Merkel cell carcinoma and the eye.

Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine tumor with a poor five-year survival rate. Yearly cases have risen nearly 350% since the early 1980s, and these are predicted to increase as the overall US population ages. MCC of the eyelid is uncommon and can be misdiagnosed as other benign inflammatory and neoplastic eyelid disorders. Although MCC of the head and neck is often more aggressive than it is at other sites, eyelid MCC shows a lower disease-specific mortality rate. A biopsy is essential for accurate diagnosis, including an immunohistochemical panel of CK20 and TTF-1, although other markers may be necessary. Staging can be assessed clinically through physical examination findings and imaging and/or pathologically with sentinel lymph node biopsy or fine-needle aspiration. Pathologic staging more accurately predicts the prognosis. Eyelid MCC treatments include Mohs micrographic surgery to allow for complete clearance and adequate reconstruction of lost tissue, followed by adjuvant radiotherapy. In advanced disease, immunotherapies are preferred over traditional chemotherapy and are a subject of ongoing research.

Adnexal neoplasms of the eye.

Adnexal neoplasms of the eyelid encompass a wide variety of benign and malignant tumors of sebaceous, follicular, and sweat gland origin. Due to the specialized structures of the eyelid, these neoplasms present differently when compared with those of other locations. Although most dermatologists and ophthalmologists are familiar with the commonly reported adnexal tumors of the eyelid, such as hidrocystoma, pilomatrixoma, and sebaceous carcinoma, many other adnexal neoplasms have been reported at this unique anatomic site. Accurate and timely identification of these neoplasms is essential, as alterations of eyelid anatomy and function can have a negative impact on eye health, vision, and quality of life. We review the clinical and histopathologic features of common and rare eyelid adnexal neoplasms and discuss proposed treatment options.

A Case of Herpes Simplex Virus Colitis in an Immunosuppressed Patient.

Herpes simplex virus (HSV) can cause severe disseminated infections in immunocompromised patients. Gastrointestinal tract involvement seldom includes the colon. We present a rare case of disseminated cutaneous HSV infection with concomitant colonic involvement in an immunosuppressed patient. The patient's clinical presentation and computerized tomography (CT) findings were concerning for colitis. She failed to improve on antibiotic therapy and subsequently underwent flexible sigmoidoscopy. Gross findings and histopathology were consistent with herpes simplex virus colitis. It is essential to recognize this pathology in immunocompromised patients to evaluate the need to hold immunosuppressive therapy and ensure successful treatment to prevent fatal outcomes.

Nivolumab-induced localized genital bullous pemphigoid in a 60-year-old male.

A 60-year-old man with metastatic renal cell carcinoma presented with a 6-month history of a pruritic, exquisitely painful genital eruption appearing 3 months after initiation of nivolumab. Examination demonstrated a poorly defined, lichenified scrotal plaque studded with erosions, yellow crust, and tense vesicles. There was no other lesion on the body or mucosae. Histopathology revealed a subepidermal blister with a mixed lymphocytic, neutrophilic, and eosinophilic infiltrate. Direct immunofluorescence of perilesional skin demonstrated subclinical blister and linear/fibrillary patchy IgG and IgA along the dermoepidermal junction. Bullous pemphigoid (BP) serologies revealed normal IgG BP230 antibodies and minimally elevated IgG BP180 antibodies. Indirect immunofluorescence revealed positive IgG at the basement membrane ("epidermal pattern") in human split skin and monkey esophagus substrates; no IgA antibodies were detected. The patient was diagnosed with nivolumab-induced localized genital BP (LGBP). BP is a reported adverse effect of immune checkpoint inhibitors including nivolumab; however, cases are typically generalized. LGBP is a rare BP variant typically presenting in children and females; there are few reports of LGBP in adult males. We report a novel case of nivolumab-induced LGBP with unique histopathologic and clinical challenges. LGBP should be considered in patients on immune checkpoint inhibitor therapy with bullous genital eruptions.

Validation of Image Quality and Diagnostic Accuracy Using a Mobile Phone Camera Microscope Adaptor Compared With Glass Slide Review in Teledermatopathology.

