early Recurrence of Eruptive Vellus Hair Cysts after Er:YAG Laser Therapy: Case Report and Review of the Literature

Background Therapy of eruptive vellus hair cysts (EVHCs) often leads to unsatisfying results or recurrences. Recently, erbium:yttrium-aluminum-garnet (Er:YAG) laser therapy has been recommended in this condition. Objective To report the results of Er:YAG laser treatment and discuss the treatment options in EVHC, presenting a review of the literature. Methods Full-face Er:YAG laser therapy was performed in a 30-year-old female patient with a 15-year history of cosmetically bothersome facial EVHCs. Results Immediately after the laser treatment, the ablated skin showed an even surface, presenting no residual signs of EVHCs. After reepithelialization, however, early recurrence of EVHCs occurred. Recurrence was also observed in the previously treated test spot, where slight atrophy indicated deeper ablation. Conclusion Er:YAG laser therapy might be a treatment option for distinct lesions of EVHCs but proved to be ineffective in a case of EVHCs in the face, where the depth of ablation is limited owing to the risk of atrophy or scarring and where deep enucleation of distict single cysts was not possible owing to the dense dissemination of the lesions. Despite numerous treatment options reported in the literature, therapy for EVHCs is still challenging owing to recurrences or side effects.

Fibroadenoma of the axilla

Background Ectopic, axillary breast tissue can develop any disease that affects the normal breast, including fibroadenoma. Objective To report and discuss a case of fibroadenoma of the axilla in a 23-year-old woman. Methods Case report and discussion of the rare entity of fibroadenoma of the axilla. Results The histology was identical to the fibroadenomas seen in the breast and those observed along the milk line. Conclusion Differential diagnosis of an axillary tumor should include ectopic breast tissue.

Antiangiogenic therapy in metastatic prostate carcinoma complicated by cutaneous lupus erythematodes

A 61-year-old man was diagnosed with progressive hormone-refractory prostate cancer complicated by paraneoplastic subacute cutaneous lupus erythematodes (SCLE). The fi rst diagnosis of prostate carcinoma was made in March, 1995, by prostatectomy. Liver metastases were fi rst diagnosed in January, 2002. From April, 2002, to November, 2003, the patient received 75 mg/m docetaxel every 21 days. In November, 2003, the patient presented with well-demarcated, raised erythematous macules and plaques with pityriasic scales and hyperaesthesia on the arms and trunk (fi gure 1). Histopathological assessment confi rmed the clinical diagnosis of SCLE (fi gure 2). Direct immunofl uorescence of involved skin was positive with a band-like deposition of immunoglobulins (IgG, IgM) and C3. We recorded no serum antibodies against double stranded DNA, Ro-SSA, or La-SSB. At this time (November, 2003), on the development of abdominal pain, renewed staging by CT showed progression of the prostate cancer, particularly of the liver metastases. The patient was therefore started on capecitabine (two doses of 1 g/m per day for days 1–14, repeated every 3 weeks), plus 60 mg pioglitazone per day and 25 mg rofecoxib per day, similar to a non-randomised phase II study regimen for the treatment of various advanced cancers at our institution. After 3 weeks, capecitabine had to be discontinued because the patient developed severe hand and foot syndrome; it was therefore replaced by trofosfamide (three doses of 50 mg per day). After 3 months’ treatment, the concentration of prostatespecifi c-antigen stabilised and went into remission— 90·23 ng/mL at treatment initiation and 60·24 ng/mL after 3 months. Repeated ultrasound scans of a large reference metastasis in segment VIII of the liver showed control of tumour progression—from 5·2 × 4·4 × 4·3 cm to 4·0 × 4·0 × 3·7 cm (fi gure 3). Stable disease was sustained for a further 12 months. By 3 months, the paraneoplastic SCLE showed complete remission (fi gure 1). For topical supportive treatment the patient received 1% mometasone and 0·1% tacrolimus ointment. Strict sun protection was also recommended. No severe side-eff ects were recorded with this regimen. During treatment, the patient developed anaemia, which might have been treatment related. The haemoglobin concentration decreased slowly from 133 g/L to about 104 g/L (nadir) during the fi rst 3 months of treatment, at which point it levelled out for the rest of the observation period. Diff erential blood counts and other standard blood measures for liver and kidney (ie, aspartate aminotransferase, glutamate pyruvate transaminase, bilirubin, alkaline phosphatase, and creatinine concentrations) were normal. Overall, the patient had no subjective symptoms. In the search for new therapeutic strategies against advanced metastatic cancer, stroma-targeted angiostatic approaches combining metronomic chemotherapy (daily long-term application of low non-toxic doses) with biomodulating drugs seem to be promising alternatives to classic chemotherapy that applies cycles of maximum tolerated doses. Specifi cally, daily low-dose metronomic scheduling of chemotherapy has antiangiogenic stromaeff ects that can control well-advanced, chemoresistant tumours of quite diff erent histogenesis even for long periods of time. Furthermore, metronomic dosing can be complemented synergistically by combination with biomodulators such as cyclo-oxygenase-2 inhibitors (eg, rofecoxib) or peroxisome proliferator activated receptor (PPAR) γ agonists (eg, pioglitazone). These substances not only have anti-infl ammatory eff ects, but also contribute to angiostasis and direct induction of apoptosis in tumour cells. They can also induce immunoaugmentive eff ects. We have found that this Lancet Oncol 2006; 7: 695–97

