Melanoma of the Vulva and Vagina: Surgical Management and Outcomes Based on a Clinicopathologic Reviewof 68 Cases.

OBJECTIVE: This study sought to evaluate the clinicopathologic features, surgical management, and survival of patients over 12 years at two academic centres. METHODS: Patients diagnosed with vulvar or vaginal melanoma between 2002 and 2014 were identified through pathology databases. Clinical and pathologic data were extracted from the medical records. The Kaplan-Meier method was used to calculate recurrence-free survival and overall survival (OS), and univariate analyses using a Cox proportional hazard model were used to detect covariates related to survival. RESULTS: Patients with vulvar melanoma were more likely to undergo surgical excision (84.0% vs. 55.6%, P = 0.0243) and were more likely to achieve negative margins (70.0% vs. 16.7%, P < 0.0001). Forty-eight percent of patients with vulvar melanoma had a lymph node evaluation; sentinel node biopsies were performed in 32%. Actuarial median OS for vulvar melanoma was 45 months compared with 10.48 months for vaginal melanoma. A subset of 10 patients with vulvar melanoma who survived longer than 60 months was identified. Eight significant predictors of OS were demonstrated for vulvar melanomas: clinical stage, maximum tumour size, tumour thickness, lymphovascular space invasion status, clinically enlarged lymph nodes, sentinel lymph nodes, lymph node status, and radiation treatment. Patients with positive or indeterminate margin status demonstrated a higher risk of recurrence than did patients with negative margins (hazard ratio 2.60; 95% CI 1.14-5.90). CONCLUSION: Surgical excision with adequate margins is the mainstay of primary management when feasible. Lymph node evaluation, including sentinel nodes, may be considered in selected patients. Vulvar and vaginal sites differ markedly with respect to pathology, initial management, and survival, and they should be evaluated separately.

Pathologic complete response to intralesional interleukin-2 therapy associated with improved survival in melanoma patients with in-transit disease.

PURPOSE: Melanoma patients with in-transit disease have a high mortality rate despite various treatment strategies. The aim of this study was to validate the role of intralesional interleukin (IL)-2, to understand its mechanism of action, and to better understand factors that may influence its response. METHODS: We retrospectively collected the clinicopathological data of 31 consecutive patients who presented to a tertiary care cancer center for treatment of in-transit melanoma with intralesional IL-2. Kaplan-Meier survival curves and multivariable Cox regression analysis were performed. Immunohistochemistry (IHC) was used to better understand the immune response to localized IL-2 therapy. Targeted next-generation sequencing was performed to genomically characterize the tumors. RESULTS: Ten patients (10/31, 32 %) achieved a pathologic complete response (pCR), 17/21 (55 %) had a partial response, and 4/21 (19 %) had progressive disease on treatment. pCR to IL-2 therapy was associated with overall survival (log-rank p = 0.004) and improved progression-free survival (PFS) [adjusted hazard ratio (HR) 0.11; 95 % CI 0.02-0.47; p = 0.003). A higher CD8+ T cell infiltrate was identified in in-transit lesions with a pCR compared with the other lesions (mean IHC score 3.78 vs. 2.61; p = 0.01). Patients with an elevated CD8+ infiltrate demonstrated an improved PFS (unadjusted HR 0.08; 95 % CI 0.01-0.52; p = 0.008). CONCLUSIONS: Thirty-two percent of patients achieved pCR with intralesional IL-2 therapy and had a significantly improved PFS compared with the rest of the cohort, which may be explained by a systemic CD8+ T-cell response.

Vasculotide, an Angiopoietin-1 mimetic, reduces acute skin ionizing radiation damage in a preclinical mouse model.

