Allison R. Larson

Systemic lupus erythematosus–associated neutrophilic dermatosis—an underrecognized neutrophilic dermatosis in patients with systemic lupus erythematosus ☆ ☆☆

Neutrophilic dermatoses are an uncommon manifestation of lupus. We describe the clinical and histopathologic features of 14 patients with systemic lupus erythematosus (SLE) and neutrophilic dermatoses, 2 of whom had no prior history of SLE. Thirteen patients were female, ranging in age from 27 to 62 years (mean age, 42.8 years). One patient was a 20-year-old man. Most lesions were described as erythematous papules and plaques and showed annular morphology in 6 patients and a photodistribution in 2 patients. Histopathologic examination in all cases showed an interstitial neutrophilic infiltrate with leukocytoclasis that ranged from sparse in 5 cases and moderate to dense in 9 cases. With one exception, those cases with moderate to dense infiltrates resembled Sweets syndrome at scanning magnification. Two cases resembled bullous SLE, and 1 case showed overlapping features of bullous SLE and Sweets syndrome. Interface changes were seen in 8 patients, which were subtle and vacuolar in 7. One case was associated with a florid interface tissue reaction. Dermal mucin was seen in 4 cases and was a prominent feature in only one of these. One case showed a minute discrete focus resembling palisaded neutrophilic and granulomatous dermatitis. It is important to consider SLE-associated neutrophilic dermatosis in the differential diagnosis of neutrophilic tissue reactions particularly because some patients will have no prior history of lupus. It is also important to be aware of the broad histologic spectrum that may be encountered in SLE-associated neutrophilic dermatosis, ranging from subtle paucicellular lesions to florid Sweets-like lesions associated with a dense neutrophilic infiltrate.

Evaluation of stromal HGF immunoreactivity as a biomarker for melanoma response to RAF inhibitors

Of more than 150 000 published studies evaluating new biomarkers, fewer than 100 biomarkers have been implemented for patient care. One reason for this is lack of rigorous testing by the medical community to validate claims for biomarker clinical relevance, and potential reluctance to publish negative results when confirmation is not obtained. Here we sought to determine the utility and reproducibility of immunohistochemical detection of hepatocyte growth factor (HGF) in melanoma tissue, an approach of potential assistance in defining patients with innate resistance to BRAF inhibitor therapy. To this end, a published and a revised method that retained sensitivity but with greater specificity for HGF detection, were evaluated in cells known to endogenously express HGF, and in models where HGF is upregulated via cytokine induction and via overexpression by gene transfection. Consequent patient evaluation in collaboration with the Melanoma Institute Australia of a cohort of 41 melanoma specimens with extensive clinical annotation failed to validate HGF immunohistochemistry as a predictor of response to BRAF inhibitors. Targeted therapies for advanced melanoma and other cancers show great promise, and rigorous validation studies are thus indicated for approaches that seek to personalize such therapies to maximize therapeutic efficacy.

The spectrum of histopathologic findings in cutaneous lesions in patients with Still disease.

OBJECTIVES Still disease is a rare disorder characterized by seronegative arthralgias/arthritis, spiking fever, and either an evanescent salmon-colored rash or persistent papules and plaques. METHODS We describe the clinical and biopsy findings in 10 patients with the evanescent rash of Still disease. RESULTS Fourteen biopsy specimens were studied from seven women and three men with a mean age of 44.4 years. The skin lesions were typically erythematous macules, papules, or plaques with a median duration of 5 weeks. All patients had systemic symptoms, including fever and arthralgias. The infiltrate was predominantly lymphocytic in six biopsy specimens, approximately equal lymphocytic and neutrophilic in four biopsy specimens, and predominantly (although never exclusively) neutrophilic in four biopsy specimens. Other findings included focal vacuolar interface changes, neutrophilic eccrine hidradenitis, epidermal neutrophils, dermal mucin, and acanthosis associated with numerous upper epidermal dyskeratotic cells. CONCLUSIONS It is important to be aware of the broad histologic spectrum that may be encountered in Still disease and to consider Still disease in the differential diagnosis of neutrophil-rich, lymphocyte-rich, and mixed inflammatory dermatoses. While the histologic findings seen in biopsy specimens of the evanescent rash are nonspecific, a distinctive variant also exists characterized by prominent epidermal apoptosis, especially involving the upper layers.

