Appropriate Statistical Methods to Assess Cross-study Diagnostic 23-Gene Expression Profile Test Performance for Cutaneous Melanocytic Neoplasms.

ABSTRACT: Comparing studies of molecular ancillary diagnostic tests for difficult-to-diagnose cutaneous melanocytic neoplasms presents a methodological challenge, given the disparate ways accuracy metrics are calculated. A recent report by Boothby-Shoemaker et al investigating the real-world accuracy of the 23-gene expression profile (23-GEP) test highlights this methodological difficulty, reporting lower accuracy than previously observed. However, their calculation method-with indeterminate test results defined as either false positive or false negative-was different than those used in previous studies. We corrected for these differences and recalculated their reported accuracy metrics in the same manner as the previous studies to enable appropriate comparison with previously published reports. This corrected analysis showed a sensitivity of 92.1% (95% confidence interval [CI], 82.1%-100%) and specificity of 94.4% (91.6%-96.9%). We then compared these results directly to previous studies with >25 benign and >25 malignant cases with outcomes and/or concordant histopathological diagnosis by ≥3 dermatopathologists. All studies assessed had enrollment imbalances of benign versus malignant patients (0.8-7.0 ratio), so balanced cohorts were resampled according to the lowest common denominator to calculate point estimates and CIs for accuracy metrics. Overall, we found no statistically significant differences in the ranges of 23-GEP sensitivity, 90.4%-96.3% (95% CI, 80.8%-100%), specificity, 87.3%-96.2% (78.2%-100%), positive predictive value, 88.5%-96.1% (81.5%-100%), or negative predictive value, 91.1%-96.3% (83.6%-100%) between previous studies and the cohort from Boothby-Shoemaker et al with this unified methodological approach. Rigorous standardization of calculation methods is necessary when the goal is direct cross-study comparability.

Characterization of ALTO-encoding circular RNAs expressed by Merkel cell polyomavirus and trichodysplasia spinulosa polyomavirus.

Circular RNAs (circRNAs) are a conserved class of RNAs with diverse functions, including serving as messenger RNAs that are translated into peptides. Here we describe circular RNAs generated by human polyomaviruses (HPyVs), some of which encode variants of the previously described alternative large T antigen open reading frame (ALTO) protein. Circular ALTO RNAs (circALTOs) can be detected in virus positive Merkel cell carcinoma (VP-MCC) cell lines and tumor samples. CircALTOs are stable, predominantly located in the cytoplasm, and N6-methyladenosine (m6A) modified. The translation of MCPyV circALTOs into ALTO protein is negatively regulated by MCPyV-generated miRNAs in cultured cells. MCPyV ALTO expression increases transcription from some recombinant promoters in vitro and upregulates the expression of multiple genes previously implicated in MCPyV pathogenesis. MCPyV circALTOs are enriched in exosomes derived from VP-MCC lines and circALTO-transfected 293T cells, and purified exosomes can mediate ALTO expression and transcriptional activation in MCPyV-negative cells. The related trichodysplasia spinulosa polyomavirus (TSPyV) also expresses a circALTO that can be detected in infected tissues and produces ALTO protein in cultured cells. Thus, human polyomavirus circRNAs are expressed in human tumors and infected tissues and express proteins that have the potential to modulate the infectious and tumorigenic properties of these viruses.

Update of pathophysiology and treatment options of seborrheic keratosis.

Seborrheic keratosis (SK) is a common, benign tumor that can occur on everybody site and can be conservatively managed. Cosmetic concerns, especially when a lesion involves the facial area, are the most common reason for excision. SK shows male gender preponderance and increasing age is an independent association with the condition. Even though more prevalent in the elderly, it has also been reported in younger age groups like adolescents and young adults. Precise pathogenesis is still obscure, but ultra-violet exposure represents a predisposing factor to SK by altering the biochemical concentration and expression of factors like Glutamine deaminases, endothelin, and stem cell factor. Moreover, the accumulation of amyloid-associated protein has also been postulated. Involvement of genitalia has been associated with human papillomavirus infection. Recently, Merkel cell polyomavirus nucleic acid was also detected in SK. Several oncogenic mutations involving FGFR-3 and FOXN1 have been identified. SKs are usually classified clinically and histologically. Dermatoscopy is a noninvasive alternative diagnostic technique widely used in differentiating SK from other benign and malignant tumors. In terms of treatment, topical agents, shave dissection, cryosurgery, electrodesiccation, laser application and curettage under local anesthesia are safe methods for eradication of SKs, mostly for cosmetic purposes. Though generally safe, the latter techniques may occasionally cause post-procedure depigmentation, scarring, and recurrence. Nanosecond-pulsed electric field technology is a promising new technique with fewer side-effects.

