Sebaceous carcinoma in Western Australia: A registry-based study of site-related outcomes.

Sebaceous carcinoma is a rare cutaneous malignancy which is typically regarded as relatively aggressive and has traditionally been subdivided into periorbital or extraorbital tumours. We conducted a retrospective review of all cases of sebaceous carcinoma reported to the Western Australian Cancer Registry between 1987 and May 2019. The incidence of sebaceous carcinoma in Western Australia has increased over the last three decades, with extraorbital tumours being much more common than periorbital tumours. Very few sebaceous carcinomas have led directly to the death of patients; however, adverse outcomes were more likely with periorbital tumours, in particular local recurrence and the need for major surgical intervention.

Mitotically Active Nevus and Nevoid Melanoma: A Clinicopathological and Molecular Study.

ABSTRACT: The distinction between nevoid melanoma and a mitotically active nevus can be challenging at the microscopic level. In this study, we performed cytogenetic testing on a cohort of 25 mitotically active melanocytic proliferations resembling common melanocytic nevus from 25 patients. Based on cytogenetic findings, the lesions were classified as "nevoid melanoma" (n = 13) or "mitotically active nevus" (n = 12). Subsequently, we compared the clinicopathological features between these 2 groups. Nevoid melanomas occurred in older patients (P = 0.007); however, there were no significant differences in gender, size, or anatomical distribution between the 2 groups. Histologically, deep/marginal mitoses (P = 0.006), lack of maturation with depth (P = 0.036), and pseudo-maturation (P = 0.006) were significantly more common in nevoid melanomas. Immunohistochemically, complete loss of p16 was an important divisive feature (P = 0.0004), seen in 70% of nevoid melanomas, and highly correlated with loss of CDKN2A gene (chromosome 9p21). Our findings suggest that such reproducible immunomorphological differences can be of value in distinguishing nevoid melanoma from mitotically active nevus. Nevoid melanomas demonstrated a spectrum of chromosomal aberrations similar to those seen in common subtypes of melanoma, which can serve as a powerful adjunct diagnostic tool in morphologically challenging lesions.

Histologically Diverse BAP1-Deficient Melanocytic Tumors in a Patient With BAP1 Tumor Predisposition Syndrome.

BRCA1-associated protein-1 (BAP1)-deficient cutaneous tumors are common in patients with BAP1 tumor predisposition syndrome, frequently presenting before other associated neoplasms, and can serve as an early marker to identify individuals with this disease. The typical lesions are dermal based and composed of a combination of larger epithelioid melanocytes with abundant glassy cytoplasm and smaller cells resembling those of a conventional nevus. There is often a component of interspersed lymphocytes. However, BAP1-deficient melanocytic tumors can show a spectrum of histologic appearances, ranging from lesions with pure epithelioid, pure conventional nevus, or rhabdoid cells and tumors with an intraepidermal component. To demonstrate such morphologic variation, we present a case of a 50-year-old woman with multiple histologically diverse BAP1-deficient melanocytic tumors and germline BAP1 mutation, identified after a diagnosis of pleural mesothelioma. We also discuss the pathogenesis and potential histopathological and clinical indications of germline versus sporadic etiology in the assessment of BAP1-deficient melanocytic tumors.

Polypoid Compound Melanocytic Proliferations: A Clinicopathological Study.

Nevi can show a polypoid appearance both clinically and histologically. Anecdotally, polypoid compound melanocytic nevus may exhibit a spectrum of junctional architectural and cytologic atypia, at times creating a diagnostic challenge by mimicking the radial growth phase of melanoma. To investigate this issue, we prospectively reviewed 40 polypoid compound melanocytic proliferations without overt malignant features. The lesions frequently occurred in young female patients and were predominantly from the trunk and intertriginous areas. Commonly observed atypical features included asymmetry (30%), shouldering (47.5%), poor circumscription (37.5%), and deep extension of melanocytes along the adnexal structures (67.5%). Severe cytologic junctional atypia (22.5%), dermal mitoses (10%), and pagetoid spread of melanocytes (5%) were less commonly seen. All lesions showed a reassuring dermal component with negligible cytologic atypia and maturation with depth. Overall, 7 lesions could not be readily classified as benign nevus; 5 of these in which a benign diagnosis was strongly favored were classified as atypical polypoid compound melanocytic nevi, whereas 2 lesions with diffuse severe junctional cytologic atypia and dermal mitoses were classified as ambiguous melanocytic proliferations. Atypical/ambiguous lesions were significantly larger and predominantly located in the axilla and groin. On molecular studies, none of the lesions tested showed the molecular profile of melanoma. We confirmed that polypoid compound melanocytic nevus can exhibit a variable degree of junctional atypia, likely related to frequent episodes of trauma and regeneration resulting in melanocytic proliferation. Pathologists should be aware of this phenomenon to avoid overdiagnosis.

