Median raphe cysts: A clinico-pathologic and immunohistochemical study of 52 cases.

BACKGROUND: Median raphe cysts (MRC) are epithelial-lined cystic lesions of the genital area that do not communicate with the urethra or the overlying epidermis. Immunohistochemically, MRC show positivity for cytokeratin (CK) 5-6, CK 7, carcinoembryonic antigen, p63 and uroplakin III (URO III). GATA3 and human milk fat globulin 1 (HMFG1) are immunohistochemical markers that have been not previously studied in MRC. METHODS: We conducted a study of 52 patients diagnosed with MRC in the Pathology Departments of eight hospitals between 1990 and 2016. The monoclonal antibodies used were CK5-6, CK7, CK20, URO III, p63, GATA3, and HMFG1. HMFG1 was studied in five cases of apocrine hidrocystomas and compared with five cases of MRC from our series. RESULTS: CK 5-6, CK7, and p63 expression showed strong positivity in the urothelial epithelium of 48 cases. CK20 was focally positive in areas of mucinous differentiation in three cases. GATA3 showed intense nuclear staining in 30 cases. HMFG1 was positive in three cases of MRC and in three cases of apocrine hidrocystoma. CONCLUSION: Positivity of GATA3 and CK7 in MRC supports the urothelial origin of these cysts. We found no differences in HMFG1 expression between MRC and apocrine hidrocystomas.

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.

Juvenile melanomas: Western Australian Melanoma Advisory Service experience.

BACKGROUND/OBJECTIVES: Juvenile melanoma (before 20 years of age) is a rare condition with poorly defined risk factors. We describe features of juvenile melanoma in Western Australia over the last two decades. METHOD: A retrospective review of juvenile melanomas was conducted from prospectively maintained databases, reviewed for patients' characteristics, clinical information, histology, treatment, recurrence and survival data. RESULTS: Altogether 95 cases of juvenile melanoma were reported to the Western Australian Cancer Registry between 2000 and 2013. Of these, 27 patients were referred to the Western Australian Melanoma Advisory Service. Over 72% were aged between 13 and 19 years. The most common site for primary melanoma was the head and neck (31.8%). Eight patients (36.4%) had a pre-existing naevus, 13.6% reported 1-5 blistering sunburns in the past and 59.1% had a Fitzpatrick skin grade of 3 or less. Most (88%) were diagnosed with a primary invasive lesion at presentation. Superficial spreading melanomas predominated (27.3%). All but one patient had localised disease at presentation, with six patients undergoing further treatment, including chemotherapy and neck dissection for metastases. At the time of review, two patients had died, due to stroke and metastatic disease. CONCLUSIONS: Juvenile melanoma remains a rarity in Western Australia despite a very high incidence of adult melanoma. Unlike in adults, no definitive risk factors have been established. A significant proportion of this cohort had a pre-existing naevus and while most melanomas occurred in sun-exposed areas in light-skinned individuals the association between sunburn and melanoma was not strong.

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.

Cutaneous presentation of cryptococcal infection with subclinical central nervous system involvement secondary to fingolimod therapy.

Fingolimod is a multiple sclerosis disease-modifying therapy which sequestrates lymphocytes in the lymph nodes, thereby reducing peripheral blood lymphocytes. Cryptococcal infection is an important adverse effect which should be recognised. We report a case of cutaneous and central nervous system infection who presented with isolated cutaneous symptoms in the absence of neurological or systemic manifestations.

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.

A peptide inhibitor of c-Jun promotes wound healing in a mouse full-thickness burn model.

Significant damage to tissue surrounding burn injuries occurs after the removal of the thermal source. This damage is caused by a combination of both necrotic and apoptotic cell death in the zone of stasis. Preserving the zone of stasis can reduce the wound size and thereby improve wound healing. We tested whether a peptide previously identified to inhibit necrotic and apoptotic cell death in neurons through c-Jun inhibition could enhance wound healing. We first tested the effects of this peptide on a keratinocyte and fibroblast cell line in culture. The peptide promoted proliferation of keratinocytes but had no effect on fibroblast proliferation, while the peptide also inhibited ultraviolet-induced apoptosis of keratinocytes. We finally tested the peptide in vivo, using a mouse model of burn injury. Wounds that were treated with the peptide reepithelialized faster than controls, while cell death surrounding the wound site was markedly reduced 24 hours postinjury, suggesting that the prevention of apoptosis as well as the proliferative effects of this peptide contribute to the wound healing process. Our data implicate c-Jun in multiple processes during wound repair and demonstrate that treatment of burn injuries using inhibitors of c-Jun dimerization at the time of injury can promote wound healing.

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.

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.