Merkel cell carcinoma expresses vasculogenic mimicry: demonstration in patients and experimental manipulation in xenografts

Merkel cell carcinoma (MCC) is a highly virulent cutaneous neoplasm that, like melanoma, is a frequent cause of patient morbidity and mortality. The cellular mechanisms responsible for the aggressive behavior of MCC remain unknown. Vasculogenic mimicry (VM) is a phenomenon associated with cancer virulence, including in melanoma, whereby anastomosing laminin networks form in association with tumor cells that express certain endothelial genes. To determine whether VM is a factor in MCC, we employed a relevant xenograft model using two independent human MCC lines. Experimentally induced tumors were remarkably similar histologically to patient MCC, and both contained laminin networks associated with vascular endothelial-cadherin (CD144) and vascular endothelial growth factor receptor 1, as well as Nodal expression typical of VM in melanoma. Moreover, two established chemotherapeutic agents utilized for human MCC, etoposide and carboplatin, induced necrosis in xenografts on systemic administration while enriching for laminin networks in apparently resistant viable tumor regions that persisted. These findings for the first time establish VM-like laminin networks as a biomarker in MCC, demonstrate the experimental utility of the MCC xenograft model, and suggest that VM-rich regions of MCC may be refractory to conventional chemotherapeutic agents.

Systemic lupus erythematosus-associated neutrophilic dermatosis: a review and update.

Neutrophilic dermatoses are a rare manifestation of systemic lupus erythematosus (SLE). In recent years, a growing body of literature describes a pathologic spectrum of neutrophilic infiltrates that may be seen in lupus patients. It is particularly important to recognize that neutrophilic dermatoses can be the initial manifestation of SLE in a third of patients. We were able to identify 47 patients with SLE associated with neutrophilic tissue reactions. In this review, we describe the histologic and clinical features of these cases in the hope that increased awareness of this unusual manifestation of SLE will generate prompt diagnosis and improved patient care.

Nestin depletion induces melanoma matrix metalloproteinases and invasion

Matrix metalloproteinases (MMPs) are key biological mediators of processes as diverse as wound healing, embryogenesis, and cancer progression. Although MMPs may be induced through multiple signaling pathways, the precise mechanisms for their regulation in cancer are incompletely understood. Because cytoskeletal changes are known to accompany MMP expression, we sought to examine the potential role of the poorly understood cytoskeletal protein, nestin, in modulating melanoma MMPs. Nestin knockdown (KD) upregulated the expression of specific MMPs and MMP-dependent invasion both through extracellular matrix barriers in vitro and in peritumoral connective tissue of xenografts in vivo. The development of three-dimensional melanospheres that in vitro partially recapitulate noninvasive tumorigenic melanoma growth was inhibited by nestin KD, although ECM invasion by aberrant melanospheres that did form was enhanced. Mechanistically, nestin KD-dependent melanoma invasion was associated with intracellular redistribution of phosphorylated focal adhesion kinase and increased melanoma cell responsiveness to transforming growth factor-beta, both implicated in pathways of melanoma invasion. The results suggest that the heretofore poorly understood intermediate filament, nestin, may serve as a novel mediator of MMPs critical to melanoma virulence.

Utility of immunofluorescence testing for vascular IgA in adult patients with leukocytoclastic vasculitis.

