The RCPA Quality Assurance Program in Dermatopathology: A Retrospective Review.

AIMS: To review the Royal College of Pathologists of Australasia (RCPA) Quality Assurance Program Dermatopathology module from 2005 to 2016 to assess diagnostic performance, changes over time, and areas of diagnostic difficulty. METHODS: The computerized records of the RCPA Dermatopathology subspecialist module were reviewed. Cases were categorized into groups including nonneoplastic disorders, neoplasms, and cases with multiple diagnoses. The performance of participants over time in each of these categories and in more specific areas (including melanocytic and adnexal neoplasms) was assessed. Cases which showed high rates of discordant responses were specifically reviewed. RESULTS: One hundred sixteen cases circulated over 10 years were evaluated. The overall concordance rate was 77%, with a major discordance rate of 7%. There was a slightly higher concordance rate for neoplasms compared with nonneoplastic lesions (80% vs. 74%). Specific areas associated with lower concordance rates included classification of adnexal tumors and identification of multiple pathologies. A spindle cell nevus of Reed yielded a 40% discordance rate, with most misclassifications indicating melanoma. CONCLUSIONS: The RCPA quality assurance program module has circulated a wide range of common and uncommon cases to participants over the 12 years studied, highlighting a low but important rate of major discordant responses. Melanocytic lesions, hematolymphoid infiltrates, adnexal tumors, and identification of multiple pathologies are identified as areas worthy of particular attention in quality improvement activities.

Cutaneous basal cell carcinosarcomas: evidence of clonality and recurrent chromosomal losses.

Cutaneous carcinosarcomas are heterogeneous group of tumors composed of malignant epithelial and mesenchymal components. Although mutation analyses have identified clonal changes between these morphologically disparate components in some subtypes of cutaneous carcinosarcoma, few cases have been analyzed thus far. To our knowledge, copy number variations (CNVs) and copy-neutral loss of heterozygosity (CN-LOH) have not been investigated in cutaneous carcinosarcomas. We analyzed 4 carcinosarcomas with basal cell carcinoma and osteosarcomatous components for CNVs/CN-LOH by comparative genomic hybridization/single-nucleotide polymorphism array, TP53 hot spot mutations by polymerase chain reaction and Sanger sequencing, and TP53 genomic rearrangements by fluorescence in situ hybridization. All tumors displayed multiple CNV/CN-LOH events (median, 7.5 per tumor). Three of 4 tumors displayed similar CNV/CN-LOH patterns between the epithelial and mesenchymal components within each tumor, supporting a common clonal origin. Recurrent changes included allelic loss at 9p21 (CDKN2A), 9q (PTCH1), and 17p (TP53). Allelic losses of chromosome 16 including CDH1 (E-cadherin) were present in 2 tumors and were restricted to the sarcomatous component. TP53 mutation analysis revealed an R248L mutation in both epithelial and mesenchymal components of 1 tumor. No TP53 rearrangements were identified. Our findings indicate that basal cell carcinosarcomas harbor CNV/CN-LOH changes similar to conventional basal cell carcinoma, with additional changes including recurrent 9p21 losses and a relatively high burden of copy number changes. In addition, most cutaneous carcinosarcomas show evidence of clonality between epithelial and mesenchymal components.

MITF positivity in atypical fibroxanthoma: a diagnostic pitfall.

Microphthalmia transcription factor (MITF) is an established melanocytic marker originally credited with a high degree of specificity. We report a series of 11 atypical fibroxanthoma (AFX) from 2 laboratories showing positive MITF staining. Although there are multiple case reports illustrating MITF staining in a range of tumors, aberrant staining in AFX has not been previously reported. Awareness of the possibility of MITF positivity in AFX is important to avoid a misdiagnosis of melanoma. We also report positive MITF staining in 2 nonneural granular cell tumors and discuss the overlap with the granular subtype of AFX.

Basal cell carcinosarcoma: a report of 4 cases and review of the literature.

BACKGROUND: To describe the features of 4 cases of basal cell carcinosarcoma and systematically review previously reported cases. METHODS: Four cases of basal cell carcinosarcoma were identified from the practice of the authors. A search of the literature revealed an additional 40 cases, variously described in small series and single case reports. The clinical and pathological features of these 44 cases are described. RESULTS: Basal cell carcinosarcoma is largely a tumor of elderly men (male:female 3:1, average age: 76 years). The majority of these lesions are relatively small (<25 mm). Heterologous elements are common, particularly an osteosarcomatous component, which is present in 45% of cases. Although there are relatively limited follow-up data, only 1 case formally reported in the literature has shown distant metastasis. CONCLUSIONS: Despite relatively high reported rates of local recurrence and metastasis for "carcinosarcoma" as an unrefined entity, it seems that the subgroup of basal cell carcinosarcoma has a relatively good prognosis, with adequate local excision being curative in the majority of cases. Recognition of this entity is critical for accurate diagnosis and its separation from other types of carcinosarcoma may have significant prognostic implications.

