Cutaneous vascular structure and perfusion in patients with chronic plaque psoriasis.

BACKGROUND: Vascular dysfunction is a significant contributor to the pathophysiology of psoriasis. Some individuals have variation within the gene for vascular endothelial growth factor-A (VEGF-A), which confers an increased risk of developing psoriasis and having a severe disease phenotype, and may determine responsiveness to treatment. AIM: To determine whether patients with psoriasis have alterations in cutaneous microvascular anatomy and physiology due to expression of VEGF and whether laser Doppler imaging has utility in the assessment of this. METHODS: Twelve adult volunteers with Type 1 chronic plaque psoriasis underwent laser Doppler imaging of plaque and uninvolved skin. Skin biopsies were taken from the areas imaged for immunohistochemistry, including blood and lymphatic vessel markers, and VEGF-A isotype analysis (VEGF-A121, VEGF-A165 and VEGF-D). Venous blood was collected for DNA extraction, VEGF-A genotyping and peripheral blood mononuclear cell culture. RESULTS: Mean blood vessel area (P < 0·01), number of blood vessels (P < 0·001), number of lymphatic vessels (P < 0·001) and blood flow (P < 0·001) was significantly increased in psoriasis plaques, as was expression of VEGF-A121 (P < 0·01), VEGF-A165 (P < 0·04) and VEGF-D (P < 0·01). Blood flow within psoriasis plaques was independent of their increased vascularity (P < 0·01) and may be associated with baseline productivity of VEGF. The number of blood vessels within uninvolved skin in patients with psoriasis was associated with the VEGF-A (rs833061) genotype (P = 0·01), in a relationship suggesting an allele dosing effect. CONCLUSION: Noninvasive imaging of blood flow may help determine the cutaneous vascular signature for individual patients. This may be a useful prognostic indicator of psoriasis susceptibility and severity, and thus support selection of treatments.

Nivolumab-Induced Lichen Planopilaris: Case Report and Literature Review of Hair Disorders Associated with Targeted Oncological Therapies.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapies. Their mechanism promotes a cytotoxic T-cell activation against the tumor cells, but as a consequence, immune-mediated toxicities are increasingly being identified. Cutaneous immune-mediated adverse events (AE) occur in 32% of patients, with possible higher grade AEs seen with anti-programmed cell death protein 1, such as nivolumab. A 67-year-old woman with metastatic melanoma, previously treated for 2 years on dual ICI (ipilimumab and nivolumab), had her treatment interrupted due to grade-3 hepatitis. She was subsequently recommenced on single-agent nivolumab with good response, before discontinuation due to remission. She reported worsening scalp pruritus with associated erythema, scaling, and global hair thinning. On examination, she had significant erythema throughout the scalp with perifollicular scaling and evidence of scarring. She reported severe distress from her symptoms. Her scalp biopsy demonstrated features of scarring alopecia with infundibular and isthmic inflammation and interface change in keeping with lichen planopilaris. Follicular toxicities are rarely reported, possibly due to imprecise AE phenotyping or underreporting. However, growing evidence suggests that patients can develop follicular pigmentary changes and nonscarring alopecia. To our knowledge, this is the first case of scarring alopecia reported with nivolumab. Current treatments for ICI-induced toxicities are limited.

Scarring Alopecias: Pathology and an Update on Digital Developments.

Primary cicatricial alopecias (PCA) represent a challenging group of disorders that result in irreversible hair loss from the destruction and fibrosis of hair follicles. Scalp skin biopsies are considered essential in investigating these conditions. Unfortunately, the recognised complexity of histopathologic interpretation is compounded by inadequate sampling and inappropriate laboratory processing. By sharing our successes in developing the communication pathway between the clinician, laboratory and histopathologist, we hope to mitigate some of the difficulties that can arise in managing these conditions. We provide insight from clinical and pathology practice into how diagnoses are derived and the key histological features observed across the most common PCAs seen in practice. Additionally, we highlight the opportunities that have emerged with advances in digital pathology and how these technologies may be used to develop clinicopathological relationships, improve working practices, enhance remote learning, reduce inefficiencies, optimise diagnostic yield, and harness the potential of artificial intelligence (AI).

Clinicopathologic Characteristics and Response to Treatment of Persistent Chemotherapy-Induced Alopecia in Breast Cancer Survivors.