New modalities of evaluating histopathology, such as whole-slide imaging, have been validated in the field of dermatopathology but are often unfeasible and unavailable in developing countries. Widely available across the globe, mobile phone camera technology represents a potential simple and inexpensive method of imaging histologic slides through the use of a mobile phone camera microscope adaptor. This study aims to validate the use of a commercially available adaptor in the diagnosis of inflammatory and infectious conditions in dermatopathology. Representative images were taken of slides for fifty-four cases using the adaptor and shared through a cloud-based platform with five dermatopathologists who rendered diagnoses and judged the quality of the images. After a washout period of 8 weeks, the same cases were assessed by the same dermatopathologists using the original glass slides. The intraobserver concordance rate was 93.3%, and the quality of the mobile phone images was rated as "excellent" or "diagnostic" in 94.4% of the cases. This study validates the use of this low-tech and low-cost adaptor as a reliable tool in teledermatopathology. Limitations of the study include those inherent to use of the adaptor and the limited panel of diagnoses. The primary value of this device may be in developing countries, but its practicality and ease of use lend itself to use in academic and consultative settings in the developed world as well.

The histopathological features of the nail plate in pachyonychia congenita.

BACKGROUND: Pachyonychia congenita (PC) is a rare autosomal dominant disorder of keratinization mediated by genetic mutations in KRT6A, KRT6B, KRT6C, KRT16, or KRT17. While nail dystrophy in PC has a significant impact on quality of life, the histopathological features of the nail plate in PC have not been previously reported. We report the histopathological features of nail plates provided by 19 patients with genetically confirmed PC. METHODS: Nineteen patients with genetically confirmed PC provided a total of 56 nail plates for histopathologic examination. The nail plates were examined for the presence of hyphae, yeast, bacteria, neutrophils, parakeratosis, plasma globules, and hemorrhage. Specimens with onychomycosis (three patients) were excluded from the analysis. RESULTS: No specific histopathological feature was identified in PC nails. Parakeratosis and plasma globules were the most prominent features in both clinically affected and unaffected PC nails. There was a significant association between clinical dystrophy of all 20 nails and KRT6A mutations, and a lack of dystrophy of all 20 nails in KRT6B mutations. CONCLUSIONS: Parakeratosis and plasma globules in the absence of other inflammatory disorders should raise PC in the histopathologic differential diagnosis. The presence of onychomycosis in a nail plate does not exclude a diagnosis of PC.

Brain tissue oxygen tension and its response to physiological manipulations: influence of distance from injury site in a swine model of traumatic brain injury.

OBJECTIVE The optimal site for placement of tissue oxygen probes following traumatic brain injury (TBI) remains unresolved. The authors used a previously described swine model of focal TBI and studied brain tissue oxygen tension (PbtO2) at the sites of contusion, proximal and distal to contusion, and in the contralateral hemisphere to determine the effect of probe location on PbtO2 and to assess the effects of physiological interventions on PbtO2 at these different sites. METHODS A controlled cortical impact device was used to generate a focal lesion in the right frontal lobe in 12 anesthetized swine. PbtO2 was measured using Licox brain tissue oxygen probes placed at the site of contusion, in pericontusional tissue (proximal probe), in the right parietal region (distal probe), and in the contralateral hemisphere. PbtO2 was measured during normoxia, hyperoxia, hypoventilation, and hyperventilation. RESULTS Physiological interventions led to expected changes, including a large increase in partial pressure of oxygen in arterial blood with hyperoxia, increased intracranial pressure (ICP) with hypoventilation, and decreased ICP with hyperventilation. Importantly, PbtO2 decreased substantially with proximity to the focal injury (contusion and proximal probes), and this difference was maintained at different levels of fraction of inspired oxygen and partial pressure of carbon dioxide in arterial blood. In the distal and contralateral probes, hypoventilation and hyperventilation were associated with expected increased and decreased PbtO2 values, respectively. However, in the contusion and proximal probes, these effects were diminished, consistent with loss of cerebrovascular CO2 reactivity at and near the injury site. Similarly, hyperoxia led to the expected rise in PbtO2 only in the distal and contralateral probes, with little or no effect in the proximal and contusion probes, respectively. CONCLUSIONS PbtO2 measurements are strongly influenced by the distance from the site of focal injury. Physiological alterations, including hyperoxia, hyperventilation, and hypoventilation substantially affect PbtO2 values distal to the site of injury but have little effect in and around the site of contusion. Clinical interpretations of brain tissue oxygen measurements should take into account the spatial relation of probe position to the site of injury. The decision of where to place a brain tissue oxygen probe in TBI patients should also take these factors into consideration.

Myxoid onychomatricoma: an unusual variant of a rare nail unit tumor.