Merkel cell polyomavirus and p63 status in Merkel cell carcinoma by immunohistochemistry: Merkel cell polyomavirus positivity is inversely correlated with sun damage, but neither is correlated with outcome.

The aim of this study was to determine the frequency of Merkel cell polyomavirus (MPyV) and p63 positivity by immunohistochemistry in a large cohort of primary Merkel cell carcinoma (MCC) from a region with high rates of actinic damage. We also aimed to determine whether there is any relationship between these markers and histological correlates of chronic sun exposure and to identify whether these markers have prognostic significance in our population. Ninety-five cases of primary cutaneous MCC were identified and stained with immunohistochemical markers for MPyV and p63. The presence of solar elastosis and squamous dysplasia in the overlying/adjacent skin were recorded as markers of actinic damage. Follow up data were obtained from the Western Australian Cancer Registry. MPyV was detected by immunohistochemistry in 23% of cases. There was a statistically significantly lower rate of positivity in tumours associated with markers of chronic sun damage as assessed by the presence of solar elastosis and squamous dysplasia. There was no association with overall or disease specific survival. p63 positivity was detected in 17% of cases. There was no association with markers of actinic damage or with overall or disease specific survival.Our data demonstrate a significant difference in rates of immunohistochemical positivity for MPyV between MCC in sun-damaged and non-sun-damaged sites. This may go some way to explaining previously identified geographical differences. When compared with a number of studies from Europe and North America, p63 positivity is less common in our population and does not show the strong prognostic significance that has been found in these other regions.

Histopathological features associated with application of black salve to cutaneous lesions: a series of 16 cases and review of the literature.

AIMS: To document the histopathological features of self-treatment of cutaneous lesions with the escharotic agent black salve. METHODS: Retrospective review of cutaneous lesions treated with black salve retrieved from the files of four pathology practices in Western Australia and review of the published literature. RESULTS: 16 lesions from 11 patients who self administered black salve for the treatment of skin lesions were reviewed. Clinical diagnoses at the time of biopsy included scar, keloid scar, pseudomelanoma, basal cell carcinoma, squamous cell carcinoma and cutaneous necrosis. Histopathological features identified in our series included scarring, granulomatous inflammation, implanted foreign material, reactive stromal atypia and suppurative necrosis. Residual neoplasia was present in two of 16 cases, including a basal cell carcinoma and a melanocytic naevus. An additional 13 lesions in 10 patients were identified in the medical literature, including cases with poor cosmetic outcomes and cases of malignant tumours masked by uncontrolled escharotic treatment. CONCLUSIONS: Availability of black salve through easily accessible internet sites appears to be associated with persisting use of this agent for the self-management of cutaneous lesions. Awareness of the potential complications and range of histopathological features associated with self-administration of escharotic agents is of importance to dermatologists and histopathologists.

Interobserver variability in the diagnosis of circumscribed sebaceous neoplasms of the skin.

AIMS: Separation of sebaceous adenoma, sebaceoma and well differentiated sebaceous carcinoma is a clinically important distinction which relies on a number of subjective criteria. In routine practice we had noted significant interobserver variability in the classification of these lesions. This study sought to determine the degree of interobserver variability between general surgical pathologists and dermatopathologists in the diagnosis of well differentiated cutaneous sebaceous neoplasms. METHODS: We circulated 61 examples of well circumscribed cutaneous sebaceous neoplasms to nine pathologists, including dermatopathologists and general surgical pathologists who were asked to submit a diagnosis for each case. Fleiss' kappa statistic was used for assessment of interobserver agreement. RESULTS: We found that only seven cases (11%) had consensus agreement across all nine pathologists. Many cases had multiple diagnoses suggested, with three or more submitted diagnoses in 26 cases (43%), while 38 cases (62%) were diagnosed as sebaceous carcinoma by at least one pathologist. There was marked variability amongst the individual pathologists in the proportion of cases diagnosed as carcinoma, ranging from 5% to 57% of cases. Fleiss' kappa statistic for all pathologists across all diagnostic categories was 0.44, amounting to only fair to moderate agreement. CONCLUSIONS: These data indicate that there is substantial interobserver variability in the diagnosis of well circumscribed sebaceous neoplasms. This was seen in both the separation of benign and malignant lesions, as well as in the classification of the benign entities. This interobserver variability is likely to have significant clinical implications in terms of potential for over- or under-treatment, as well as in selection of cases for mismatch repair protein evaluation.

A critical review of melanoma pathology reports for patients referred to the Western Australian Melanoma Advisory Service.

