A case of cutaneous malignant glomus tumor.

Glomus tumors are well-known but relatively rare vascular neoplasms, with their malignant counterparts still being rarer. There are very few reports of cutaneous malignant glomus tumors, and the current limited evidence suggests that they follow a more indolent course than deep-seated malignant glomus tumors. Herein, we are reporting a case of cutaneous malignant glomus tumor. A 94-year-old male presented with a right-sided ulcerated scalp lesion, which, on biopsy, showed a diffusely infiltrative epithelioid malignancy with considerable pleomorphism and a notable perivascular growth pattern. The tumor cells were positive for smooth muscle actin (SMA) and h-caldesmon, and negative for cytokeratin MNF116, CK5, p40, S100, SOX10, HMB45, Melan-A, ERG, CD31, CD45, CD3, CD20, ALK, desmin, CD68, CD34, and HHV8. A diagnosis of cutaneous malignant glomus tumor was made, and the patient underwent a wider excision. Cutaneous malignant glomus tumors are extremely rare and should be considered when examining unusual cutaneous mesenchymal tumors.

A case of omalizumab as a successful treatment for telangiectasia macularis eruptiva perstans.

Treatment for telangiectasia macularis eruptiva perstans (TMEP) is often challenging due to lack of an established first-line therapy and as such is primarily focused on symptomatic relief. Omalizumab shows promise as a potential therapy for mast cell disorders; however, its efficacy in TMEP is yet to be established. This case describes a 72-year-old woman with chronic refractory TMEP achieving symptomatic remission within 4 months of commencing omalizumab therapy.

Molecular markers to complement sentinel node status in predicting survival in patients with high-risk locally invasive melanoma.

Sentinel lymph node status is a major prognostic marker in locally invasive cutaneous melanoma. However, this procedure is not always feasible, requires advanced logistics and carries rare but significant morbidity. Previous studies have linked markers of tumour biology to patient survival. In this study, we aimed to combine the predictive value of established biomarkers in addition to clinical parameters as indicators of survival in addition to or instead of sentinel node biopsy in a cohort of high-risk melanoma patients. Patients with locally invasive melanomas undergoing sentinel lymph node biopsy were ascertained and prospectively followed. Information on mortality was validated through the National Death Index. Immunohistochemistry was used to analyse proteins previously reported to be associated with melanoma survival, namely Ki67, p16 and CD163. Evaluation and multivariate analyses according to REMARK criteria were used to generate models to predict disease-free and melanoma-specific survival. A total of 189 patients with available archival material of their primary tumour were analysed. Our study sample was representative of the entire cohort (N = 559). Average Breslow thickness was 2.5 mm. Thirty-two (17%) patients in the study sample died from melanoma during the follow-up period. A prognostic score was developed and was strongly predictive of survival, independent of sentinel node status. The score allowed classification of risk of melanoma death in sentinel node-negative patients. Combining clinicopathological factors and established biomarkers allows prediction of outcome in locally invasive melanoma and might be implemented in addition to or in cases when sentinel node biopsy cannot be performed.

Galectin-1 is associated with poor prognosis in patients with cutaneous head and neck cancer with perineural spread.

Spread of head and neck cancer along the cranial nerves is often a lethal complication of this tumour. Current treatment options include surgical resection and/or radiotherapy, but recurrence is a frequent event suggesting that our understanding of this tumour and its microenvironment is incomplete. In this study, we have analysed the nature of the perineural tumour microenvironment by immunohistochemistry with particular focus on immune cells and molecules, which might impair anti-tumour immunity. Moderate to marked lymphocyte infiltrates were present in 58.8% of the patient cohort including T cells, B cells and FoxP3-expressing T cells. While human leukocyte antigen (HLA) class I and more variably HLA class II were expressed on the tumour cells, this did not associate with patient survival or recurrence. In contrast, galectin-1 staining within lymphocyte areas of the tumour was significantly associated with a poorer patient outcome. Given the known role of galectin-1 in immune suppression, the data suggest that galectin inhibitors might improve the prognosis of patients with perineural spread of cancer.

A pilot study to compare the detection of HPV-16 biomarkers in salivary oral rinses with tumour p16(INK4a) expression in head and neck squamous cell carcinoma patients.