Cutaneous tumoural melanosis: a presentation of complete regression of cutaneous melanoma.

Partial regression is common in cutaneous melanoma; however, complete regression manifesting as tumoural melanosis is rare, conceptually challenging and under-reported. In this study we report on clinical, histological and molecular findings in four cases of completely regressed cutaneous melanoma with nodal or brain metastasis, followed by a comprehensive review of the literature. Our series included three women and one man with an average age of 60 years, and clinical presentation with hyper-pigmented cutaneous lesions. The main histological findings were expansile aggregates of melanophages with complete absence of malignant melanocytes on microscopic and immunohistochemical examination of the entire primary skin lesions, as well as substantial reduction in the number of junctional melanocytes in the overlying epidermis. NRAS mutant/BRAF wild type metastatic deposits were identified in three patients, with one patient having a BRAF V600E mutant metastatic tumour. Tumoural melanosis likely represents a partially effective immunological response to melanoma, with complete eradication of cutaneous disease and less effective systemic results. Patients with tumoural melanosis should be managed as potential completely regressed cutaneous melanoma, with comprehensive physical examination, imaging work up and close follow up.

'Why don't they ever call?' Expectations of clinicians and pathologists regarding the communication of critical diagnoses in dermatopathology.

Certain diagnoses in dermatopathology have significant implications for patient management and on occasion appropriate clinical care may be facilitated by a phone call from the reporting dermatopathologist to the referring doctor. Whether this is appropriate depends on a number of factors. The concept of 'critical diagnoses' is now well established in surgical pathology, having evolved from critical value policies in clinical pathology and haematology. However, only limited attempts have been made to assess perceptions among different clinical groups. We designed a survey to assess the attitudes of pathologists, dermatologists, surgeons and general practitioners as to what circumstances warrant telephone contact in addition to a standard written report, as well as their approaches to routine histology follow-up. The survey was distributed Australia-wide via a combination of specialist colleges, medical forums and collegiate contacts. A total of 262 responses were received, encompassing representations from all of the targeted specialties. Approximately 20% of respondents were aware of adverse outcomes or 'near misses' which they felt had been due in some part to inadequate communication of histopathology results. While most practitioners have formal systems in place to review histopathology reports, this practice is not universal. There were a number clinical situations where there was a discrepancy between the expectations of clinicians and those of pathologists, in particular with regard to a diagnosis of cutaneous melanoma as well as cutaneous lesions which might be associated with inherited cancer syndromes. It is our hope that the results of this study will facilitate discussion between pathologists and referring clinicians at a local level to minimise the potential for miscommunication.

Sebaceous lesions of the skin.

Sebaceous differentiation is commonly seen in cutaneous neoplasms, both in the context of lesions showing predominantly sebaceous differentiation (e.g., sebaceous adenoma, sebaceoma and sebaceous carcinoma), or as more focal sebaceous components in neoplasms with other primary lines of differentiation. Sebaceous changes can also be a component of benign cystic lesions or epidermal tumours, and sebaceous hyperplasia is commonly encountered. This review is intended to provide an overview of the cutaneous lesions with sebaceous differentiation, with a particular emphasis on facilitating histological diagnosis of neoplasms. In addition, the role of immunohistochemical studies is outlined, as well as the evaluation of potential cases of Muir-Torre syndrome.

Pathological Sampling of Basal Cell Carcinoma Re-excision Specimens: How Much is Enough?

Basal cell carcinoma (BCC) is the most common cutaneous malignancy, comprising approximately 75%-80% of all skin cancers. Surgical excision is the most common first line treatment modality, with the intent of obtaining clear margins. If the initial excision is incomplete or inadequate, a re-excision will often be performed in an attempt to achieve histological clearance. The pathological examination of these specimens requires a balance between the need for adequate assessment and efficient use of laboratory resources. In this study, we sought to systematically compare different approaches to the pathological sampling of these specimens in the hope of providing an evidential basis for a rational approach. Seventy-four BCC re-excision specimens were entirely sampled and retrospectively examined to determine the rate of detection of residual BCC which would have been achieved using different sampling methodologies. Residual BCC was identified in 37 specimens (50%). Limited transverse sections through the centre of the ellipse resulted in a sensitivity for detection of residual BCC of 78% (or 85% if only "significant" residual tumor is considered). By including the entire scar or the remainder of the specimen except the polar pieces, the sensitivity improved to 95% and 97%, respectively. Only one case showed residual tumor in the apical sections alone, with tumor extending to the new surgical margin in that case. We hope that this data may help laboratories develop sampling protocols appropriate to their own cost-benefit analyses and patient populations.

Skin biopsy in the diagnosis of inflammatory skin disease.

