Trevor W. Beer

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.

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.

Vascular density has prognostic value in Merkel cell carcinoma.

Merkel cell carcinomas are aggressive tumours for which histological prognostic factors need to be established. This study examines the prognostic role of vascular density, based on CD34 immunohistochemical staining in Merkel cell carcinoma. Thirty-six cases of Merkel cell carcinoma were immunohistochemically stained for the endothelial marker CD34. Vascular density was assessed in the tumor and stroma with a Chalkley eyepiece graticule. The scores of vascular density were correlated with other clinical and histological parameters to determine the prognostic significance of tumor vascularity. Increased vascular density was shown to be significantly associated with a worse prognosis (P = 0.005). A 1-unit increase in total vessel score was associated with a 3.9 times increase in the risk of death (95% hazard ratio confidence limits 1.50-10.32). Other factors associated with a worse outcome included tumor size (P = 0.05), the presence of lymphovascular invasion (P = 0.03), and tumor mast cell count (P < 0.002). Increased vascular density is associated with a worse prognosis in Merkel cell carcinomas. Assessment of vascular density may assist in predicting clinical behavior in these tumors and in evaluating the effects of adjuvant therapy.

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.

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.

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

Summary 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.

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 (&kgr; = 0.61–0.80) for Clark level, mitotic rate, completeness of excision and neurotropism; moderate concordance (&kgr; = 0.41–0.60) for vascular invasion, regression, predominant cell type and histological type; and only slight concordance (&kgr; = 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%, &kgr; = 0.79). Lowest concordance was found for stage 1b (91.3%, &kgr; = 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.

CD117 in atypical fibroxanthoma: tumor or stroma?

To the Editor: Mathew et al reported in the February edition of this journal that 15 of 16 atypical fibroxanthomas (AFXs) studied were CD117 positive. This could potentially be helpful in identifying AFXs, although there are some confounding factors. Other tumors may be CD117 positive (including leiomyosarcoma and Merkel cell carcinoma). CD117 also stains mast cells, melanocytes, and various types of epithelia and in some cases Langerhans cells. In the article by Mathew et al Figures 2 and 3 demonstrate evenly spaced dendritic cells with strong positive staining for CD117. These cells are present between unstained adjacent cells, which are present in greater number. The positively stained cells do not show the degree of atypia seen in Figure 1. The fine dendritic processes present in some of these cells are reminiscent of Langerhans cells or mast cells, and I wonder if at least some of these cells are in fact Langerhans cells and mast cells. It is stated that there were CD117-positive mast cells in the tumor, but how were these differentiated from CD117-positive tumor cells, particularly when many of the cells illustrated in Figure 3 appear bland and could represent mast cells. Tissue mast cells on immunohistochemistry often show an elongated to dendritic morphology. S100 was reported as negative in all the tumors, but it would be surprising if no cells at all were positive. It is frequent to see some included positive cells in AFXs that may be a combination of melanocytes, Langerhans cells, or cells of unknown lineage. In fact, AFX frequently shows large numbers of Langerhans cells. Eleven of 12 AFXs studied by Ricci et al showed Langerhans cells on immunohistochemistry or electron microscopy. Although in most cases Langerhans cells comprised 5% or less of the cells in the tumor, focally they formed up to 80% of the cells. Birbeck-like granules have also been noted in a further case of FIGURE 1. This AFX showed large numbers of Langerhans cells which were CD1a and S100 positive. Before CD1a was performed, the case had been misdiagnosed as melanoma. Immunohistochemical stain for CD1a.

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.