BACKGROUND: Most cancer patients are treated with radiotherapy, but the treatment can also damage the surrounding normal tissue. Acute skin damage from cancer radiotherapy diminishes patients' quality of life, yet effective biological interventions for this damage are lacking. Protecting microvascular endothelial cells from irradiation-induced perturbations is emerging as a targeted damage-reduction strategy. Since Angiopoetin-1 signaling through the Tie2 receptor on endothelial cells opposes microvascular perturbations in other disease contexts, we used a preclinical Angiopoietin-1 mimic called Vasculotide to investigate its effect on skin radiation toxicity using a preclinical model. METHODS: Athymic mice were treated intraperitoneally with saline or Vasculotide and their flank skin was irradiated with a single large dose of ionizing radiation. Acute cutaneous damage and wound healing were evaluated by clinical skin grading, histology and immunostaining. Diffuse reflectance optical spectroscopy, myeloperoxidase-dependent bioluminescence imaging of neutrophils and a serum cytokine array were used to assess inflammation. Microvascular endothelial cell response to radiation was tested with in vitro clonogenic and Matrigel tubule formation assays. Tumour xenograft growth delay experiments were also performed. Appreciable differences between treatment groups were assessed mainly using parametric and non-parametric statistical tests comparing areas under curves, followed by post-hoc comparisons. RESULTS: In vivo, different schedules of Vasculotide treatment reduced the size of the irradiation-induced wound. Although skin damage scores remained similar on individual days, Vasculotide administered post irradiation resulted in less skin damage overall. Vasculotide alleviated irradiation-induced inflammation in the form of reduced levels of oxygenated hemoglobin, myeloperoxidase bioluminescence and chemokine MIP-2. Surprisingly, Vasculotide-treated animals also had higher microvascular endothelial cell density in wound granulation tissue. In vitro, Vasculotide enhanced the survival and function of irradiated endothelial cells. CONCLUSIONS: Vasculotide administration reduces acute skin radiation damage in mice, and may do so by affecting several biological processes. This radiation protection approach may have clinical impact for cancer radiotherapy patients by reducing the severity of their acute skin radiation damage.

Tumour necrosis is a valuable histopathological prognostic parameter in melanomas of the vulva and vagina.

Vulvar and vaginal melanomas (VVMs) are rare and aggressive malignancies with limited prognostic models available and there is no standard reporting protocol. VVMs were selected from six tertiary Canadian hospitals from 2000-2021, resected from patients aged ≥18 years, with 6 months or longer follow-up data, and confirmation of melanocytic differentiation by at least two immunohistochemical markers. Cases were reviewed by pathologists to identify histological biomarkers. Survival outcomes were tested with Kaplan-Meier log-rank, univariate Cox, and multivariate Cox regression. There were 79 VVMs with median follow-up at 26 months. Univariate analysis revealed that tumour necrosis, tumour ulceration, positive lymph nodes, and metastasis at diagnosis were significantly associated with disease-specific mortality, progression, and metastasis. Multivariate analysis identified tumour necrosis as an independent prognostic factor for disease-specific mortality (HR 4.803, 95% CI 1.954-11.803, p<0.001), progression (HR 2.676, 95% CI 1.403-5.102, p=0.003), and time-to-metastasis for non-metastatic patients at diagnosis (HR 3.761, 95%CI 1.678-8.431, p=0.001). Kaplan-Meier survival analyses demonstrated that tumour necrosis was a poor prognostic factor for disease-specific, progression-free, and metastasis-free survival (p<0.001 for all comparisons). Vaginal melanomas displayed decreased survival compared to vulvar or clitoral melanomas. This study identifies tumour necrosis as an independent prognostic factor for VVMs. Vaginal melanomas specifically showed worse survival outcomes compared to vulvar or clitoral melanomas, consistent with previously reported findings in the literature, emphasising the importance of differentiating between these primary tumour epicentres for prognostication and treatment planning in the care of genital melanoma patients.

Extradigital glomus tumour of the thigh causing 8 years of undiagnosed debilitating pain.