BACKGROUND: Most non-neoplastic skin conditions are readily diagnosed by a combination of clinical history and examination, but in a small number of cases, biopsy for histopathology and other laboratory investigations can be invaluable tools. Close attention to communication of appropriate clinical details, selection of biopsy site and biopsy technique have a marked impact on the diagnostic yield of this procedure. OBJECTIVE: The objectives of this article are to provide general principles related to the biopsy of non-neoplastic skin conditions and offer practical advice on the approach to some common skin conditions. DISCUSSION: In this article, we discuss a number of general principles that will ensure maximum benefits can be achieved when a biopsy is per-formed for the diagnosis of non-neoplastic skin disease.

Skin biopsy in the diagnosis of neoplastic skin disease.

BACKGROUND: Biopsy for diagnostic and therapeutic purposes is a central component in the management of neoplastic skin conditions. While the technical aspects of performing biopsies are familiar to most clinicians, a number of other aspects of the skin biopsy pathway are equally important. OBJECTIVE: The objectives of this article are to provide general principles related to the biopsy of neoplastic skin conditions and offer practical advice on the approach to some common skin neoplasms. DISCUSSION: Careful attention to the selection of biopsy site and type, and communication of appropriate clinical details will ensure optimal patient care, minimising the chance of diagnostic errors with potentially serious medical and medico-legal consequences.

Detection of copy number variations in melanocytic lesions utilising array based comparative genomic hybridisation.

Distinction between melanocytic naevi and melanoma occasionally poses a diagnostic challenge in ambiguous cases showing overlapping histological features. Melanomas are characterised by the presence of multiple genomic copy number variants (CNVs), while this is not a feature of naevi. We assessed the feasibility and utility of array-based comparative genomic hybridisation (aCGH) to assess CNVs in melanocytic lesions. DNA was extracted from formalin fixed, paraffin embedded (FFPE) sections of unambiguous naevi (n=19) and melanomas (n=19). The test DNA and gender mismatched human reference DNA were differentially labelled with fluorophores. Equal quantities of the two DNA samples were mixed and co-hybridised to a SurePrint G3 Human CGH 8x60K array, and digitally scanned to capture and quantify the relative fluorescence intensities. The ratio of the fluorescence intensities was analysed by Cytogenomics software (Agilent). Frequent large CNVs were identified in 94.7% of melanoma samples, including losses of 9p (73.6%), 9q (52.6%), 10q (36.8%), 11q (36.8%), 3p (21%), and 10p (21%), and gains of 6p (42.1%), 7p (42.1%), 1q (36.8%), 8q (31.5%) and 20q (21%). Only one naevus showed two large copy number changes. Overall aCGH showed a specificity and sensitivity of 94.7% in separating naevi from melanomas. Based on our results, aCGH can be successfully used to analyse CNVs of melanocytic lesions utilising FFPE derived biopsy samples, providing a potentially useful adjunctive test for the classification of diagnostically challenging melanocytic proliferations.

Cutaneous Metastatic Melanoma Resembling a Halo Nevus, in the Setting of PD-1 Inhibition.

Malignant melanoma is a common source of cutaneous metastases and can occasionally adopt a histological appearance which mimics a primary melanocytic lesion, either benign or malignant. The authors describe a case of new cutaneous deposits of metastatic melanoma in a 70-year-old woman with a prominent admixed lymphocytic infiltrate, imparting a striking resemblance to a halo nevus. The authors believe this appearance was a direct reflection of treatment with pembrolizumab, a humanized antibody against the immune checkpoint inhibitor programmed death-1. With increasing use of immune-modulating drugs, this potential histological mimic may be seen more frequently in the future.

Circumscribed sebaceous neoplasms: a morphological, immunohistochemical and molecular analysis.

Sebaceous neoplasms encompass a range of lesions, including benign entities such as sebaceous adenoma and sebaceoma, as well as sebaceous carcinoma. The distinction of sebaceous carcinoma from benign lesions relies on histological identification of architectural or cytological features of malignancy. In this study we have assessed the diagnostic discriminatory ability of mitotic rate and immunohistochemical markers (p53, bcl-2 and p16) in a selected group of well circumscribed sebaceous neoplasms, incorporating examples of sebaceous adenoma, sebaceoma and sebaceous carcinoma. We found that mitotic rate was significantly higher in malignant lesions as compared to benign lesions, but none of the immunohistochemical markers showed a discriminatory expression pattern. In addition, we performed a mutational analysis on the same group of lesions using next generation sequencing (NGS) technology. The most commonly mutated gene was TP53, although there was no correlation between the p53 immunohistochemical results and number or type of TP53 mutation detected. CDKN2A, EGFR, CTNNB1 and KRAS were also commonly mutated across all lesions. No particular gene, mutation profile or individual mutation could be identified which directly correlated with the consensus histological diagnosis. In conclusion, within this diagnostically challenging group of lesions, mitotic activity, but not immunohistochemical labelling for p16 or bcl-2, correlates with diagnostic category. While a number of genes potentially involved in the genesis of sebaceous neoplasia were uncovered, any molecular differences between the histological diagnostic categories remain unclear.