Arni Kristjansson

microRNA in situ hybridization for miR-211 detection as an ancillary test in melanoma diagnosis

Some melanocytic tumors can be histologically ambiguous causing diagnostic difficulty, which could lead to overtreatment of benign lesions with an unwarranted psychological distress or undertreatment of malignant cancers. Previously, we demonstrated that significantly decreased miR-211 expression in melanomas compared with melanocytic nevi could accurately discriminate malignant from benign tumors. Herein we show microRNA in situ hybridization for fluorescent detection of miR-211, suitable for paraffin-embedded tissues in 109 primary melanocytic tumors. miR-211 expression was significantly lower in melanomas vs nevi (P<0.0001), and receiver operating characteristic curve (area under the curve=0.862) accurately discriminated melanomas from nevi with 90% sensitivity and 86.2% specificity. Qualitatively, all dysplastic nevi expressed miR-211 at high (86%) and low (14%) levels, independent of the degree of nuclear atypia. All 35 melanocytic tumors with Spitz morphology expressed miR-211 independent of morphological classification, where clinical follow-up of these patients showed no recurrence at the site or metastasis in mean and median of 3 (ranging 2–5) years. Moreover, a decision tree learning analysis selected age and miR-211 miRNA in situ hybridization as the predictive variables for benign or malignant outcome in 88 patients correctly classified 92% (81 out of 88) of cases as proven by receiver operating characteristic curve (area under the curve=0.9029). These results support miR-211 as a leading miRNA candidate for melanoma diagnosis and miRNA in situ hybridization as a uniquely uncomplicated ancillary test.

Pagetoid reticulosis in a 5-year-old boy

We present a rare case of pagetoid reticulosis arising in a 5-year-old white boy. He had a history of a large chronic erythematous, scaly patch on his left buttock that had shown intermittent partial response to a topical antifungal medication. A punch biopsy specimen revealed dramatic epidermal hyperplasia, with parakeratosis and prominent exocytosis of single and clustered mononuclear cells (Pautriers microabscesses) into the epidermis. Some of these exhibited hyperchromatic nuclei with irregular contours. They stained prominently for CD3, CD4, and CD8, with a predominance of CD8(+) cells. T-cell receptor gene rearrangement by polymerase chain reaction was negative for a clonal process on a second biopsy specimen that was nondiagnostic on routine sections. Pagetoid reticulosis is an indolent, unilesional variant of mycosis fungoides, in which the atypical T cells may express a CD4(-)/CD8(+) phenotype. This is in contrast to primary cutaneous epidermotropic CD8(+) cytotoxic T-cell lymphoma, which is often very aggressive with a poor outcome. Pagetoid reticulosis is exceedingly rare in children and adolescents. Two features predict a benign course in this 5-year-old child: the unilesional clinical presentation and the CD8 predominance of the epidermal lymphocytes.

A case of recurrent pseudolymphomatous folliculitis: A mimic of cutaneous lymphoma

Pseudolymphomatous folliculitis is a rare entity. We present a 62-year-old man with a recurrent solitary nodule on his nose requiring multiple excisions. Microscopic examination of the excisions showed a dense lymphocytic infiltrate containing numerous histiocytes and S100+, CD1a+ dendritic cells that surrounded and infiltrated hypertrophic hair follicles. Diffuse sheets of CD3+ T cells and nodular clusters of CD20+ B cells were also seen. There was normal reactive pattern of follicular centers. Light chain restriction was not detected. T-cell receptor and immunoglobulin heavy chain gene rearrangements by polymerase chain reaction revealed negative findings. A diagnosis of pseudolymphomatous folliculitis was made based on the hypertrophic hair follicles, periadnexal S100+ and CD1a+ dendritic cells, and negative clonal gene rearrangement study findings. This case of recurrent pseudolymphomatous folliculitis is instructive because of the resemblance to cutaneous lymphomas and cutaneous lymphoid hyperplasias, and the need for correct diagnosis to avoid overtreatment of this indolent condition.