Scurvy and Tinea Corporis Simulating Leukocytoclastic Vasculitis.

ABSTRACT: Leukocytoclastic vasculitis (LCV) is a small vessel inflammatory condition considered to be caused by circulating immune complexes and often occurs after an acute infection or exposure to a new medication, although it may be associated with an underlying systemic disease or be idiopathic in nature. It is important to determine the etiology, identify the extent of the disease for early intervention and appropriate management, and treat and/or eliminate the underlying cause. Here, we report cases of scurvy and tinea corporis that presented with histopathologic features of LCV and had significant clinical improvement with treatment of the underlying etiologies. These cases emphasize that histopathologic features of early evolving LCV may be seen in other settings including scurvy and tinea corporis. Appropriate treatment of the underlying condition is important for optimized patient management.

Advances and Considerations in the Management of Actinic Keratosis: An Expert Consensus Panel Report.

BACKGROUND: Actinic Keratosis (AK) is a potentially pre-malignant tumor with a poorly defined risk of progression to invasive squamous cell carcinoma (SCC). Because of the typical need for recurrent cycles of AK treatment, outcomes can be limited by both therapeutic efficacy and patient adherence. OBJECTIVE: To synthesize the available and most current literature into overarching principles to provide guidance on the management of AKs, improving patient experiences and treatment outcomes. METHODS: A systematic review querying epidemiology, natural history, prognosis, management of AKs as well as the mechanism of action of and adherence to current AK therapy was conducted. After reviewing the literature, an expert consensus panel consisting of 10 expert dermatologists and dermatopathologists used a modified Delphi process to develop statements regarding the pathogenesis and management of AKs. Final statements were only adopted with a supermajority vote (≥7/10). RESULTS: The panel developed 7 consensus statements regarding AKs pathogenesis and management. CONCLUSION: The poorly defined risk for AK progression into invasive SCC without universally accepted clinical-histopathological factors highlights the importance of long-term efficacious treatment. To effectively counsel and treat patients with actinic keratoses, dermatologists must understand how newer therapeutic approaches with mechanisms of action that have more rapid onset of action, shorter treatment courses, and less intense local skin reaction (LSRs) may promote adherence and improve long-term outcomes. J Drugs Dermatol. 2021;20(8):888-893. doi:10.36849/JDD.6078 THIS ARTICLE HAD BEEN MADE AVAILABLE FREE OF CHARGE. PLEASE SCROLL DOWN TO ACCESS THE FULL fTEXT OF THIS ARTICLE WITHOUT LOGGING IN. NO PURCHASE NECESSARY. PLEASE CONTACT THE PUBLISHER WITH ANY QUESTIONS.

Corrigendum: Impact on clinical practice of a non-invasive gene expression melanoma rule-out test: 12-month followup of negative test results and utility data from a large US registry study.

The revised version of the article corrected Figure 2. This change appears in the revised online PDF copy of this article.

Impact on clinical practice of a non-invasive gene expression melanoma rule-out test: 12-month follow-up of negative test results and utility data from a large US registry study.

The Pigmented Lesion Assay (PLA, sensitivity 91-95%, specificity 69-91%, negative predictive value ?99%) is a commercially available, non-invasive gene expression test that helps dermatologists guide pigmented lesion management decisions and rule out melanoma. Earlier studies have demonstrated high clinical utility and no missed melanomas in a 3-6-month follow-up period. We undertook the current investigations to provide 12-month follow-up data on PLA(-) tests, and to further confirm utility. A 12-month chart review follow-up of 734 pigmented lesions that had negative PLA results from 5 US dermatology centers was performed. Thirteen of these lesions (1.8%) were biopsied in the follow-up period and submitted for histopathologic review. None of the lesions biopsied had a histopathologic diagnosis of melanoma. The test's utility was studied further in a registry (N=1575, 40 US dermatology offices, 62 participating providers), which demonstrated that 99.9% of PLA(-) lesions were clinically monitored, thereby avoiding a surgical procedure, and 96.5% of all PLA(+) lesions were appropriately biopsied, most commonly with a tangential shave. This long-term follow-up study confirms the PLA's high negative predictive value and high utility in helping guide the management of pigmented lesions to avoid unnecessary surgical procedures.