BACKGROUND: Human papilloma virus-16 (HPV-16) infection is a major risk factor for a subset of head and neck squamous cell carcinoma (HNSCC), in particular oropharyngeal squamous cell carcinoma (OPSCC). Current techniques for assessing the HPV-16 status in HNSCC include the detection of HPV-16 DNA and p16(INK4a) expression in tumor tissues. When tumors originate from hidden anatomical sites, this method can be challenging. A non-invasive and cost-effective alternative to biopsy is therefore desirable for HPV-16 detection especially within a community setting to screen at-risk individuals. METHODS: The present study compared detection of HPV-16 DNA and RNA in salivary oral rinses with tumor p16(INK4a) status, in 82 HNSCC patients using end-point and quantitative polymerase chain reaction (PCR). RESULTS: Of 42 patients with p16(INK4a)-positive tumours, 39 (sensitivity = 92.9 %, PPV = 100 % and NPV = 93 %) had oral rinse samples with detectable HPV-16 DNA, using end-point and quantitative PCR. No HPV-16 DNA was detected in oral rinse samples from 40 patients with p16(INK4a) negative tumours, yielding a test specificity of 100 %. For patients with p16(INK4a) positive tumours, HPV-16 mRNA was detected using end-point reverse transcription PCR (RT-PCR) in 24/40 (sensitivity = 60 %, PPV = 100 % and NPV = 71 %), and using quantitative RT-PCR in 22/40 (sensitivity = 55 %, PPV = 100 % and NPV = 69 %). No HPV-16 mRNA was detected in oral rinse samples from the p16(INK4a)-negative patients, yielding a specificity of 100 %. CONCLUSIONS: We demonstrate that the detection of HPV-16 DNA in salivary oral rinse is indicative of HPV status in HNSCC patients and can potentially be used as a diagnostic tool in addition to the current methods.

Evidence for steroidogenic potential in human prostate cell lines and tissues.

Malignant prostate cancer (PCa) is usually treated with androgen deprivation therapies (ADTs). Recurrent PCa is resistant to ADT. This research investigated whether PCa can potentially produce androgens de novo, making them androgen self-sufficient. Steroidogenic enzymes required for androgen synthesis from cholesterol (CYP11A1, CYP17A1, HSD3ß, HSD17ß3) were investigated in human primary PCa (n = 90), lymph node metastases (LNMs; n = 8), and benign prostatic hyperplasia (BPH; n = 6) with the use of IHC. Six prostate cell lines were investigated for mRNA and protein for steroidogenic enzymes and for endogenous synthesis of testosterone and 5α-dihydrotestosterone. All enzymes were identified in PCa, LNMs, BPH, and cell lines. CYP11A1 (rate-limiting enzyme) was expressed in cancerous and noncancerous prostate glands. CYP11A1, CYP17A1, HSD3ß, and HSD17ß3 were identified, respectively, in 78%, 52%, 16%, and 82% of human BPH and PCa samples. Approximately 10% of primary PCa, LNMs, and BPH expressed all four enzymes simultaneously. CYP11A1 expression was stable, CYP17A1 increased, and HSD3ß and HSD17ß3 decreased with disease progression. CYP17A1 expression was significantly correlated with CYP11A1 (P = 0.0009), HSD3ß (P = 0.0297), and HSD17ß3 (P = 0.0090) in vivo, suggesting CYP17A1 has a key role in prostatic steroidogenesis similar to testis and adrenal roles. In vitro, all cell lines expressed mRNA for all enzymes. Protein was not always detectable; however, all cell lines synthesized androgen from cholesterol. The results indicate that monitoring steroidogenic metabolites in patients with PCa may provide useful information for therapy intervention.

The use of frozen section in the excision of cutaneous malignancy: a Queensland experience.

Frozen section is known to be a valuable tool in the setting of indistinct lesions, lesions in cosmetically or functionally important areas, and those with recurrent or residual tumors. Most non-Mohs surgery studies comparing frozen section with paraffin sections suggest a concordance rate of 85% to 90%, whereas studies with Mohs surgery often suggest concordance rates of 95% to 98%. We do not perform Mohs surgery at our institutions but feel that the accuracy of frozen section is relatively high. Frozen-section data from between 2005 and 2011 was analyzed, and a total of 150 cases was found and assessed. Most of the cases were basal cell carcinomas and squamous cell carcinomas, with most arising in the head and neck region. Half of the resections were for previous incomplete margins with the other half being primary excisions. The frozen section was accurate in 97.7% of the cases when compared with the formal paraffin sections. However, the incomplete rate was higher at 14.8% because of patients with known positive margins on frozen section and the use of less accurate techniques of specimen analysis. We feel that, when used appropriately, frozen section can be a reliable tool and that a negative result should provide the surgeon enough reassurance as to undertake immediate reconstruction.