Unusual flexural drug reaction with epidermal pustules associated with adalimumab treatment

The use of tumor necrosis factor-alpha (TNF-alpha) inhibitors in the management of chronic inflammatory conditions is increasing in dermatology and rheumatology practices. We report a case of an unusual drug eruption in flexural areas occurring in a patient treated with adalimumab for rheumatoid arthritis. A fifty-one-year old woman with a fourteen-month history of seropositive rheumatoid arthritis presented for evaluation of an erythematous, pruritic rash in flexural areas. The eruption began four months after initiating adalimumab, a TNF-alpha inhibitor for her rheumatoid arthritis. Adalimumab was temporarily discontinued for four weeks with improvement of the cutaneous eruption; however, the eruption reappeared three weeks after the medication was reinitiated and had an identical appearance. Drug regimen review revealed no other recent medication adjustments. The patient did not have a personal or family history of psoriasis. Concurrent medications included aspirin, hydrochlorothiazide, hydroxychloroquine, and metformin. Rheumatoid factor, ESR-Westergreen, and C-reactive protein levels were elevated at 825 IU/ml, 72mm/h and 3.63 mg/dl, respectively. ESR and C-reactive protein were within normal limits 4 months prior to the eruption. Physical examination after adalimumab re-challenge revealed red-brown plaques with slightly mammilated/pebbly surface involving both axillae and smaller plaques in the left antecubital fossa and on the left wrist (Fig 1). There were no other skin or nail findings or oral lesions. A punch biopsy showed epidermal hyperplasia and spongiosis, with multiple foci of neutrophils and eosinophils within variably sized intraepidermal pustules (Figs 2a and b). The papillary dermis also contained numerous neutrophils and eosinophils. Sterile biopsy did not grow bacteria, fungi or mycobacteria. The diagnosis of pustular drug eruption was made. Figure 1 Red-brown plaques in axillae after rechallenge with adalimumab Figure 2 Figure 2a. Routine histology showing acanthotic epidermis with intraepidermal pustule (10x) Adalimumab, a recombinant human IgG1 monoclonal antibody specific for TNF-alpha, is administered via subcutaneous injection every two weeks for rheumatoid arthritis. The most common side effect is a local injection site reaction. This was seen in 20.9% of patients treated with adalimumab compared to 13.8% treated with placebo in an analysis of four clinical trials.1 Other adalimumab associated skin reactions are rare and include leukocytoclastic vasculitis,2urticaria 3, eczema 4 and a pustular eruption involving the palms and soles.5 There are increased numbers of patients with rheumatological conditions treated with TNF-alpha inhibitor that develop new onset or worsening psoriasis, often with prominent palmoplantar involvement.6+7 5 Table 1 summarizes some cutaneous reactions reported with TNF-alpha inhibitors. Table I Adverse cutaneous reactions with recombinant TNF-alpha inhibitors 1–7 We favor adalimumab as a causative agent in this pustular eruption due to the temporal nature of the adalimumab initiation and onset of cutaneous lesions. The rapid improvement of the eruption with discontinuation and flare with re-challenge further support our theory. Biopsy showing numerous eosinophils, commonly seen in drug eruptions, is also consistent with an adalimumab-induced pustular eruption. Cutaneous pustular adverse events have been reported in patients treated with infliximab, adalimumab, and etanercept, . The mechanism for these eruptions is not known, but it has been postulated that TNF-alpha and interferon cross regulation play an important role in pathogenesis. 7. Our case is unusual in that it involves flexural areas and has eosinophilic pustules in the epidermis. In conclusion, physicians monitoring patients utilizing antibody-type TNF-alpha inhibitors must recognize the potential for induction of pustular dermatoses.