An independent validation of a gene expression signature to differentiate malignant melanoma from benign melanocytic nevi.

BACKGROUND: Recently, a 23-gene signature was developed to produce a melanoma diagnostic score capable of differentiating malignant and benign melanocytic lesions. The primary objective of this study was to independently assess the ability of the gene signature to differentiate melanoma from benign nevi in clinically relevant lesions. METHODS: A set of 1400 melanocytic lesions was selected from samples prospectively submitted for gene expression testing at a clinical laboratory. Each sample was tested and subjected to an independent histopathologic evaluation by 3 experienced dermatopathologists. A primary diagnosis (benign or malignant) was assigned to each sample, and diagnostic concordance among the 3 dermatopathologists was required for inclusion in analyses. The sensitivity and specificity of the score in differentiating benign and malignant melanocytic lesions were calculated to assess the association between the score and the pathologic diagnosis. RESULTS: The gene expression signature differentiated benign nevi from malignant melanoma with a sensitivity of 91.5% and a specificity of 92.5%. CONCLUSIONS: These results reflect the performance of the gene signature in a diverse array of samples encountered in routine clinical practice. Cancer 2017;123:617-628. © 2016 American Cancer Society.

Human polyomavirus 6 and 7 are associated with pruritic and dyskeratotic dermatoses.

BACKGROUND: Human polyomavirus (HPyV)6 and HPyV7 are shed chronically from human skin. HPyV7, but not HPyV6, has been linked to a pruritic skin eruption of immunosuppression. OBJECTIVE: We determined whether biopsy specimens showing a characteristic pattern of dyskeratosis and parakeratosis might be associated with polyomavirus infection. METHODS: We screened biopsy specimens showing "peacock plumage" histology by polymerase chain reaction for HPyVs. Cases positive for HPyV6 or HPyV7 were then analyzed by immunohistochemistry, electron microscopy, immunofluorescence, quantitative polymerase chain reaction, and complete sequencing, including unbiased, next-generation sequencing. RESULTS: We identified 3 additional cases of HPyV6 or HPyV7 skin infections. Expression of T antigen and viral capsid was abundant in lesional skin. Dual immunofluorescence staining experiments confirmed that HPyV7 primarily infects keratinocytes. High viral loads in lesional skin compared with normal-appearing skin and the identification of intact virions by both electron microscopy and next-generation sequencing support a role for active viral infections in these skin diseases. LIMITATION: This was a small case series of archived materials. CONCLUSION: We have found that HPyV6 and HPyV7 are associated with rare, pruritic skin eruptions with a distinctive histologic pattern and describe this entity as "HPyV6- and HPyV7-associated pruritic and dyskeratotic dermatoses."

Cutaneous malignancies simulating seborrheic keratoses: An underappreciated phenomenon?

BACKGROUND: Seborrheic keratosis (SK), a common and benign entity, is generally diagnosed clinically without the need for a biopsy. Given their variable appearance, SK may mimic cancer clinically and require biopsy for clinically equivocal cases. A clinician may also choose to perform biopsies on SK based on other circumstances, such as cosmetic reasons or SK being in an inconvenient and irritative location. METHODS: Dermatopathology samples from 2015 obtained from private and university locations were retrospectively assessed. Cases included in the study were those with "SK" or "ISK" (irritated seborrheic keratosis) and no other diagnosis in the clinical data. Cases with modifiers suggestive of malignancy such as "SK rule out others," changing, growing and so on were excluded. A total of 4361 eligible cases were identified and used for analysis. RESULTS: Of the 4361 cases identified as only "SK" or "ISK" in the clinical data, 3759 (86.2%) were, in fact, SK or ISK. A total of 466 (10.7%) were an assortment of non-malignancy diagnoses such as dermatofibroma. There were 136 (3.1%) cases histologically diagnosed as malignancies. The majority (9/136 cases; 67%) were in situ or invasive squamous cell carcinoma; 24.3% (33/136) were basal cell carcinoma and 8.8% (12/136) were melanoma. CONCLUSION: SK may mimic cancer even in clinically unsuspicious cases.