A 57-year-old woman presented with a 3-year history of a thickened, yellowed, over-curved nail plate of the left second toe. The proximal nail fold had an associated nodule. When observed head-on, the distal nail plate demonstrated multiple circular perforations. Avulsion of the nail plate revealed a 0.7 cm pale white mass within the proximal nail matrix, which was excised. Histologic sections of the nail plate showed longitudinal cystic spaces associated with papillary projections of nail matrix epithelium. The parenchyma of the lesion demonstrated bland-appearing spindled cells in a prominent myxoid stroma with abundant mast cells. The spindled cells were focally positive for CD34 and factor XIIIa and negative for S100, pan-cytokeratin, desmin, smooth muscle actin, epithelial membrane antigen, and MART-1. Onychomatricoma (OM) is a rare nail unit biphasic fibroepithelial tumor with multiple radiating digitations lined by papillomatous matrix epithelium. The epithelial component is consisted of matrix cells that generate the thickened nail plate, and the digitations cause characteristic "wormwood" perforations of the nail plate. A fibrous stroma is characteristic with staining positive for CD34 and negative for CD99, epithelial membrane antigen, and S100. This case is unique with the presence of a prominent myxoid stroma associated with the fibrous component of the OM. Only 1 previous report of OM highlights a related finding of a myxocollagenous stroma. This purely myxoid variant represents a new distinct form of OM. Clinicopathologic correlation is essential to avoid confusion with other myxoid tumors such as a superficial acral myxoma, superficial angiomyxoma, or a digital myxoid cyst.

CD30 positive atypical lymphocytes in perniosis: a potential histopathologic pitfall in a benign condition.

In classical clinical perniosis (chilblains), the presence of atypical lymphocytes with immunohistochemical staining positive for CD30 is unusual and rarely reported. Here we report 2 cases of clinical perniosis, one in a 16-year-old girl and another in a 67-year-old woman. The biopsies revealed lymphocytic infiltrates, papillary dermal edema, and atypical cells highlighted with a CD30 immunohistochemical stain. Our cases demonstrate the importance of clinicopathologic correlation in the assessment of CD30 positive lymphocytes in benign nonneoplastic conditions. Dermatopathologists must be aware of this potential histologic pattern in perniosis to prevent misdiagnosis and overtreatment of this condition.

Coxsackievirus A6-induced hand-foot-mouth disease.

IMPORTANCE: Hand-foot-mouth disease (HFMD) is an acute, self-limited, highly contagious viral illness that commonly affects children younger than 5 years. It is most typically caused by enterovirus 71 or coxsackievirus A16 and results in asymptomatic infection or mild disease. Immunocompetent adults are rarely affected. Recently, there have been increasing reports of a more severe form of HFMD associated with fevers, joint pains, and widespread painful eruptions. Some of these patients required hospitalization for supportive care. These severe cases were most commonly caused by coxsackievirus A6. OBSERVATIONS: We describe a 37-year-old white man with widespread, crusted, pruritic papules on the scalp, ears, and face and a purpuric and targetoid painful vesicular eruption on his hands and feet, with associated fevers, neurologic symptoms, and arthritis, who required hospitalization for supportive care. His infection with coxsackievirus A6 was confirmed based on polymerase chain reaction from his oral mucosa and cutaneous vesicle fluid. CONCLUSIONS AND RELEVANCE: Dermatologists should be familiar with the severe variant of HFMD caused by coxsackievirus A6, include it in their differential diagnosis of acute febrile blistering diseases, and be aware that certain patients may require hospitalization.

Equestrian perniosis: a report of 2 cases and a review of the literature.

Equestrian perniosis (EP) is a rare condition in which patients develop tender burning nodular plaques on their bilateral thighs after riding in the cold. These lesions tend to resolve rapidly with minimal exposure to cold, and wearing loose, layered warm clothing. Unlike acral perniosis, EP has no known systemic disease associations, although 2 reported cases did have elevated cold agglutinins. The histology of this disease is similar to perniosis; however, EP is distinct in that the perivascular lymphocytic infiltrate prominently involves the fat. In this case report, we discuss the clinical and histological findings in 2 cases of EP, including the first documented in a man.

Update: nail unit dermatopathology.

Nail unit dermatopathology is a growing field filled with many challenges. Many advances in this field have been made in the last 5 years. This review article provides an update on new information and studies published in that period of time. We divided these works into different sections, including clinical and pathologic challenges in diagnosis and treatment of nail disorders, nail unit biopsy and processing techniques, normal nail unit histology, nail plate structural and growth pathology, metabolic disease, inflammatory conditions, onychomycosis, benign growths, malignant growths, and dyschromias. Specific highlights include advances in the marking and orientation of nail unit biopsies for improved histologic interpretation, improved nail plate softening techniques, new methods for histologic evaluation of onychomycosis, descriptions of newly described benign growths unique to the nail unit, and the morphologic and immunohistochemical distinction between benign and malignant pigmented lesions of the nail unit.