IMPORTANCE: Alopecia induced by classic chemotherapy affects up to 65% of patients and is usually reversible. However, there are increasing reports of persistent chemotherapy-induced alopecia (pCIA), especially for patients treated with taxane-containing chemotherapy regimens. OBJECTIVE: To analyze the clinicopathologic characteristics and response to treatment of patients with pCIA after chemotherapy for breast cancer. DESIGN, SETTING, AND PARTICIPANTS: In this case series, a retrospective evaluation was performed of patients with a diagnosis of pCIA after chemotherapy for breast cancer in 4 specialist hair clinics from November 1, 2011, to February 29, 2020. MAIN OUTCOMES AND MEASURES: Clinical, trichoscopic, and histopathologic characteristics and treatment outcomes were analyzed. For patients who presented with diffuse alopecia or diffuse rarefaction of hair over the midfrontal scalp with widening of the central part line and preservation of the frontal hairline, the Sinclair scale (grades 1-5, where 1 indicates normal hair density and 5 indicates the most severe stage of hair loss, with little or no hair in the centroparietal region) was used to assess severity. RESULTS: One hundred patients (99 women [99%]; mean age at presentation, 54.0 years [range, 29.0-74.1 years]) were included. Most patients had diffuse nonscarring alopecia (n = 39), female pattern hair loss (n = 55), or male pattern hair loss (n = 6). Six patients developed cicatricial alopecia. Taxane-containing regimens were used for most patients (92 [92%]) and were associated with more severe alopecia than regimens that did not contain taxanes (median Sinclair grade, 4 [IQR, 3-5] vs 2 [IQR, 2-2.5]; P < .001). A total of 76 of 86 patients (88%) had trichoscopic signs indistinguishable from those of androgenetic alopecia. Of 18 patients who had biopsies, 14 had androgenetic alopecia-like features, 2 had cicatricial alopecia, and 2 had features of both. Both topical and oral minoxidil, sometimes combined with antiandrogen therapy, were associated with an improvement in hair density (median Sinclair grade, 4 [IQR, 3-5] before treatment vs 3 [IQR, 2-4] after treatment; P < .001). CONCLUSIONS AND RELEVANCE: This case series outlines previously unreported features of pCIA in patients with breast cancer, including a trichoscopic description. Cosmetically significant regrowth was achieved for a significant proportion of patients with topical or systemic treatments, suggesting that pCIA may be at least partly reversible.

Hidradenoma masquerading digital ganglion cyst: A rare phenomenon.

INTRODUCTION: Mucous cyst is the commonest soft tissue tumor in the dorsum of the distal interphalangeal joint (DIPJ) of the finger. We report the first case of a recurring eccrine tumor (nodular hidradenoma), mimicking a mucous/ganglion cyst, on the dorsum of the DIPJ. CASE REPORT: A 54 year old man presented with painless, hemispherical, colored swelling on the dorsum of his right middle finger (dominant hand), which appeared to have recurred from a previous surgery. The lesion was excised and operative findings from the medical notes showed the gross appearance to be a soft, white, glistening, smooth-surfaced, myxoid nodule resembling a "ganglion cyst". Immunohistochemistry showed the tumour to be positive for S100, smooth muscle actin and cytokeratin 7. Ductal differentiation was confirmed by staining for epithelial membrane antigen and carcinoembryonic antigen. The histological features were that of atypical and solid cystic hidradenoma. DISCUSSION: This is the first reported case of this rare tumour presenting as mucous cyst. We conduct a review of the literature of nodular hidradenomas, illustrating the immunohistologic findings in this tumour to emphasise the atypical features.We emphasise the importance of considering hidradenoma in the differential diagnosis of such lesions of the finger, in view of its high recurrence rate and the possibility of malignant transformation.

Primary cutaneous adenoid cystic carcinoma: a clinicopathologic and immunohistochemical study of 27 cases.