A woman in her mid-50s was referred to a plastic surgeon with an 8-year history of undiagnosed, localised severe, reproducible pain of the right thigh. Treatment with oral and topical analgesics, corticosteroids, acupuncture and physiotherapy did not provide symptom relief. She was referred to multiple specialists over the preceding 8 years including chronic pain physicians, physiatry, orthopaedic surgery and plastic surgery. Investigations including sonographic and MRI eventually revealed a non-specific soft tissue abnormality in the area of tenderness, which was excised en bloc. Histopathology revealed an extradigital glomus tumour. The patient's symptoms immediately and permanently resolved postexcision.Physicians seeing patients suffering from undiagnosed focal, reproducible pain should consider extradigital glomus tumours in their differential diagnosis. Workup for extradigital glomus tumour includes focused sonographic or MRI over the area of pain. Additionally, local injection of an anaesthetic agent can be used to assist with diagnosis.

Oral melanosis after tyrosine kinase inhibition with Imatinib for chronic myelogenous leukemia: report of a case and review of the literature.

Dermatologic manifestations from therapy with imatinib are well known and frequently include hypopigmentation, and less commonly, hyperpigmentation. There have been few reports of oral hyperpigmentation. We present a case of palatal melanosis related to imatinib therapy for chronic myelogenous leukemia. This case is reported to add to the sparse literature concerning mucosal reactions related to this medication.

Malignant Melanoma within a Cellular Blue Nevi Presenting as a Vascular Malformation and the Connection to Sporadic KRAS Mutations.

We present a case of malignant melanoma (MM) developing within a vascular malformation showing features of cellular blue nevi. A 47-year-old male presented with acute symptoms of a temporal and zygomatic mass, which were both previously asymptomatic upon development 30 years ago. These masses were diagnosed as vascular malformations upon imaging and were treated with sclerotherapy. Embolization and surgical excision were performed 3 years later due to symptomatic growth. Final pathology reports showed MM with congenital blue nevi. We hypothesize a possible linkage to a sporadic KRAS mutation, linking both presentations of vascular malformation, MM, and cellular blue nevi. A literature search for similar cases is also reported.

Ultra high-frequency ultrasound with seventy-MHz transducer in hair disorders: Development of a novel noninvasive diagnostic methodology.

BACKGROUND: Ultra high-frequency ultrasound (uHFUS) is a recently developed diagnostic technology. Despite its potential usefulness, no study has assessed its advantage in diagnosis and evaluation of hair disorders in comparison with other diagnostic methods. OBJECTIVES: To assess the practicability of uHFUS in diagnosing hair disorders and propose a diagnostic methodology. METHODS: Ultrasonographic images of scalp and forehead from patients with hair disorders (n = 103) and healthy controls (n = 40) were obtained by uHFUS and analyzed by both descriptive and numerical parameters. Furthermore, the data were compared with trichoscopic and histopathological findings. RESULTS: The pattern of inflammation and fibrosis, hair cycle abnormality, and the findings in subcutis were detected by uHFUS. Significant differences were noted in the numerical parameters associated with the number of hair shafts and follicles, hair diameters and their diversity, and dermal echogenicity in both cicatricial and non-cicatricial hair disorders. Findings in uHFUS were associated with those observed in trichoscopy and scalp biopsy but uHFUS was able to detect pathological findings associated with hair cycle, inflammation, fibrosis, and subcutaneous abnormalities, which are hardly assessable by trichoscopy. CONCLUSION: The findings of this study highlighted usefulness of uHFUS in diagnosing hair disorders, while overcoming the weaknesses and limitations of other diagnostic tools.

Influence of the phenotype on mycosis fungoides prognosis, a retrospective cohort study of 160 patients.

