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.

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.

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.

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.

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.

Histologic mimics of perineural invasion.

BACKGROUND: Perineural invasion (PNI) by primary cutaneous cancers is an important adverse risk factor. Certain benign conditions may mimic microscopic PNI. Mohs surgery is being performed more frequently on smaller primary cutaneous malignancies. While PNI may be present in these cases, it is likely to be microscopic and asymptomatic, affecting as little as one cutaneous nerve branch. METHODS: Review of the literature base regarding PNI as well as contribution of original findings. RESULTS: Four benign entities that could easily be confused with microscopic PNI are presented. CONCLUSION: At least four benign mimics of microscopic PNI exist, important in the differential diagnosis of microscopic PNI. Knowledge of these entities should help dermatopathologists to correctly distinguish them from PNI and avoid unnecessary additional treatment.

Perineural invasion: identification, significance, and a standardized definition.

BACKGROUND: Mohs surgeons have expanded the range of cancers treated using the Mohs technique. Mohs surgeons today are expected to diagnose perineural invasion (PNI) when as little as one nerve is involved. OBJECTIVE: To address the issue of identification and significance of perineural invasion from the perspective of the Mohs surgeon. The experience of other medical specialties dealing with the same issue are reviewed and applied. METHODS AND MATERIALS: This article is based on a review of the entire medical literature regarding PNI. RESULTS: PNI is a significant complication of cancers, regardless of the organ of origin. The most common complication of PNI is recurrence of the cancer. Leptomeningeal carcinomatosis occurs in neglected or aggressive cancers. The process is indolent and contiguous, lending itself well to treatment with Mohs surgery. There are diagnostic mimics of PNI. Variation of reported incidences and cure rates suggest that diagnostic criteria for PNI may not be consistent from study to study. CONCLUSION: We propose the following definition for the minimum histopathologic criteria required to make a diagnosis of PNI: "In the presence of a malignancy, PNI may be diagnosed according to the observation of cytologically malignant cells in the perineural space of nerves. In equivocal cases, the observation of total or near-total circumferential involvement is supportive, as is the presence of perineural tracking in tangential sections and intraneural involvement."

Reparative perineural hyperplasia: a series of 10 cases.

Healing wounds are commonly examined by pathologists at the time of reexcision of skin tumors to ensure complete removal of the lesion. In addition to searching for residual tumor, possible perineural invasion must be assessed. During routine examination of reexcision specimens, 10 cases of prominent perineural proliferation were seen associated with fine nerves in the mid or deep dermis. The process showed a concentric cellular proliferation with no, or only limited, nuclear hyperchromasia or pleomorphism. In a number of cases, immunohistochemistry was essential to exclude the possibility of malignant perineural invasion or other mimics of this process such as reexcision perineural invasion. The term reparative perineural hyperplasia is proposed for this entity, which is important for pathologists to be aware of to avoid misdiagnosis.

CD117 is not a useful marker for diagnosing atypical fibroxanthoma.

Atypical fibroxanthoma (AFX) is a rare skin tumor that generally pursues an indolent course despite its alarming histological appearances. It is important for the pathologist to distinguish this neoplasm from more aggressive lesions that may show very similar histological features. Recently, it has been suggested that demonstration of CD117 is of value in identifying AFX. To test this hypothesis, 50 cases of AFX were stained immunohistochemically for CD117 to determine the diagnostic value of this antibody. Cases were also stained for tryptase to identify mast cells, which are CD117 positive. In addition, S100 and CD1a stains were performed to assess any possible contribution of melanocytes or Langerhans cells to CD117 staining. Only 1 of 50 AFXs (2%) showed CD117 positivity in the neoplastic cells, but all tumors demonstrated included CD117- and tryptase-positive mast cells in similar distribution. CD117 is only rarely stainable in the neoplastic cells of AFX and is therefore not useful in identifying these tumors. Mast cells are also CD117 positive, frequently present in AFX, and can lead to misinterpretation. Using immunohistochemistry for mast cell tryptase may be of value where there is doubt as to the nature of CD117-positive cells in neoplasms.

Mast cells have prognostic value in Merkel cell carcinoma.

We examined the role of mast cell infiltrates and other clinical and histological factors in the prognosis of Merkel cell carcinoma. Mast cells were stained immunohistochemically in 36 Merkel cell carcinomas with an antibody to tryptase. The number of stainable cells was quantified within the tumors and surrounding stroma. Other clinical and histological parameters were examined, statistically analyzed, and compared to subsequent clinical course and prognosis. Patient prognosis was worse with higher tumor mast cell numbers (P < 0.002). Prognosis was also found to be adversely affected by the presence of lymphovascular invasion (P = 0.03) and increased tumor size (P = 0.05). Increased mast cells counts, tumor size, and lymphovascular invasion are associated with an adverse prognosis in Merkel cell carcinomas. Evaluation of mast cell infiltrates may provide useful prognostic data and ultimately could assist in selecting patients that require adjuvant treatment in this aggressive form of skin cancer.

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.

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.