Primary low-grade neuroendocrine carcinoma of the skin: An exceedingly rare entity.

Low-grade neuroendocrine tumors (NETs), also known as carcinoid tumor, commonly arise from the gastrointestinal (GI) and pulmonary tracts, but rarely occur in the skin. Cutaneous NET typically occurs as metastases or high-grade primary lesions, called Merkel cell carcinoma. In the few cases described in literature, primary low-grade neuroendocrine carcinomas of the skin (LGNECS) are usually indolent cutaneous nodules, presenting on the head and trunk of elderly patients. LGNECS tumors are histologically similar to its counterparts arising in other anatomic locations. As there is no NET cut-off for the skin due to their rarity, the GI scale was used instead; low-grade NETs have a Ki-67 proliferative index of less than 3%. The distinction between primary and metastatic NET, however, is not absolute and can be difficult. A primary vs metastatic NET diagnosis relies on clinical exclusion of a NET in other, more common, anatomic locations. Here, we present a case of an LGNECS on the scalp of a 72-year-old female patient. Whole body imaging failed to identify any octreotide-avid lesions elsewhere in the patient, aside from 2 positive cervical lymph nodes, which were confirmed with a node dissection and histologic evaluation. This is the 19th reported case of LGNECS and the 2nd reported case of LGNECS with nodal metastasis.

Novel Cutaneous Manifestations of Pleuroparenchymal Fibroelastosis.

Pleuroparenchymal fibroelastosis (PPFE) is a rare progressive disease that manifests as parenchymal fibrosis of the upper lobe and pleura. Approximately 100 cases have been reported. Cutaneous manifestations of PPFE have not previously been described. Diagnosis is dependent on histologic identification of fibrosis with atypical elastic fibers, necessitating an invasive peripheral lung wedge biopsy.A 68-year-old male with a history of pleuroparenchymal fibroelastosis presented with an asymptomatic, telangiectatic erythematous eruption on bilateral lower extremities. Biopsies demonstrated a subtle perivascular infiltrate with marked increase in atypical elastic fibers, similar to the elastosis in the patient's lungs.This is the first documented case of cutaneous manifestations in PPFE. Clinicians need to be aware that cutaneous eruptions clinically simulating telangiectasia macularis eruptiva perstans but lacking a mast cell infiltrate histologically, may have increased abnormal elastic fibers. Thus, early recognition of these lesions in patients with an undefined restrictive lung disorder, may facilitate the diagnosis of PPFE in some patients.

Characterization of tissue and slide artifacts from automated embedding systems.

With recent technological advances and cost reductions, automated embedding systems are rapidly becoming routine in the processing of skin biopsy specimens. The efficiency advantages of this technique are due in part to the use of patented sectionable cassettes that hold formalin-fixed tissue from the time of grossing through tissue sectioning. In this process, the final paraffin block contains both the tissue and the cassette, which are sectioned and stained in unison. Here, we report the multiple tissue and slide artifacts commonly seen with automated embedding systems that are unique to this method of tissue processing. The most frequently observed tissue changes are patterned molding of the biopsy specimen around the cassette material. The most common slide artifacts are due to the presence of geometrically shaped polarizable cassette material adjacent to or overlying the stained tissue. As many of these artifacts strongly resemble the shapes seen in the classic 1980s video game, Tetris, we propose the term of Tetris-like artifacts for these findings. Although we remain confident that use of an automated embedding system does not decrease diagnostic reliability, increased familiarity with the standard appearance of slides processed using this technique will help avoid confusion when evaluating these cases.

Multinucleate cell angiohistiocytoma: a case report and review of the literature.