Dysplastic melanocytic nevi of the lower leg: sex- and site-specific histopathology.

Site-specific histopathology features have been reported for acral, auricular, flexural, and genital melanocytic nevi, however, to the best of our knowledge, site- and sex-specific histology of dysplastic nevi on the lower leg (between knee and ankle) of women (DN-LW) has not been reported. In this retrospective histopathology study, we compared DN-LW (N = 42) with appropriate control groups of (1) DN of the lower leg of men (N = 20; DN-LM), (2) DN from the back of women (N = 20), (3) common nevi of the lower leg of women (N = 40), and (4) levels 1-2 superficial spreading melanoma of the lower leg of women (N = 20). Compared with dysplastic nevi on the back, DN-LW were smaller in diameter and exhibited a significantly higher score for pagetoid spread (P < 0.05). DN-LW compared with DN-LM showed sex-specific differences with (1) pagetoid spread (P < 0.05), (2) cytologic atypia (P < 0.05), (3) presence of large melanocytes (P < 0.05), and (4) band-like pigmentation in the dermis underlying the nevus (54% in DN-LW vs. 15% in DN-LM). As with other body sites, the dermatopathologist should be aware that dysplastic nevi occurring on the lower leg in women have site- and sex-specific features. Knowing this profile may lower the risk of misdiagnosing DN-LW and melanoma of the lower leg of women.

Unique brown star shape on dermatoscopy of generalized Dowling‐Degos disease

An otherwise healthy 49-year-old woman presented with a 15-year history of a slowly extending rash and pigment changes particularly on the thighs and between the breasts. She described episodic pruritus, worse with heat, friction and perspiration. Her family history was unremarkable. Clinical examination revealed numerous generalized 2–4 mm brown and hypopigmented macules. Excoriated papules were seen over the thighs and intermammary skin (Fig. 1). There were pitted acneiform scars with hypoand hyperpigmentation in the perioral area. Dermatoscopy of the papules consistently revealed an irregular star-shaped brown outline on a red–brown background (Fig. 2). Follicular plugging and inclusion cysts were seen centrally. Skin biopsies from papules on the thighs and chest revealed flattened epidermis centrally and on the periphery, adenoid proliferations of the rete ridges in a filiform pattern with basal hyperpigmentation, inclusion cysts and follicular plugging (Fig. 3). Parakeratosis was seen in some lesions, possibly due to excoriation. There were scattered melanophages in the upper papillary dermis. Acantholysis was not seen despite examination of multiple sections of multiple papules. S100, Melan A and HMB45 stains showed increased pigment especially at the periphery. The diagnosis of generalized Dowling-Degos disease was made on the clinical and histological findings.

Weißlich belegte Erosionen an der Wangenschleimhaut mit rechtsseitig betonter Tonsillenschwelllung

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