Erythematous keratotic papules in a patient with Fabry disease

Without treatment, disseminated disease and cryptococcal meningitis are almost invariably fatal. Treatment regimens recommended by the 2000 Infectious Disease Society of America practice guidelines for the management of cryptococcal disease depend on the presenceor absence ofCNS disease and theHIV status of the patient. The treatment of choice for disseminated disease, including the CNS, is intravenous amphotericin B plus flucytosine for 2 weeks followed by oral fluconazole 400 mg per day for a minimum of 10 weeks or amphotericin B plus flucytosine for 6 to 10 weeks. In patients with dissemination and HIV infection, lifelong fluconazole maintenance is recommended. In patients with pulmonary or other non-CNS disease, treatment with fluconazole 200 to 400 mg per day for 6 to 12 months or lifelong in HIV patients is recommended. There are no randomized, prospective trials of treatment regimens for cryptococcosis in SOTrecipients, but the recommendation is similar with amphotericin B plus flucytosine for 2 weeks followed by 8 weeks of fluconazole 400 mg per day and then 6 to 12 months of maintenance therapy with fluconazole 200 mg per day. Despite treatment, the mortality rate of cryptococcus in transplant patients ranges from 15% to 20% and is close to 40% in those with CNS disease. The type of immunosuppressive regimen used in transplant patients may influence presentation and outcome of cryptococcosis andother fungal infections. Patientson calcineurin inhibitor regimens have been associated with improved outcomes in SOT recipients with cryptococcosis. This is thought to be related to calcineurin inhibitor agents having potent in vitro antifungal activity against C neoformans that is mediated through inhibition of fungal homologs of calcineurin. Another immunosuppressive medication, rapamycin, also has antifungal activity via FKBP12 (12-kDa FK506 binding protein)-dependent inhibition of Tor kinases in C neoformans. Calcineurin inhibitors and rapamycin have also been found to work synergistically with amphotericin B and fluconazole. In a multicenter study of 111 SOT recipients, the patients on a tacrolimus-based therapy were independently associated with a lower mortality and a decreased rate of dissemination andCNS infection compared topatients onother regimens.More investigation is needed to see if the association of improvedmortality and decreased dissemination of fungal disease in patients on certain immunosuppressive regimens is solely related to the antifungal properties of these medications or from other unknownmechanisms.Asorgan transplantation and the treatment of dermatologic diseases with immunosuppressive medications increases, we must have a higher index of suspicion for the cutaneous signs of systemic fungal infections and further investigate the influence of various immunosuppressive regimens on the outcome of these infections. For this series, the recommended answer choices are as follows: 6, b; 7, d; 8, b; 9, e; 10, a; 11, c; 12, d.

Paired comparison of the sensitivity and specificity of multispectral digital skin lesion analysis and reflectance confocal microscopy in the detection of melanoma in vivo: A cross-sectional study

BACKGROUND Several technologies have been developed to aid dermatologists in the detection of melanoma in vivo including dermoscopy, multispectral digital skin lesion analysis (MDSLA), and reflectance confocal microscopy (RCM). To our knowledge, there have been no studies directly comparing MDSLA and RCM. OBJECTIVE We conducted a repeated measures analysis comparing the sensitivity and specificity of MDSLA and RCM in the detection of melanoma (n = 55 lesions from 36 patients). METHODS Study patients (n = 36) with atypical-appearing pigmented lesions (n = 55) underwent imaging by both RCM and MDSLA. Lesions were biopsied and analyzed by histopathology. RESULTS RCM exhibited superior test metrics (P = .001, McNemar test) compared with MDSLA. Respectively, sensitivity measures were 85.7% and 71.4%, and specificity rates were 66.7% and 25.0%. LIMITATIONS The sample size was relatively small and was collected from only one dermatologists patient base; there was some degree of dermatopathologist interobserver variability; and only one confocalist performed the RCM image evaluations. CONCLUSION RCM is a useful adjunct during clinical assessment of in vivo lesions suspicious for melanoma or those requiring re-excision because of high level of dysplasia or having features consistent with an atypical melanocytic nevus with severe cytologic atypia.

A quantitative comparison between SOX10 and MART-1 immunostaining to detect melanocytic hyperplasia in chronically sun-damaged skin

Histologic differentiation of melanoma in situ (MIS) from solar keratosis on chronically sun‐damaged skin is challenging. The first‐line immunostain is usually MART‐1/Melan‐A, which can exaggerate the epidermal melanocytes, causing a diagnostic pitfall for MIS. By comparing MART‐1 and SOX10 immunostaining, we scored the percentage of epidermal melanocytes per 2‐mm diameter fields in pigmented actinic keratosis (n = 16), lichenoid keratosis (n = 7), junctional melanocytic nevus (n = 6), keratosis with atypical melanocytic proliferation (n = 17) and MIS (n = 10). These cases represented an older population (68 years median age) and the head and neck (50%) was the most common anatomic site. MART‐1 score was significantly higher than SOX10 (P value <.05) in solar keratoses, but showed no difference in detecting melanocytic proliferations, demonstrating their equal detection rate of melanocytes. The sensitivity of both MART‐1 and SOX10 was 100%, while their specificities were 17% and 96%, respectively. These results show that SOX10 is more specific than MART‐1 in distinguishing epidermal melanocytes on sun‐damaged skin by avoiding overdiagnosis of melanoma.