AIMS: This study examines clinical and pathologic features of primary cutaneous adenoid cystic carcinoma (ACC), with emphasis on biological behavior of these tumors. A total of 27 cases of primary cutaneous ACC with detailed follow-up information were evaluated. Clinically, these were solitary, slow-growing lesions, half of which were in the head and neck area. The median age was 62 years with a male predilection. Surgical excision was the treatment of choice. Histologically, the lesions were similar to those seen in the salivary glands. Tumors were classified as grade 1 (17), grade 2 (3), and grade 3 (7). The mitotic count was generally low (mean=1.9/mm), except in 2 high-grade tumors (>10 mitotic figures/mm). Sixteen cases showed perineural invasion. Immunohistochemically, cytokeratin positivity was noted in 13/13 cases, and CD117 was observed in 10/10 cases, with luminal/cytoplasmic staining for epithelial membrane antigen (14/16) and at least focal luminal expression for carcinoembryonic antigen (11/16), smooth muscle actin (10/13), and S100 staining (9/13). Eighteen cases had follow-up data (median 54 mo), 9 of which had local recurrences (50%). Three cases showed metastatic disease. No statistical difference was noted between tumor grade and local recurrence (P=0.77). Primary cutaneous ACC is a distinct entity with a more indolent behavior compared with its salivary counterpart. The cutaneous lesions tend to recur locally but have a low metastatic potential.

Identification of molecular phenotypic descriptors of breast capsular contracture formation using informatics analysis of the whole genome transcriptome.

Breast capsular contracture formation following silicone implant augmentation/reconstruction is a common complication that remains poorly understood. The aim of this study was to identify potential biomarkers implicated in breast capsular contracture formation by using, for the first time, whole genome arrays. Biopsy samples were taken from 18 patients (23 breast capsules) with Baker Grade I-II (Control) and Baker Grade III-IV (Contracted). Whole genome microarrays were performed and six significantly dysregulated genes were selected for further validation with quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. Hematoxylin and eosin was also carried out to compare the histological characteristics of control and contracted samples. Microarray results showed that aggrecan, tissue inhibitor of metalloproteinase 4 (TIMP4), and tumor necrosis factor superfamily (ligand) member 11 were significantly down-regulated in contracted capsules; while matrix metallopeptidase 12, serum amyloid A 1, and interleukin 8 (IL8) were significantly up-regulated. The dysregulation of aggrecan, tumor necrosis factor superfamily (ligand) member 11, TIMP4, and IL8 was validated by quantitative reverse transcriptase polymerase chain reaction (p < 0.05). Immunohistochemistry confirmed an increased protein expression for IL8 and matrix metallopeptidase 12 in contracted capsules (p < 0.05), and decreased protein expression of TIMP4 (p < 0.05). This study has shown, for the first time, a number of unique biomarkers of significance in capsular contracture formation. IL8 and TIMP4 may serve as potential key diagnostic, therapeutic, and prognostic biomarkers in capsular contracture formation.

Lichen planopilaris is characterized by immune privilege collapse of the hair follicle's epithelial stem cell niche.

Lichen planopilaris (LPP) is a chronic inflammatory disease of unknown pathogenesis that leads to permanent hair loss. Whilst destruction of epithelial hair follicle stem cells (eHFSCs) that reside in an immunologically protected niche of the HF epithelium, the bulge, is a likely key event in LPP pathogenesis, this remains to be demonstrated. We have tested the hypotheses that bulge immune privilege (IP) collapse and inflammation-induced eHFSC death are key components in the pathogenesis of LPP. Biopsies of lesional and non-lesional scalp skin from adult LPP patients (n = 42) were analysed by quantitative (immuno)histomorphometry, real-time quantitative polymerase chain reaction (qRT-PCR), laser capture microdissection and microarray analysis, or skin organ culture. At both the protein and transcriptional level, lesional LPP HFs showed evidence for bulge IP collapse (ie increased expression of MHC class I and II, ß2microglobulin; reduced TGFß2 and CD200 expression). This was accompanied by a Th1-biased cytotoxic T cell response (ie increased CD8(+) GranzymeB(+) T cells and CD123(+) plasmacytoid dendritic cells, with increased CXCR3 expression) and increased expression of interferon-inducible chemokines (CXCL9/10/11). Interestingly, lesional LPP eHFSCs showed both increased proliferation and apoptosis in situ. Microarray analysis revealed a loss of eHFSC signatures and increased expression of T cell activation/binding markers in active LPP, while bulge PPARγ transcription was unaltered compared to non-lesional LPP HFs. In organ culture of non-lesional LPP skin, interferon-γ (IFNγ) induced bulge IP collapse. LPP is an excellent model disease for studying and preventing immune destruction of human epithelial stem cells in situ. These novel findings raise the possibility that LPP represents an autoimmune disease in whose pathogenesis IFNγ-induced bulge IP collapse plays an important role. Therapeutically, bulge IP protection/restoration may help to better manage this highly treatment-resistant cicatricial alopecia.