Implementing structured pathology reporting protocol for non-melanocytic skin cancers: practical considerations.

Non-melanocytic skin cancers (NMSCs) account for five times the incidence of all other cancers combined and cost US $6 billion annually. These are the most frequent specimens encountered in community pathology practice in many Western countries. Lack of standardised structured pathology reporting protocols (SPRPs) can result in omission of critical information or miscommunication leading to suboptimal patient management. The lack of standardised data has significant downstream public health implications, including insufficient data for reliable development of prognostic tools and health-economy planning. The Royal College of Pathologists of Australasia has developed an NMSC SPRP. A multidisciplinary expert committee including pathologists, surgeons, dermatologists, and radiation and medical oncologists from high volume cancer centres was convened. A systematic literature review was performed to identify evidence for including elements as mandatory standards or best practice guidelines. The SPRP and accompanying commentary of evidence, definitions and criteria was peer reviewed by external stakeholders. Finally, the protocol was revised following feedback and trialled in multiple centres prior to implementation. Some parameters utilised clinically for determining management and prognosis including tumour depth, lymphovascular invasion or distance to the margins lack high level evidence in NMSC. Dermatologists, surgeons, and radiation oncologists welcomed the SPRP. Pathologists indicated that the variety of NMSC specimens ranging from curettes to radical resections as well as significant differences in the biological behaviour of different tumours covered by the NMSC umbrella made use of a single protocol difficult. The feedback included that using a SPRP for low risk NMSC was neither clinically justified nor compensated adequately by the Australian Medicare Reimbursement Schedule. Following stakeholder feedback, the SPRP implementation was restricted to excision specimens of head and neck NMSC; and low-risk NMSC, such as superficial basal cell carcinoma, were excluded. Implementing NMSC SPRP fulfils an unmet clinical need. Unlike other cancers, NMSCs generate a range of specimen types and are reported in a wide range of pathology practices. Limiting use of SPRP to NMSC at higher risk of progression and providing formatted templates for easy incorporation into laboratory information systems were essential to successful deployment. In the future, further consideration should be given to implementing the SPRP to include all relevant specimens, including non-head and neck and low-risk NMSC specimens.

A blueprint for staging of murine melanocytic lesions based on the Cdk4 ( R24C/R24C ) ::Tyr- NRAS ( Q ) ( 61K ) model.

It has been shown that gene mutations which drive the development of malignant melanoma (MM) in humans also lead to emergence of MM when engineered mice. However, little attention has been paid to the clinical and histopathological features of melanocytic lesions and their natural history in a given mouse model. This knowledge is crucial to enable us to understand how engineered mutations influence the initiation and evolution of melanocytic lesions, and/or for the use of mice as a preclinical model to test specific treatments. We recently reported the development of melanocytic proliferations along the spectrum of naevi to MM in a Cdk4 ( R24C/R24C ) ::Tyr- NRAS ( Q ) ( 61K ) mouse model. In this study, we followed the development of lesions over time using digital photography and dermoscopy with the aim to correlate the clinical and histopathological features of lesions developing in this model. We identified two types of lesions. The first are slow-growing dermal MMs that emanate from dermal naevi. The second did not emanate from naevi, grew rapidly, and appeared to be solely confined to the subcutaneous fat. We present a simple staging system for the MMs that progress from naevi, based on depth of extension into the dermis and subcutis. This represents a blueprint for documentation and follow-up of MMs in the live animal, which is critical for the proper use of murine melanoma models.

Confocal features of equivocal facial lesions on severely sun-damaged skin: four case studies with dermatoscopic, confocal, and histopathologic correlation.

BACKGROUND: Facial skin has a distinct histologic architecture and reveals specific dermatoscopic features. Diagnosis of lentigo maligna on the face is often challenging because of the overlap of clinical and morphologic features with other lesions. OBJECTIVES: We aim to show the value of reflectance confocal microscopy (RCM) as a noninvasive diagnostic tool for facial lesions and to increase knowledge of RCM morphologic features among the scientific community. METHODS: We describe a series of 4 facial lesions on severely sun-damaged skin that was evaluated via RCM immediately after face-to-face examination, followed by shave biopsy for histopathological analysis. RESULTS: Lesions included a lentigo maligna, a pigmented seborrheic keratosis, pigmented basal cell carcinoma, and a pigmented actinic keratosis. In the presented cases, RCM enabled an accurate diagnosis. LIMITATIONS: The study describes morphologic features on selected cases, but does not test accuracy of RCM criteria. CONCLUSIONS: RCM is a useful adjuvant for the accurate and precise diagnosis of equivocal facial lesions.