A neutropenic child with a purple lesion on the thigh.

Abstract:  Zygomycosis is an aggressive infection by an angioinvasive fungus seen in patients with defects in phagocytosis. We describe a neutropenic child with primary cutaneous Rhizopus infection presenting with a bull’s‐eye appearance. The patient was treated with aggressive surgical debridement along with amphotericin B followed by skin grafting, with full recovery.

Basal cell carcinoma, arising within a granular cell‐type fibrous papule

Fig. 1. A) A 3-mm flesh-colored papule on the bridge of the nose. B–D) Histopathologic examination showed architectural features of a fibrous papule with large cytoplasmic granules. Irregular nests of atypical basaloid epithelial cells with hyperchromatic nuclei, mitoses and peripheral palisading, consistent with basal cell carcinoma, are present. skin-colored, firm and dome-shaped papules. Histopathologically, seven variants of fibrous papules, in addition to the classic type, have been identified: hypercellular, clear cell, pleomorphic, pigmented, inflammatory, epithelioid

Blue Nevus-Smooth Muscle Hamartoma: A Rarely Reported Entity.

To the Editor: The presence of smooth muscle hyperplasia in association with a blue nevus is rarely reported. Tieche first reported a case of blue nevus with fibromatous and myogenic elements. Park et al later described another case of plaque-type blue nevus combined with nevus spilus and hyperplastic arrector pili muscles. An example of congenital melanocytic nevus combined with smooth muscle hamartoma, arising in association with a Becker’s nevus was subsequently described by Patrizi et al. More recently, Tzu et al reviewed the clinicopathological features of a series of combined blue nevi (comprising 2 or more cytologically different populations of melanocytes) with smooth muscle hyperplasia. In the latter study, all cases contained thickened, elongated bundles of smooth muscle interspersed with the melanocytes and arranged parallel to the epidermis, with no relationship to follicular structures. In addition, all lesions were noted to have lentiginous melanocytic proliferation and varying degrees of epidermal change, neither of which correlated with the degree of smooth muscle hyperplasia. We report 2 additional cases of this unusual cutaneous lesion. Similar to most previously reported examples, our cases arose on the back of middle-aged to older patients, were less than 6 mm in diameter, and clinically interpreted as melanocytic lesions. The first example was diagnosed on the left upper back of a 54-year-old woman, demonstrating features of a combined nevus (blue nevus and common-type nevus) admixed with hyperplastic smooth muscle bundles (Figs. 1A, B). The second case was from the right back of a 76-year-old man and comprised a common blue nevus, also occurring in conjunction with a hyperplastic myomatous component (Figs. 1C, D). Immunohistochemical studies for actin confirmed the presence of thickened smooth muscle bundles admixed with dermal melanocytes in both cases (Fig. 1, inserts). Like previously described examples, case 1 demonstrated epidermal acanthosis, with elongation of rete ridges and basilar hyperpigmentation. Case 2 did not exhibit significant overlying epidermal changes. An associated overlying intraepidermal melanocytic proliferation was not identified in either case. Per discussion with referring physicians, both cases did not demonstrate any specific macroscopic features to allow clinical distinction from other subtypes of melanocytic nevi. The 2 nevi arose on clinically normal skin, with no adjacent nevi or cutaneous pigmentation. A number of theories have been proposed to explain the presence of admixed blue nevus cells and hyperplastic smooth muscle bundles in these rarely described cases. Tzu et al suggest that these neoplasms exist on a spectrum of lesions derived from aberrant migration and development of pluripotent neural crest cells, with evidence of phenotypic heterogeneity as a result of focal nonneural crest cellular differentiation. Other putative explanations include the presence of dermal stem cells and/or melanoblasts with the potential to differentiate into divergent cell lineages, including melanocytes and smooth muscle cells. Another possible theory is segmental, postzygotic mosaicism, which is when an individual loses a wild-type allele at early developmental stage leading to loss of heterozygosity in a mosaic patch. FIGURE 1. A and B, Combined nevus (blue nevus and common-type nevus) admixed with hyperplastic smooth muscle bundles on the left upper back of a 54-year-old woman. C and D, Common blue nevus, occurring in conjunction with a hyperplastic myomatous component on the right back of a 76-year-old man. Immunohistochemical studies for actin confirmed the presence of thickened smooth muscle bundles admixed with dermal melanocytes in both cases (inserts).