OBJECTIVES The purpose of this study was to examine the utility of immunofluorescence (IF) testing in patients with leukocytoclastic vasculitis (LCV), particularly with regard to usefulness in the diagnosis of Henoch-Schönlein purpura (HSP). METHODS We retrospectively analyzed the results of IF testing in 96 patients with LCV and compared results with clinical criteria and clinical impression at the time of biopsy by review of the medical record. RESULTS Sensitivity and specificity of vascular immunoglobulin A (IgA) for the diagnosis of HSP were 0.86 and 0.84, respectively. Positive predictive value was 0.48 and negative predictive value was 0.97. Of the 53 patients with LCV who did not meet clinical criteria for HSP and carried a low clinical suspicion for the disease at the time of biopsy, seven had moderate to strong staining for vascular IgA. Only one of these patients was determined to have HSP. CONCLUSIONS Our data confirm that vascular IgA is nonspecific and also demonstrate that the utility of IF studies for vasculitis is influenced by the clinical presentation and the clinicians level of suspicion for HSP. Our data show that the clinical features and the overall clinical impression are helpful in selecting which patients are most likely to benefit from IF testing.

Unforeseen ethical challenges for isotretinoin treatment in transgender patients

A 28-year-oldmale-appearing patient comes into Dr. Miller’s dermatology clinic for the first time. The patient reveals that he is here for the evaluation of severe acne. Dr. Miller soon learns that the patient is a transgender man and has been receiving hormone replacement therapy for the past year. He is on a regimen of weekly self-administered 100 mg intramuscular testosterone enthanate injections, and he has had nomenses since shortly after beginning testosterone. His testosterone levels have remained in a normal male range. The patient is not on any other medications and has not had any procedural interventions for his transition. He is sexually active with a female partner. He has had his gendermarkers legally changed to male on his driver’s license and in his medical record. After a long history of moderate acne, the patient states that his acne became severe shortly after initiating testosterone. Dr. Miller examines him and finds severe nodulocystic acne with areas of postinflammatory hyperpigmentation and scarring distributed over his face and back. The patient has been on a regimen of a topical retinoid and oral doxycycline for the past 3monthswithout any relief and is requesting oral isotretinoin. Dr. Miller is unsure of how to proceed because the patient’s acne could possibly be improved if he stops taking his tes-

Uncovering bias in the cytologic evaluation of cervical squamous lesions.

OBJECTIVES It is well recognized that biases exist in medical decision making. We sought evidence for such bias in diagnostic testing. METHODS We investigated whether a cytotechnologists Papanicolaou (Pap) test interpretation of a squamous cell abnormality influenced the likelihood of making the same interpretation again that day using analysis based on the β distribution. RESULTS For squamous intraepithelial lesion (SIL) interpretations, significant deviation away from the mean daily diagnostic rate was seen within all three cytotechnologists and, for atypical squamous cells of undetermined significance interpretations, within two of three. CONCLUSIONS Cytotechnologists are not influenced by an expected number of abnormal Pap cases per day since this would result in deviation toward the mean daily rate of diagnosis. Possible explanations for the unanticipated clustering of SIL interpretations include clinical clustering effects or, alternatively, the influence a SIL interpretation might have on lowering the threshold for this interpretation again in subsequent specimens on the same day. The analysis presented here could serve as a model to detect bias in other aspects of medical decision making.

Calciphylaxis and the Persistence of Medical Misinformation in the Era of Google

OBJECTIVES We illustrate the important and troubling issue of persistent misinformation and false claims in the medical literature using a frequently cited case inaccurately believed by many to be the first case of calciphylaxis. METHODS We identified a recurring error in the medical literature in the form of numerous citations of a study from the 1890s of a 6-month-old child with idiopathic infantile arterial calcification that is purported to be the first description of a case of calciphylaxis. We performed searches to determine the frequency of this error. Google Scholar and PubMed were searched for references citing the Bryant and White article. Accuracy of the citations was determined. RESULTS A Google Scholar search identified 33 references that incorrectly cite the Bryant and White article as the first description of a case of calciphylaxis. Of the 100 most recent PubMed publications on calciphylaxis, we identified five studies that incorrectly attribute the Bryant and White article as the first description of calciphylaxis, which accounts for approximately 5% of the contemporary literature on this topic. CONCLUSIONS Medical misinformation such as this is frequently perpetuated. We propose that computational resources could be better used to flag erroneous and contradicted claims to update and correct the literature.