Pembrolizumab-induced toxic epidermal necrolysis: case report.

A 63-year-old man with metastatic lung adenocarcinoma presented with biopsy confirmed toxic epidermal necrolysis (TEN). Symptoms commenced following 3 cycles of carboplatin, pemetrexed and pembrolizumab, with the first cycle given ~9.5 weeks prior to presentation. The patient was managed with immunosuppressive therapy including high dose methylprednisolone, cyclosporine, intravenous immunoglobulin, antibiotics and optimal skin care, and achieved excellent recovery of the skin lesions with minimal sequelae. This rare occurrence of pembrolizumab-induced TEN has only been reported previously in a few cases with limited evidence on management. Given the increasing use of immune checkpoint inhibitors and the long half-life of these agents, our case highlights the importance of recognizing this complication and of a multidisciplinary approach to management.

Genome-Scale DNA Methylation Analysis Identifies Repeat Element Alterations that Modulate the Genomic Stability of Melanocytic Nevi.

Acquired melanocytic nevi grow and persist in a stable form into adulthood. Using genome-wide methylation profiling, we evaluated 32 histopathologically and dermoscopically characterized nevi to identify the key epigenetic regulatory mechanisms involved in nevogenesis. Benign (69% globular and 31% nonspecific dermoscopic pattern) and dysplastic (95% reticular/nonspecific dermoscopic pattern) nevi were dissimilar, with only two shared differentially methylated loci. Benign nevi showed an increase in both genome-scale methylation and methylation of Alu/LINE-1 retrotransposable elements, a marker of genomic stability, as well as global methylation. In contrast, dysplastic nevi showed evidence for genomic instability through the hypomethylation of Alu/LINE-1 (Alu: P = 0.00019; LINE-1: P = 0.000035). Using dermoscopic classifications, reticular/nonspecific patterned nevi had 59,572 5'-C-phosphate-G-3' differentially methylated loci (Q < 0.05), whereas globular nevi had no significant differentially methylated loci. In reticular/nonspecific patterned nevi, the tumor suppressor PTEN had the greatest proportion of hypermethylated 5'-C-phosphate-G-3' loci in its promoter region than all other assayed gene promoters. The relative activity of reticular/nonspecific nevi was evidenced by 50,720 hypomethylated loci being enriched for accessible chromatin and 8,852 hypermethylated loci strongly enriched, for example, marks of active gene promoters, which suggests that gain of DNA methylation observed in these nevus types plays a role in gene regulation.

BRAF mutation testing for patients diagnosed with stage III or stage IV melanoma: practical guidance for the Australian setting.

Targeted therapy (BRAF inhibitor plus MEK inhibitor) is now among the possible treatment options for patients with BRAF mutation-positive stage III or stage IV melanoma. This makes prompt BRAF mutation testing an important step in the management of patients diagnosed with stage III or IV melanoma; one that can help better ensure that the optimal choice of systemic treatment is initiated with minimal delay. This article offers guidance about when and how BRAF mutation testing should be conducted when patients are diagnosed with melanoma in Australia. Notably, it recommends that pathologists reflexively order BRAF mutation testing whenever a patient is found to have American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage III or IV melanoma (i.e., any metastatic spread beyond the primary tumour) and that patient's BRAF mutation status is hitherto unknown, even if BRAF mutation testing has not been specifically requested by the treating clinician (in Australia, Medicare-subsidised BRAFV600 mutation testing does not need to be requested by the treating clinician). When performed in centres with appropriate expertise and experience, immunohistochemistry (IHC) using the anti-BRAF V600E monoclonal antibody (VE1) can be a highly sensitive and specific means of detecting BRAFV600E mutations, and may be used as a rapid and relatively inexpensive initial screening test. However, VE1 immunostaining can be technically challenging and difficult to interpret, particularly in heavily pigmented tumours; melanomas with weak, moderate or focal BRAFV600E immunostaining should be regarded as equivocal. It must also be remembered that other activating BRAFV600 mutations (including BRAFV600K), which account for ∼10-20% of BRAFV600 mutations, are not detected with currently available IHC antibodies. For these reasons, if available and practicable, we recommend that DNA-based BRAF mutation testing always be performed, regardless of whether IHC-based testing is also conducted. Advice about tissue/specimen selection for BRAF mutation testing of patients diagnosed with stage III or IV melanoma is also offered in this article; and potential pitfalls when interpreting BRAF mutation tests are highlighted.