Radiation arteriopathy in the transgenic arteriovenous fistula model.

OBJECTIVE: The transgenic arteriovenous fistula model, surgically constructed with transgenic mouse aorta interposed in common carotid artery-to-external jugular vein fistulae in nude rats, has a 4-month experimental window because patency and transgenic phenotype are lost over time. We adapted this model to investigate occlusive arteriopathy in brain arteriovenous malformations after radiosurgery by radiating grafted aorta before insertion in the fistula. We hypothesized that high-dose radiation would reproduce the arteriopathy observed clinically within the experimental time window and that deletions of endoglin (ENG) and endothelial nitric oxide synthase (eNOS) genes would modify the radiation response. METHODS: Radiation arteriopathy in the common carotid arteries of 171 wild-type mice was examined with doses of 25, 80, 120, or 200 Gy (Experiment 1). Radiation arteriopathy in 68 wild-type arteriovenous fistulae was examined histologically and morphometrically with preoperative radiation doses of 0, 25, or 200 Gy (Experiment 2). Radiation arteriopathy in 51 transgenic arteriovenous fistulae (36 ENG and 15 eNOS knock-out fistulae) was examined using preoperative radiation doses of 0, 25, or 200 Gy (Experiment 3). RESULTS: High-dose radiation (200 Gy) of mouse common carotid arteries induced only mild arteriopathy (mean score, 0.66) without intimal hyperplasia and with high mortality (68%). Radiation arteriopathy in wild-type arteriovenous fistulae was severe (mean score, 3.5 at 200 Gy), with intimal hyperplasia and medial disruption at 3 months, decreasing luminal areas with increasing dose, and no mortality. Arteriopathy was robust in transgenic arteriovenous fistulae with ENG +/- and with eNOS +/-, with thick intimal hyperplasia in the former and distinct smooth muscle cell proliferation in the latter. CONCLUSION: The transgenic arteriovenous fistula model can be adapted to rapidly reproduce radiation arteriopathy observed in resected brain arteriovenous malformations after radiosurgery. High radiation doses accelerate the progression of arteriopathy to fit the 4-month time limitation of the model, allowing transgenic tissues to retain their phenotypes throughout the experimental window. Modified radiation responses in ENG and eNOS knock-out fistulae indicate that arteriopathy after arteriovenous malformation radiosurgery might potentially be enhanced by altered gene expression.

The transgenic arteriovenous fistula in the rat: an experimental model of gene therapy for brain arteriovenous malformations.

OBJECTIVE: To introduce the transgenic arteriovenous fistula model in the rat, constructed by interposing mouse aorta in a fistula between the common carotid artery and external jugular vein in a nude rat, and to describe the model's technical feasibility, long-term patency, and expression of reporter genes. METHODS: Carotid-jugular fistulae were surgically created in 112 rats. In 25 immunodeficient nude rats, wild-type mouse thoracic aorta (TAo) was interposed in the fistula; in 10 immunocompetent rats, TAo was interposed; in 19 nude rats, transgenic TAo with reporter genes for beta-galactosidase or green fluorescent protein was interposed; in 18 nude rats, wild-type mouse ascending aorta was interposed; and in 40 rats, a simple fistula was constructed without an interpositional graft. Host tolerance and graft viability were analyzed by histopathology and immunohistochemistry for CD31 (mouse endothelial cell marker), endothelial nitric oxide synthase, smooth muscle actin, fibronectin, beta-galactosidase, and green fluorescent protein. RESULTS: The transgenic arteriovenous fistula was technically feasible and immunologically tolerated in nude rats but not in immunocompetent rats. The overall angiographic patency rate was 41% with TAo grafts and 56% with ascending aorta grafts, both lower than the 98% patency rate in fistulae with a single anastomosis and no interpositional graft. Mouse endothelium survived on the graft for 3 months according to CD31 staining, but longer survival by transgenic smooth muscle cells resulted in continued expression of beta-galactosidase for 6 months and green fluorescent protein for 4 months. Endothelium and smooth muscle in the fistula were functional, with normal expression of endothelial nitric oxide synthase as well as smooth muscle actin and fibronectin, respectively. CONCLUSION: The transgenic arteriovenous fistula model enhances other carotid-jugular fistula models by integrating transgenic tissue, thereby creating an experimental system for investigating the molecular biology of and gene therapies for arteriovenous malformations.