AIM: To assess concordance between the histopathological reports of referring pathologists and those of pathologists reviewing the cases for the Western Australia Melanoma Advisory Service. METHODS: A retrospective review of 721 pathology reports from 2000 to 2009 was conducted. Histological features including Breslow thickness, Clark level, tumour type and clinicopathological staging [American Joint Committee on Cancer (AJCC)] were compared. Further analysis was undertaken for 169 cases to compare mitotic rate, excision margins, regression, growth phase, vascular invasion, neurotropism, tumour infiltrating lymphocytes, microsatellites and predominant cell type. RESULTS: Referring pathologists consistently reported Breslow thickness, Clark level and excision margins. Reporting of other parameters including ulceration, mitotic rate and vascular invasion, however, was variable. There was almost perfect concordance (kappa = 0.81-1.00) for tumour thickness, ulceration, microsatellites and growth phase; substantial concordance (κ = 0.61-0.80) for Clark level, mitotic rate, completeness of excision and neurotropism; moderate concordance (κ = 0.41-0.60) for vascular invasion, regression, predominant cell type and histological type; and only slight concordance (κ = 0-0.2) for tumour infiltrating lymphocytes. There was a high level of agreement for diagnosis of lesions as melanoma versus benign (97.3%). Overall concordance for pathological tumour staging was substantial (81.9%, κ = 0.79). Lowest concordance was found for stage 1b (91.3%, κ = 0.62). CONCLUSION: Overall concordance in clinicopathological stage was high due to consistency of reporting of tumour thickness and ulceration. Lower concordance was found for pathological substages due to discrepancies in Clark level, highlighting its limited reliability as a prognostic indicator and supporting the revision of its use in the latest AJCC melanoma staging protocol.

CD163 is not a sensitive marker for identification of atypical fibroxanthoma.

The histopathological features of atypical fibroxanthoma (AFX) overlap with those of poorly differentiated carcinoma, melanoma and leiomyosarcoma in the skin. As there are no specific stains to identify AFX, the diagnosis is essentially one of exclusion and requires completion of a panel of immunostains. Recently, it has been suggested that the macrophage/monocyte-specific marker CD163 is of value in identifying AFX. To investigate this claim, 57 AFX were stained for CD163. Only 21 of 57 (37%) of AFX stained positively, and intratumoral macrophages confounded interpretation of the stain at times. In four cases, it was not possible to definitively interpret the tumor staining reaction because of this effect. While a lack of stainable CD163 antigenicity may indicate that AFX is not of histiocytic lineage, it is conceivable that expression of the antigen has been lost for some reason in cells that are in fact of macrophage lineage. In summary, CD163 only stains a minority of AFX and staining results can be difficult to interpret. CD163 is therefore of very limited value in the diagnosis of AFX. Beer TW. CD163 is not a sensitive marker for identification of atypical fibroxanthoma.

Atypical fibroxanthoma: a histological and immunohistochemical review of 171 cases.

The clinical and histological features of 171 atypical fibroxanthomas (AFX) from a single institution in Western Australia are outlined. This area experiences high levels of solar radiation, and all assessable biopsies showed solar elastosis. Patients were aged between 41 and 97 years (median age 74), with 76% of tumors occurring in men (male to female ratio approximately 3 to 1). Most tumors were small, with a median diameter of 10 mm and a range of 4-35 mm. Only 5% exceeded 20 mm in diameter. Most AFX were well-circumscribed dermal lesions, with limited invasion of subcutis in a minority. Histological variants identified included keloidal (n = 8), clear cell (n = 3), and granular cell (n = 3), plaque like (n = 4), and myxoid (n = 1). Bland cytological appearances (spindle cell nonpleomorphic AFX) were noted in 5 tumors, with osteoclast-like giant cells in 2. Features suggesting regression were present in 22 cases. Two cases recurred locally, none metastasized. No tumors expressed melanocytic or epithelial markers. Seventy-four percent of cases expressed smooth muscle actin, typically strongly and diffusely. No AFX stained with desmin. Only 1 of 50 cases was CD117 positive. In conclusion, AFX may show a wide range of histological appearances, and a panel of immunohistochemical markers is essential to make the correct diagnosis. Histological mimics, such as poorly differentiated squamous cell carcinoma, must be carefully excluded. Specific diagnosis is important because there seems to be a very low risk of recurrence or metastasis despite the frequently alarming histology.

Clear cell change in eccrine glands is not associated with diabetes.

The significance of clear cell change (clear reticulated cytoplasmic change) in the secretory portion of eccrine glands remains an enigma. It has been postulated to be a product of defective cellular glucose metabolism and potentially a predictor of diabetes. A series of 61 specimens from 38 patients were assessed to establish any demographic, seasonal, or metabolic associations. Sixty-one specimens from 38 patients with eccrine clear cell changes were identified prospectively by one of the authors (T.W.B.). Each specimen was stratified by site, age, sex, and season. For each patient, the general practitioner was contacted and diabetes status was ascertained. This was possible in 34 of 38 patients. Fifty routine consecutive cases from the archive in both summer and winter were studied for possible clear cell changes, looking for any seasonal variance. No clear association between the presence of eccrine clear cell change and any demographic or seasonal pattern was found. Specifically, there did not seem to be any significant association between diabetes and this histological finding. The prevalence of diabetes in cases with eccrine clear cell change was similar to the background population prevalence of diabetes in Australia (7.9% vs. 7.4%). The incidence of this finding is approximately 1 case in 189 specimens (0.5%) examined in this practice. Clear cell change within the secretory portion of eccrine glands seems to be an incidental finding, with no clear clinicopathological implication. In particular, there does not seem to be any association with diabetes.