Proficiency at Tick Identification by Pathologists and Clinicians Is Poor.

OBJECTIVES: Prompt accurate identification of tick species is required for appropriate administration of single dose antimicrobial prophylaxis for Lyme disease in selected patients. To determine the proficiency of clinicians at tick identification in the northeastern United States where Lyme disease has its highest incidence, we undertook a survey. METHODS: We analyzed the results of a voluntary survey testing proficiency in identifying tick species using high-resolution photographs of ticks. RESULTS: Only 35% of ticks were correctly identified. Although 60% of respondents could identify a nonengorged adult blacklegged tick, only 34% could correctly identify a partially engorged blacklegged tick. Participants performed even worse at classifying brown dog, American dog, and Lone Star ticks. CONCLUSIONS: Proficiency of tick identification by pathologists and clinicians is poor.

Identification of Hard Ticks in the United States: A Practical Guide for Clinicians and Pathologists.

ABSTRACT: According to guidelines published by the Infectious Disease Society of America, Lyme disease prophylaxis is possible if a tick can be identified as Ixodes scapularis (nymphal or adult) within 72 hours of tick removal. However, a recent survey of medical practitioners indicates generally poor proficiency in tick identification. In this study, we provide a simple, practical guide to aid medical practitioners in identifying the most commonly encountered human biting ticks of North America.

Direct immunofluorescence is of limited utility in patients with low clinical suspicion for an oral autoimmune bullous disorder.

OBJECTIVES: Oral autoimmune bullous disorders show clinical overlap with diseases such as lichen planus and others that may cause desquamative gingivitis. As direct immunofluorescence is expensive, we sought to determine if routine histology alone would be sufficient to distinguish between oral autoimmune bullous disorders and mimics. METHODS: We searched the records for patients with a suspected oral autoimmune bullous disorder who underwent biopsies for concurrent routine histologic evaluation and direct immunofluorescence and who had at least one follow-up visit. Cases were separated into high and low suspicion subgroups based on clinical findings. RESULTS: Within 148 cases, the sensitivity of routine histology alone was 0.810, with a negative predictive value of 0.889. However, the specificity was 0.989 with a positive predictive value of 0.979. Of the high suspicion cases, 57 (47.1%) were found to be consistent with an oral autoimmune bullous disorder, with a total of 11 histologic false negatives. 8 cases, all in the high suspicion subgroup, showed indeterminate direct immunofluorescence results. There were no histologic false negatives or inconclusive direct immunofluorescence results in the low suspicion subgroup. CONCLUSIONS: In patients with a low clinical suspicion for an oral autoimmune bullous disorder, it is reasonable and more cost-effective to evaluate the lesion with routine histology alone.

Frozen sections are unreliable for the diagnosis of necrotizing soft tissue infections.

Necrotizing soft tissue infections are rare but are associated with high rates of morbidity and mortality. The use of bedside or intraoperative frozen sections has been reported to be associated with faster diagnosis and better outcomes; however, to date no large studies have been published to determine the sensitivity and specificity of frozen sections in this setting. Twenty years of cases suspicious for necrotizing soft tissue infection at a large academic referral center were reviewed, blinded to the final clinical diagnosis (gold standard). Cases were assessed for the number of neutrophils, extent of necrosis, presence of thrombi, bacteria, karyorrhexis, and fibrin, and concordance with permanent sections. A total of 166 cases suspicious for necrotizing soft tissue infection had frozen section slides available for review. Sixty-three cases were clinically determined to be positive and 103 negative. Neutrophils, necrosis, thrombi, bacteria, karyorrhexis, and fibrin were present in both positive and negative cases; however, no histological feature or combination of features was found to be both sensitive and specific for necrotizing soft tissue infection. The combined presence of necrosis and frequent neutrophils was 73% sensitive and 68% specific, with a 58% positive predictive value and 80% negative predictive value. The additional observation of bacteria decreased sensitivity to 32%, whereas raising specificity to 91%, with 69% positive predictive value and 68% negative predictive value. Thirty-two cases (19%) contained findings identified on permanent sections (eg, bacteria) not observed on frozen section slides, highlighting the risk of false negatives owing to technical limitations or sampling errors. Frozen sections in necrotizing soft tissue infections and negative cases may show similar histological findings. Combined with the risk of false negatives, these results suggest that frozen sections are likely to be of limited clinical utility due to lack of sensitivity and specificity, and risk for delayed diagnosis and treatment.

Epidermodysplasia Verruciformis-like HPV Infection of the Vulva in Immunosuppressed Women.