A double-blind controlled clinical trial assessing the effect of topical gels on striae distensae (stretch marks): a non-invasive imaging, morphological and immunohistochemical study.

Striae distensae (SD) are cutaneous lesions often presenting post-pregnancy with atrophy and flattening of the epidermis. SD is poorly understood and treatment remains ill-defined. Our aim was to assess the effect of topical application of silicone gel compared with placebo on SD using non-invasive devices and by immunohistochemical analysis of sequential tissue biopsies in a double-blind controlled trial. Twenty volunteers massaged silicone and placebo gels into separate sides of the abdomen, daily for 6 weeks. Objective non-invasive imaging plus subjective self-assessment of SD were performed on days 0, 21, 42, 90, in addition to tissue biopsies on days 0 and 42. Non-invasive imaging demonstrated an increase in melanin and a decrease in haemoglobin, collagen and pliability over the 6-week period on both sides. Additionally, collagen levels in SD were significantly higher (p value = 0.001) and melanin levels lower (p value = 0.048) with silicone gel compared with placebo. Histological analysis revealed epidermal flattening with a reduction of rete ridges in SD on both sides. Vascular count significantly decreased with placebo gel (p = 0.002). Corroborating the clinical results, melanin levels increased, whilst collagen type 1 and elastin decreased on both sides. Non-invasive techniques showed that the application of silicone gel increased collagen levels and reduced pigmentation compared with placebo. However, both clinical and histological data revealed that melanin increased whilst collagen, elastin and pliability decreased over the 6-week period with both gels. Furthermore, vascularity significantly decreased with placebo gel. These findings provide preliminary evidence of the utility of topical gels in the clinical management of SD.

Clear cell nodular hidradenoma involving the lymphatic system: a tumor of uncertain malignant potential or a novel example of "metastasizing" benign tumor?

Exceedingly rare cases of neoplasms with clear-cut histopathologic features of benignity can show locoregional or even distant spread. Such cases can become putative examples of "benign metastasis" when a completely favorable clinical outcome is documented after an adequately long follow-up. We report 8 cases of morphologically benign clear cell nodular hidradenoma (CCNH) with lymphatic involvement. In 5 cases the cutaneous tumor showed small foci of intravascular deposits of neoplastic cells; in 2 cases the cutaneous tumor presented with a synchronous tumor in a regional node; in 1 case a nodal location CCNH was found with no evidence of any primary in the skin. All the cases were treated with conservative surgery and none of them showed disease progression during a follow-up period ranging from 2 to 11 years. These data suggest that in the absence of other histopathologic features of malignancy, lymphatic spread in CCNH can still carry an excellent prognosis and can be therefore considered as an example of "benign metastasis." As the latter concept can be set forth only after an uneventful long-term follow-up, in routine practice, cases of morphologically benign CCNH with lymphatic involvement are best labeled "atypical CCNH," or "CCNH-like tumor of uncertain malignant potential."

Identification of biomarkers in sequential biopsies of patients with chronic wounds receiving simultaneous acute wounds: a genetic, histological, and noninvasive imaging study.

Chronic wounds are common and lead to significant patient morbidity. A better understanding of their pathogenesis and relevant biomarkers are required. We compared acute and chronic wounds in the same individual using noninvasive imaging including spectrophotometric intracutaneous analysis (SIAscopy) and full-field laser perfusion imaging. Gene expression analysis was also performed on sequential biopsies. Whole genome gene expression microarray analysis (44k), quantitative polymerase chain reaction, and immunohistochemistry were carried out to determine gene expression levels in tissue biopsies. Fifteen Caucasian patients with chronic venous ulcers had biopsies of the wound edges and simultaneously had an acute wound created on their upper arm on days 0, 7, and 14. SIAscopy revealed increased levels of melanin (p < 0.001), reduced levels of collagen (p < 0.001), and hemoglobin (p = 0.022) in chronic wounds. Microarray and subsequent quantitative polymerase chain reaction analysis confirmed an overall differential expression in acute and chronic wounds for several genes. Significantly higher levels of inhibin, beta A (INHBA) expression were confirmed in the dermis of chronic wounds (p < 0.05). Additionally, INHBA and thrombospondin 1 messenger RNA levels significantly correlated with SIAscopy measurements (p < 0.05). This unique study has showed aberrant expression of INHBA in chronic wounds using a sequential biopsy model of chronic vs. acute wounds in the same individual.