Multinucleate cell angiohistiocytoma (MCAH) is a rare, benign vascular proliferation. Fewer than 80 cases have been reported to date, which may relate to under-recognition of this entity. Lesions are commonly asymptomatic and appear as erythematous to violaceous papules on the lower extremities and dorsal hands of middle-aged to elderly women. The characteristic histopathologic and immunohistochemical features of MCAH are essential for definitive diagnosis of MCAH. Multinucleate cell angiohistiocytoma follows a slowly progressive course, although spontaneous regression has been reported in rare cases. We present a case of MCAH to increase awareness and elucidate the characteristic clinical and histopathologic features of this disorder.

Sarcoidosis Resembling Angiokeratomas: A Case Report.

Sarcoidosis, a multifaceted systemic disorder characterized histologically by the presence of non-caseating granulomas, has a wide array of cutaneous manifestations. We describe a case of a 74-year-old woman with a complex medical history, who presented with asymptomatic hyperpigmented papules on her lower extremities. Histological examination of a punch biopsy specimen showed nodular and angiocentric patterns of granulomatous inflammation consistent with sarcoidosis, and chest radiography demonstrated bilateral hilar opacities, supporting the diagnosis. To our knowledge, this specific cutaneous presentation of sarcoidosis has not been described before, and it can easily be mistaken for other conditions. Therefore, this case underscores the importance of recognizing atypical cutaneous morphologies of sarcoidosis, particularly in patients with complex medical histories, to facilitate accurate diagnosis and timely intervention. We aim to increase awareness among clinicians regarding the diverse manifestations of sarcoidosis, thereby enhancing diagnostic acumen and patient care.

Iterative refinement of a histologic algorithm for burn depth categorization based on 798 consecutive burn wound biopsies.

INTRODUCTION: Our group previously reported a burn biopsy algorithm (BBA-V1) for categorizing burn wound depth. Here, we sought to promulgate a newer, simpler version of the BBA (BBA-V2). METHODS: Burn wounds undergoing excision underwent 4 mm biopsies procured every 25 cm2. Serial still photos were obtained at enrollment and at excision intraoperatively. Burn wounds assessed as likely to heal by 21 days were imaged within 72 h of injury and at 21 days. A sample of 798 burn wound biopsies were classified by both BBAV1 and BBAV2 algorithms. For nonoperative burn wounds, the proportion of healing versus nonhealing pixels at 21 days after injury were compared. RESULTS: The 798 biopsies were classified by BBAV1 as 24% SPT, 47% DPT, 28% FT and by BBAV2 as 3% SPT, 67% DPT, and 30% FT (p < 0.0001). Overall, the proportion of biopsies whose wound reclassification changed from a nonoperative to operative pathway was 21% (95% CI: 18-24%). Nonoperative wounds judged at injury as being SPT contained 12.8 million pixels. Repeat 21-day imaging revealed 11.3 million healed pixels (accuracy = 89.6% (95% CI: 89.59-89.62)). CONCLUSIONS: BBA-V2 was associated with a significantly higher concordance with visual assessment for burn wounds clinically judged as deep partial and full thickness.

Pathobiology of actinic keratosis: ultraviolet-dependent keratinocyte proliferation.

Actinic keratoses are proliferations of transformed neoplastic keratinocytes in the epidermis that are the result of cumulative ultraviolet (UV) radiation from sun exposure. They are commonly found on sites of sun-exposed skin such as the face, balding scalp, and back of the hand. Although UV exposure does exert certain beneficial effects on the skin, excessive exposure to UV radiation induces multiple cascades of molecular signaling events at the cellular level that produce inflammation, immunosuppression, failure of apoptosis, and aberrant differentiation. Cumulatively, these actions result in mutagenesis and, ultimately, carcinogenesis. This article provides a brief overview of the key mediators that are implicated in the pathobiology of actinic keratosis. Three evolutionary possibilities exist for these keratoses in the absence of treatment: (1) spontaneous remission, which can be common; (2) remaining stable, without further progression; or (3) transformation to invasive squamous cell carcinoma, which may metastasize. Because the effects of UV radiation on the skin are complex, it is not yet fully clear how all of the mediators of actinic keratosis progression are interrelated. Nonetheless, some represent potential therapeutic targets, because it is clear that directing therapy to the effects of UV radiation at a number of different levels could interrupt and possibly reverse the mechanisms leading to malignant transformation.