The vast majority of vulvar human papilloma virus infections are produced by α human papilloma viruses and consist of exophytic or flat warts and classic or "usual" vulvar intraepithelial neoplasia. This report details 2 examples of epidermodysplasia verruciformis-like lesions of the vulva in women who were immunosuppressed. The most consistent morphologic feature was the presence of abnormal mature keratinocytes with large pale open nuclei with small nucleoli and eosinophilic cytoplasm, situated in the upper epithelial layers. In addition to these features, which are commonly seen in epidermodysplasia verruciformis-associated lesions, 1 case displayed in addition more extensively distributed abnormal nuclei, including involvement of both the upper epithelial strata and the epithelial/stromal interface. Both lesions were associated with ß-papilloma virus type 5. The unique aspects of epidermodysplasia verruciformis-like lesions relative to the more common human papilloma virus infections of the vulva are highlighted and these cases illustrate the range of epithelial distribution that might be encountered in lesions involving the vulvar mucosa.

A 48-Year-Old Male with Cutaneous Metastases of NUT Midline Carcinoma Misdiagnosed as Herpes Zoster.

NUT (nuclear protein of the testis) midline carcinoma (NMC) is a rare, poorly differentiated neoplasm with dismal prognosis. Though NMC are often metastatic by the time of presentation, cutaneous metastases have not been well described in the literature. We report a case of NMC in a patient who presented with grouped well-demarcated tender non-ulcerated erythematous nodules on the right mid-back. The lesions were initially diagnosed and treated as herpes zoster. Following failure to improve with antiviral therapy, imaging and skin biopsy revealed that the lesions were in fact cutaneous NUT carcinoma. Although NMC is an uncommon diagnosis, clinicians should be aware that affected patients can develop skin involvement to avoid unnecessary and harmful treatments.

Histopathologic Spectrum of Connective Tissue Diseases Commonly Affecting the Skin.

Connective tissue disorders (CTDs), also known as collagen vascular diseases, are a heterogeneous group of diseases with a common pathogenic mechanism: autoimmunity. Precise classification of CTDs requires clinical, serologic, and pathologic correlation and may be difficult because of overlapping clinical and histologic features. The main contribution of histopathology in the diagnosis of these disorders is to confirm, rule out, or alert clinicians to the possibility of CTD as a disease category, rather than producing definitive diagnoses of specific entities. This article discusses the histopathologic spectrum of 3 common rheumatologic skin disorders: lupus erythematosus, dermatomyositis, and morphea (localized scleroderma).

5-Hydroxymethylcytosine is a nuclear biomarker to assess biological potential in histologically ambiguous heavily pigmented melanocytic neoplasms.

BACKGROUND: 5-Hydroxymethylcytosine (5-hmC) is an epigenetic marker detectable through immunohistochemistry (IHC) that has been shown to distinguish benign nevi from melanoma with high sensitivity and specificity. The purpose of the study was to explore its diagnostic utility in a subset of histologically challenging, heavily pigmented cutaneous melanocytic neoplasms. METHODS: 5-hmC IHC was performed on 54 heavily pigmented melanocytic tumors. Semi-quantitative analysis of immunoreactivity was correlated with clinical, pathologic and follow-up data. RESULTS: Benign melanocytic neoplasms (4 of 4 blue nevi with epithelioid change; 12 of 12 combined nevi; 5 of 5 deep penetrating nevi, DPN) exhibited strong 5-hmC nuclear reactivity. Eight heavily pigmented blue nevus-like melanomas and 7 of 8 pigmented epithelioid melanocytomas (PEM) showed significant 5-hmC loss. Five of 7 atypical DPN cases and 8 of 10 melanocytic tumors of uncertain malignant potential (MELTUMP) showed low to intermediate 5-hmC immunoreactivity. These differences were statistically significant (P-value <.0001). CONCLUSIONS: Loss of 5-hmC may be helpful in differentiating benign, diagnostically challenging, heavily pigmented melanocytic tumors from those with malignant potential. The intermediate to low 5-hmC immunoreactivity in atypical DPNs, PEMs and so-called MELTUMP categories further underscores the need to consider these neoplasms as having some potential for lethal biological behavior.

Analysis of a Mouse Skin Model of Tuberous Sclerosis Complex.

Tuberous Sclerosis Complex (TSC) is an autosomal dominant tumor suppressor gene syndrome in which patients develop several types of tumors, including facial angiofibroma, subungual fibroma, Shagreen patch, angiomyolipomas, and lymphangioleiomyomatosis. It is due to inactivating mutations in TSC1 or TSC2. We sought to generate a mouse model of one or more of these tumor types by targeting deletion of the Tsc1 gene to fibroblasts using the Fsp-Cre allele. Mutant, Tsc1ccFsp-Cre+ mice survived a median of nearly a year, and developed tumors in multiple sites but did not develop angiomyolipoma or lymphangioleiomyomatosis. They did develop a prominent skin phenotype with marked thickening of the dermis with accumulation of mast cells, that was minimally responsive to systemic rapamycin therapy, and was quite different from the pathology seen in human TSC skin lesions. Recombination and loss of Tsc1 was demonstrated in skin fibroblasts in vivo and in cultured skin fibroblasts. Loss of Tsc1 in fibroblasts in mice does not lead to a model of angiomyolipoma or lymphangioleiomyomatosis.