Acceleration of cutaneous healing by electrical stimulation: degenerate electrical waveform down-regulates inflammation, up-regulates angiogenesis and advances remodeling in temporal punch biopsies in a human volunteer study.

We previously demonstrated the beneficial effect of a novel electrical stimulation (ES) waveform, degenerate wave (DW) on skin fibroblasts, and now hypothesize that DW can enhance cutaneous wound healing in vivo. Therefore, a punch biopsy was taken from the upper arm of 20 volunteers on day 0 and repeated on day 14 (NSD14). A contralateral upper arm biopsy was taken on day 0 and treated with DW for 14 days prior to a repeat biopsy on day 14 (ESD14). A near-completed inflammatory stage of wound healing in ESD14, compared to NSD14 was demonstrated by up-regulation of interleukin-10 and vasoactive intestinal peptide using quantitative real time polymerase chain reaction and down-regulation of CD3 by immunohistochemistry (IHC) (p < 0.05). In addition to up-regulation (p < 0.05) of mRNA transcripts for re-epithelialization and angiogenesis, IHC showed significant overexpression (p < 0.05) of CD31 (15.5%), vascular endothelial growth factor (66%), and Melan A (8.6 cells/0.95 mm²) in ESD14 compared to NSD14 (9.5%, 38% and 4.3 cells/0.95 mm², respectively). Furthermore, granulation tissue formation (by hematoxylin and eosin staining), and myofibroblastic proliferation demonstrated by alpha-smooth muscle actin (62.7%) plus CD3+ T lymphocytes (8.1%) showed significant up-regulation (p < 0.05) in NSD14. In the remodeling stage, mRNA transcripts for fibronectin, collagen IV (by IHC, 14.1%) and mature collagen synthesis (by Herovici staining, 71.44%) were significantly up-regulated (p < 0.05) in ESD14. Apoptotic (TUNEL assay) and proliferative cells (Ki67) were significantly up-regulated (p < 0.05) in NSD14 (5.34 and 11.9 cells/0.95 mm²) while the proliferation index of ESD14 was similar to normal skin. In summary, cutaneous wounds receiving DW electrical stimulation display accelerated healing seen by reduced inflammation, enhanced angiogenesis and advanced remodeling phase.

Fibro-osseous pseudotumor of the digit: a clinicopathological study of 17 cases.

Fibro-osseous pseudotumor (FP) of the digit is a rare, non-neoplastic heterotopic ossifying lesion involving the subcutaneous tissues of the digits. To date, there are only a few published series in the literature. Our study of 17 cases, retrieved from the authors' referral archives, shows that the condition chiefly affects young to middle-aged adults (median = 34 years), with a slight female predominance and involves the fingers (n = 8) and toes (n = 8). One identical lesion was identified on the forehead (n = 1). Lesional size ranges from 0.8 to 5.6 cm. Treatment was by surgical excision. Histologically, 14 cases show a fairly well-circumscribed dermal (n = 10) or dermal and subcutaneous (n = 7) lesion with surface ulceration (n = 7). The lesion is composed of fascicles of variably cellular, spindle-shaped cells [calponin (n = 14) and smooth muscle actin (SMA) (n = 11) positivity], with minimal to mild atypia (n = 5), dispersed in a myxoid stroma, focally reminiscent of nodular fasciitis. At least focal irregular trabeculae with osteoid formation and osteoblastic rimming are seen in all cases. The main differential diagnosis is an extraskeletal osteosarcoma; however, this afflicts an older age group, with prominent cytological atypia and atypical mitoses. Clinical follow-up (range: 18 months - 14 years, n = 12) reveals evidence of local recurrence in some cases (n = 2), but no evidence of metastases. In conclusion, we report an additional 17 cases of this rare lesion to increase awareness amongst dermatopathologists.