BACKGROUND: Mycosis fungoides (MF) typically has a CD4+ CD8- T-cell phenotype. Rare cases of CD4- CD8+ , CD4- CD8- , or CD4+ CD8+ immunophenotypes have been described. Little is known about the impact of MF immunophenotypes on disease behavior. METHODS: We conducted a retrospective cohort study to review all cases of MF from 2007 to 2017 from Sunnybrook Health Sciences Centre, Toronto, Canada. CD4+ CD8- (Group 1) was compared to the three less common subtypes (Group 2) with respect to stage at diagnosis, progression, and transformation. Potential confounding factors (demographic, clinical, and laboratory parameters) were assessed. RESULTS: A total of 160 patients with confirmed MF were analyzed, including 126 CD4+ CD8- MF (79%), 26 CD4- CD8+ MF (16%), six CD4+ CD8+ MF (4%), and two CD4- CD8- MF (1%). Both groups were similar with respect to demographics and laboratory parameters at the time of diagnosis. There was no difference between patients with late stage disease (10% vs. 9%) for groups 1 and 2, respectively (P = 0.901). There was no statistically significant difference either in 5-year progression (27.7% vs. 23.5%, P = 0.283) or transformation (16.2% vs. 17.3%, P = 0.350) estimates. We did find that atypical immunophenotypes presented with different clinical morphologies and were less likely to require systemic therapy. CONCLUSION: Our large cohort study indicates that atypical MF immunophenotypes do not seem to influence prognosis. Hypopigmented MF was more frequent in the CD4- CD8+ group while folliculotropic MF was exclusively seen in the CD4+ CD8- group. We believe that cases of CD8+ MF with aggressive behavior described in the literature represent misclassified primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma. The small number of patients included in the study is a limiting factor.

Eosinophils in the skin-a red herring masking lymphoma: a case series.

Eosinophilia, both peripheral and in cutaneous tissue, is not a typical finding in mycosis fungoides; in fact, when faced with a lymphoeosinophilic infiltrate, mycosis fungoides is often not part of initial differential considerations. However, eosinophilia has been described in certain subtypes of mycosis fungoides, namely, in folliculotropic mycosis fungoides. We describe three challenging cases of folliculotropic mycosis fungoides presenting with varied clinical morphologies and a dense lymphoeosinophilic infiltrate and/or severe hypereosinophilia that obscured the final diagnosis for years. Only after treatment of the eosinophilia were the underlying atypical lymphocytes more apparent on histology and a correct diagnosis made. Thus, when characteristic features of mycosis fungoides are subtle, eosinophils can act as a red herring in terms of clinico-pathologic correlation and may prevent early and accurate diagnosis of mycosis fungoides. We suggest that further studies are needed to evaluate whether treatments to reduce eosinophilia, once other causes have been excluded, may help clear the confounding reactive inflammatory infiltrate and facilitate the diagnosis of mycosis fungoides.

Severe Physical Complications among Survivors of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.

INTRODUCTION: Few studies have reported the physical complications among Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) survivors. OBJECTIVE: The aim of this study was to comprehensively characterize the physical complications among SJS/TEN survivors and to learn about patients' perspectives of surviving SJS/TEN. METHODS: SJS/TEN survivors older than 18 years of age were assessed by different methods: a medical interview; a questionnaire assessing patients' perspectives; thorough skin, oral mucous membrane, and ophthalmic examinations; and a retrospective assessment of medical records. RESULTS: Our cohort consisted of 17 patients with a mean time of 51.6 ± 74.7 months (median 9, range 1-228) following SJS/TEN. The most common physical complications identified in the medical examination were post-inflammatory skin changes (77%), cutaneous scars (46%), dry eyes (44%), symblepharon, and chronic ocular surface inflammation (33% each). Novel physical sequelae included chronic fatigue (76%) and pruritus (53%). We also found a novel association between the number of mucous membranes affected in the acute phase of SJS/TEN and hair loss during the 6 months following hospital discharge; hair loss was reported in 88% of the group of patients who had three or more mucous membranes affected versus 29% of patients who had less than three mucous membranes involved (p = 0.0406). Following hospital discharge due to SJS/TEN, 59% of patients were followed by a dermatologist, although 88% had dermatological complications; 6% were followed by an ophthalmologist, even though 67% had ophthalmological complications; and 6% of female survivors were followed by a gynecologist, even though 27% had gynecological complications. CONCLUSION: Survivors of SJS/TEN suffer from severe physical complications impacting their health and lives that are mostly under recognized and not sufficiently treated by medical professionals.