A phase I trial of panobinostat (LBH589) in patients with metastatic melanoma.

Epigenetic alterations by histone/protein deacetylases (HDACs) are one of the many mechanisms that cancer cells use to alter gene expression and promote growth. HDAC inhibitors have proven to be effective in the treatment of specific malignancies, particularly in combination with other anticancer agents. We conducted a phase I trial of panobinostat in patients with unresectable stage III or IV melanoma. Patients were treated with oral panobinostat at a dose of 30 mg daily on Mondays, Wednesdays, and Fridays (Arm A). Three of the six patients on this dose experienced clinically significant thrombocytopenia requiring dose interruption. Due to this, a second treatment arm was opened and the dose was changed to 30 mg oral panobinostat three times a week every other week (Arm B). Six patients were treated on Arm A and 10 patients were enrolled to Arm B with nine patients treated. In nine patients treated on Arm B, the response rate was 0% (90% confidence interval [CI]: 0-28%) and the disease-control rate was 22% (90% CI: 4-55%). Among all 15 patients treated, the overall response rate was 0% (90% CI: 0-17%) and the disease-control rate was 27% (90% CI: 10-51%). There was a high rate of toxicity associated with treatment. Correlative studies suggest the presence of immune modifications after HDAC inhibition. Panobinostat is not active as a single agent in the treatment of melanoma. Further exploration of this agent in combination with other therapies may be warranted.

A PGC1α-mediated transcriptional axis suppresses melanoma metastasis.

Melanoma is the deadliest form of commonly encountered skin cancer because of its rapid progression towards metastasis. Although metabolic reprogramming is tightly associated with tumour progression, the effect of metabolic regulatory circuits on metastatic processes is poorly understood. PGC1α is a transcriptional coactivator that promotes mitochondrial biogenesis, protects against oxidative stress and reprograms melanoma metabolism to influence drug sensitivity and survival. Here, we provide data indicating that PGC1α suppresses melanoma metastasis, acting through a pathway distinct from that of its bioenergetic functions. Elevated PGC1α expression inversely correlates with vertical growth in human melanoma specimens. PGC1α silencing makes poorly metastatic melanoma cells highly invasive and, conversely, PGC1α reconstitution suppresses metastasis. Within populations of melanoma cells, there is a marked heterogeneity in PGC1α levels, which predicts their inherent high or low metastatic capacity. Mechanistically, PGC1α directly increases transcription of ID2, which in turn binds to and inactivates the transcription factor TCF4. Inactive TCF4 causes downregulation of metastasis-related genes, including integrins that are known to influence invasion and metastasis. Inhibition of BRAFV600E using vemurafenib, independently of its cytostatic effects, suppresses metastasis by acting on the PGC1α-ID2-TCF4-integrin axis. Together, our findings reveal that PGC1α maintains mitochondrial energetic metabolism and suppresses metastasis through direct regulation of parallel acting transcriptional programs. Consequently, components of these circuits define new therapeutic opportunities that may help to curb melanoma metastasis.

Ipilimumab for Patients with Relapse after Allogeneic Transplantation.

BACKGROUND: Loss of donor-mediated immune antitumor activity after allogeneic hematopoietic stem-cell transplantation (HSCT) permits relapse of hematologic cancers. We hypothesized that immune checkpoint blockade established by targeting cytotoxic T-lymphocyte-associated protein 4 with ipilimumab could restore antitumor reactivity through a graft-versus-tumor effect. METHODS: We conducted a phase 1/1b multicenter, investigator-initiated study to determine the safety and efficacy of ipilimumab in patients with relapsed hematologic cancer after allogeneic HSCT. Patients received induction therapy with ipilimumab at a dose of 3 or 10 mg per kilogram of body weight every 3 weeks for a total of 4 doses, with additional doses every 12 weeks for up to 60 weeks in patients who had a clinical benefit. RESULTS: A total of 28 patients were enrolled. Immune-related adverse events, including one death, were observed in 6 patients (21%), and graft-versus-host disease (GVHD) that precluded further administration of ipilimumab was observed in 4 patients (14%). No responses that met formal response criteria occurred in patients who received a dose of 3 mg per kilogram. Among 22 patients who received a dose of 10 mg per kilogram, 5 (23%) had a complete response, 2 (9%) had a partial response, and 6 (27%) had decreased tumor burden. Complete responses occurred in 4 patients with extramedullary acute myeloid leukemia and 1 patient with the myelodysplastic syndrome developing into acute myeloid leukemia. Four patients had a durable response for more than 1 year. Responses were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells in the blood. CONCLUSIONS: Our early-phase data showed that administration of ipilimumab was feasible in patients with recurrent hematologic cancers after allogeneic HSCT, although immune-mediated toxic effects and GVHD occurred. Durable responses were observed in association with several histologic subtypes of these cancers, including extramedullary acute myeloid leukemia. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01822509.).