First experiences using reflectance confocal microscopy on equivocal skin lesions in Queensland.

BACKGROUND/OBJECTIVES: Reflectance confocal microscopy (RCM) is a non-invasive method of imaging human skin in vivo. The purpose of this study was to observe the experience of using RCM on equivocal skin lesions in a tertiary clinical setting in Queensland. METHODS: Fifty equivocal lesions on 42 patients were imaged using a reflectance confocal microscope immediately prior to being excised. The images were then analysed blind to the histopathological diagnosis. The experience and problems encountered when using RCM on skin lesions for the first time was also observed. RESULTS: On RCM analysis 12/13 melanomas (92.3% sensitivity, 75% specificity), 19/22 benign naevi (86% sensitivity, 95% specificity), 6/9 basal cell carcinomas (66.7% sensitivity, 100% specificity)and 6/6 squamous cell carcinomas and its precursors (100% sensitivity, 75% specificity) were diagnosed correctly when using histology as the gold standard. We identified three common problems that affected image quality: object artefacts; positioning artefacts; and movement artefacts. CONCLUSIONS: Using simple techniques we found that common RCM features were readily identifiable and common artefacts could be minimized, making RCM a useful tool to aid the diagnosis of equivocal skin lesions in a clinical setting.

Effectiveness and limitations of reflectance confocal microscopy in detecting persistence of basal cell carcinomas: a preliminary study.

BACKGROUND/OBJECTIVES: Reflectance confocal microscopy (RCM) can accurately and non-invasively diagnose basal cell carcinoma (BCC). The use of RCM in assessing responses to saucerization or curettage and cautery of BCC has not been established. The aim of the present study was to expound the usefulness of RCM in assessing treatment responses of BCC to saucerization or curettage and cautery 8-12 weeks after treatment. METHODS: Eight sequential patients, with 11 superficial BCCs, were recruited. Lesions were evaluated clinically and dermoscopically. Three operators performed RCM imaging for each BCC at baseline and 8-12 weeks after treatment. Diagnostic criteria for RCM diagnosis included streaming of basal cells and the presence of cord-like structures and horizontal vessels. Results were compared against histopathology. Difficulties in establishing tumour clearance were identified and the effectiveness of RCM in assessing the response to treatment was explored. RESULTS: At baseline, all lesions were consistent with superficial BCC. At 8-12 weeks after treatment, RCM correctly diagnosed 10 of 11 lesions as tumour free. Furthermore, RCM was reliable across operators of variable experience and the findings were confirmed histopathologically. Limitations were identified, but appeared to be related to operator experience. CONCLUSION: The diagnosis of BCC was straightforward and reliable in the present study. Thus, RCM appears useful in assessing the early treatment response of superficial BCC treated with saucerization or curettage and cautery despite operator-dependent limitations.

Heterotopic ossification within the gallbladder - First reported Australian case.

INTRODUCTION: We report the rare and unusual case of heterotopic ossification within the gallbladder secondary to chronic calculi debris. PRESENTATION OF CASE: A 35-year-old female underwent routine laparoscopic cholecystectomy for recurrent intermittent right upper quadrant pain which had persisted for three months and was worse post prandial with associated nausea. Abdominal ultrasound prior to surgery was reported by a consultant radiologist as demonstrating a thin-walled gallbladder and cholelithiasis, without features of cholecystitis. At four-week review, she had recovered well with no concerns. The histopathology report revealed fibromuscular hyperplasia and patchy chronic inflammation. Rokitansky-Aschoff sinuses were present and cholesterosis was noted. Additionally, there was a focus of eroded mucosa showing adherent microlithiasis with an incidental focus of heterotopic ossification within the mucosa, there was no evidence of dysplasia or malignancy. DISCUSSION: Gallbladder heterotopic ossification is exceedingly rare, with few cases reported. To our knowledge this is the first reported case in Australia. CONCLUSION: In conclusion, we report the rare and unusual finding of heterotopic ossification of the gallbladder, and suspect that inflammation secondary to calculous debris initiated the ossification. Current technical limitations preclude diagnosis prior to surgery. Appropriate follow-up is unclear, but we feel a single report associated the finding with adenocarcinoma was sufficient to warrant follow-up.