Design of a Subtarsal Ultrasonic Transducer for Mild Hyperthermia Treatment of Dry Eye Disease.

Dry eye disease is a disorder of the ocular surface that causes pain and low vision in a significant portion of the adult population. A common cause is obstructive Meibomian gland dysfunction, whereby the Meibomian glands secrete abnormal meibum with a melting point elevated by 3°C-4°C; hence, hyperthermia is the typical treatment. A design is proposed for an ultrasound hyperthermia device made of a transducer contained inside a contact lens with an internal air gap. The transducer heats the posterior of the tarsus, and the air gap provides an air backing to the transducer, preventing direct heating of the cornea. A prototype device was built, and hyperthermia experiments were performed on a porcine subject in vivo. A therapeutic temperature rise of 5°C-7°C was achievable in 10-15 min. The temperature of the cornea did not rise more than 2°C during any of the experiments.

Performance of residents using digital images versus glass slides on certification examination in anatomical pathology: a mixed methods pilot study.

BACKGROUND: It is anticipated that many licensing examination centres for pathology will begin fully digitizing the certification examinations. The objective of our study was to test the feasibility of a fully digital examination and to assess the needs, concerns and expectations of pathology residents in moving from a glass slide-based examination to a fully digital examination. METHODS: We conducted a mixed methods study that compared, after randomization, the performance of senior residents (postgraduate years 4 and 5) in 7 accredited anatomical pathology training programs across Canada on a pathology examination using either glass slides or digital whole-slide scanned images of the slides. The pilot examination was followed by a post-test survey. In addition, pathology residents from all levels of training were invited to participate in an online survey. RESULTS: A total of 100 residents participated in the pilot examination; 49 were given glass slides instead of digital images. We found no significant difference in examination results between the 2 groups of residents (estimated marginal mean 8.23/12, 95% confidence interval [CI] 7.72-8.87, for glass slides; 7.84/12, 95% CI 7.28-8.41, for digital slides). In the post-test survey, most of the respondents expressed concerns with the digital examination, including slowly functioning software, blurring and poor detail of images, particularly nuclear features. All of the respondents of the general survey (n = 179) agreed that additional training was required if the examination were to become fully digital. INTERPRETATION: Although the performance of residents completing pathology examinations with glass slides was comparable to that of residents using digital images, our study showed that residents were not comfortable with the digital technology, especially given their current level of exposure to it. Additional training may be needed before implementing a fully digital examination, with consideration for a gradual transition.

Spindle cell melanocytic lesions: part II--an approach to intradermal proliferations and horizontally oriented lesions.

Melanocytic lesions show great morphological diversity in their architecture and the cytomorphological appearance of their composite cells. Whereas functional melanocytes show a dendritic cytomorphology and territorial isolation, lesional nevomelanocytes and melanoma cells typically show epithelioid, spindled or mixed cytomorphologies, and a range of architectural arrangements. Spindling is common to melanocytic lesions, and may either be a characteristic feature or a divergent appearance. The presence of spindle cells may mask the melanocytic nature of a lesion, and is often disconcerting, either due to its infrequent appearance in a particular lesion or its interpretation as a dedifferentiated phenotype. Spindle cell melanocytic lesions follow the full spectrum of potential biological outcomes, and difficulty may be experienced judging the nature of a lesion due to a lack of consistently reliable features to predict biological behaviour. Over time, recognition of numerous histomorphological features that may portend a more aggressive lesion have been identified; however, the translation of these features into a diagnostic entity requires a gestalt approach. Although most spindle cell melanocytic lesions may reliably be resolved through this standard approach, problem areas do exist for the surgical pathologist or dermatopathologist. With this review (part II of II), we complete our discussion of spindle cell melanocytic lesions, in order to: (1) model a systematic approach to such lesions; and (2) provide familiarity with those melanocytic lesions which either typically or occasionally display a spindled cytomorphology.