M. Angelica Selim

Spitz nevi and atypical Spitz nevi/tumors: a histologic and immunohistochemical analysis

A subset of Spitz nevi poses substantial diagnostic difficulty, even among experts, due to its resemblance to malignant melanoma. These lesions are termed atypical Spitz nevi/tumors and there is currently a lack of objective criteria for predicting their biologic behavior. We compared the expression of Ki-67, p21, and fatty acid synthase by immunohistochemistry in 10 atypical Spitz nevi, 28 typical Spitz nevi, 19 compound melanocytic nevi and 18 invasive malignant melanomas. There was a progressive increase in fatty acid synthase cytoplasmic expression with statistically significant differences observed between Spitz nevi and atypical Spitz nevi (P=0.003) and between atypical Spitz nevi and malignant melanoma (P<0.050). Ki-67 nuclear staining was lower in both typical and atypical forms of Spitz lesions than in malignant melanoma (P<0.001). The degree of P21 nuclear expression in atypical Spitz nevi was not significantly different than in Spitz nevi, but was significantly greater than expression in conventional nevi and approached significance after multiple comparisons corrections for malignant melanoma. Thus, a high level of P21 expression makes a tumor more likely to be a typical or atypical Spitz nevus than a malignant melanoma, especially when coupled with a low Ki-67 index and weak expression of fatty acid synthase. These immunohistochemical observations support the concept that atypical Spitz nevi are distinct lesions of borderline biologic behavior residing between Spitz nevi and malignant melanoma. The study also compared a large array of histologic features of 16 cases of typical Spitz nevi in children with 12 typical Spitz nevi in adults. The adult lesions were significantly more likely to be intradermal and to display dermal fibroplasia, but were histologically similar to their pediatric counterparts in all other respects.

CD10 expression in trichoepithelioma and basal cell carcinoma

Background:  Trichoepithelioma (TE) is a benign neoplasm that shares both clinical and histologic features with basal cell carcinoma (BCC). However, it is important to distinguish these neoplasms. Limited immunohistochemical stains are available to separate these two tumors.

Cutaneous γδ T-cell lymphomas: a spectrum of presentations with overlap with other cytotoxic lymphomas.

We reviewed our multicenter experience with gamma-delta (&ggr;&dgr;) T-cell lymphomas first presenting in the skin. Fifty-three subjects with a median age of 61 years (range, 25 to 91 y) were diagnosed with this disorder. The median duration of the skin lesions at presentation was 1.25 years (range, 1 mo to 20 y). The most common presentation was deep plaques (38 cases) often resembling a panniculitis, followed by patches resembling psoriasis or mycosis fungoides (10 cases). These lesions tended to ulcerate overtime (27 cases). Single lesions or localized areas of involvement resembling cellulitis or pyoderma were reported in 8 cases. The most common anatomic site of involvement was the legs (40 cases), followed by the torso (30 cases) and arms (28 cases). Constitutional symptoms were reported in 54% (25/46) of the patients, including some with limited skin involvement. Significant comorbidities included autoimmunity (12 cases), other lymphoproliferative disorders (5 cases), internal carcinomas (4 cases), and viral hepatitis (2 cases). Lymphadenopathy (3/42 cases) and bone marrow involvement (5/28 cases) were uncommon, but serum lactose dehydrogenase (LDH) was elevated in 55% (22/39) of the patients. Abnormal positron emission tomography and/or computed tomography scans in 20/37 subjects mostly highlighted soft tissue or lymph nodes. Disease progression was associated with extensive ulcerated lesions resulting in 27 deaths including complications of hemophagocytic syndrome (4) and cerebral nervous system involvement (3). Median survival time from diagnosis was 31 months. Skin biopsies varied from a pagetoid pattern to purely dermal or panniculitic infiltrates composed of intermediate-sized lymphocytes with tissue evidence of cytotoxicity. The most common immunophenotype was CD3+/CD4−/CD5−/CD8−/BF1−/&ggr;-M1+/TIA-1+/granzyme-B+/CD45RA−/CD7−, and 4 cases were Epstein-Barr virus positive. This is the largest study to date of cutaneous &ggr;&dgr; T-cell lymphomas and demonstrates a variety of clinical and pathologic presentations with a predictable poor outcome.

Histopathologic characteristics, recurrence patterns, and survival of 129 patients with desmoplastic melanoma

BackgroundDesmoplastic melanoma (DM) has been associated with higher local recurrence rates than other types of cutaneous melanoma. Current controversies regarding locoregional treatment strategies warrant further investigation.MethodsRetrospective review of a prospectively maintained melanoma database identified 129 patients with DM out of >12,500 melanoma patients referred for treatment from 1980 to 2003. Clinical and histopathologic characteristics, recurrence, and survival were analyzed.ResultsThe median follow-up was 4.0 years. Of the 129 patients identified, 82 (63.6%) were male, and the median age was 55.2 years. American Joint Committee on Cancer staging was I, II, and III in 25.6%, 68.0%, and 6.4% of patients, respectively, and the mean tumor thickness was 4.42 mm. Overall survival was 76% at 5 years and 64% at 10 years; median survival was 13.0 years. A total of 51 patients (39.5%) experienced disease recurrence, with a median time to recurrence of 1.3 years. The first recurrence was local in 18 patients (14.0%), nodal in 18 patients (14.0%), and distant in 15 patients (11.6%), with median survivals of 6.7, 7.8, and 1.8 years, respectively. Statistically significant predictors of recurrence were a final positive margin status and stage, and predictors of overall survival were patient age and stage.ConclusionsCompared with other types of melanoma, DMs do demonstrate a tendency toward local recurrence, thus suggesting that narrower excision margins may not be appropriate in this population. Scrutiny of final surgical margins is critical to the local management of DM. In addition, the potential for regional nodal involvement must be considered at the time of diagnosis and during surveillance for disease recurrence.

Paget disease of the vulva: a study of 56 cases

OBJECTIVE To resolve controversial issues regarding vulvar Paget disease through analysis of a substantial number of cases. STUDY DESIGN The medical records and pathology slides of 56 patients with a diagnosis of vulvar Paget disease were reviewed. Possible correlation between clinical and pathological data was examined. RESULTS Most patients were Caucasian and their mean age at diagnosis was 69 years. The average length of follow-up was 5.6 years. The most common symptom was pruritus, almost always accompanied by erythematous-white plaques. Substantial delay between appearance of symptoms and diagnosis was observed in many patients, and was significantly associated with larger lesions. Recurrence rate after surgical management was 32%, with disease involving the perineum being the only statistically significant risk factor. Patients with positive surgical margins had an increased recurrence rate, but this was not statistically significant. Intra-operative frozen section analysis of the margins as well as radical surgery as initial treatment did not reduce recurrence rate. In general, stromal invasion was not associated with worse prognosis, but the single patient who died of disease had the deepest stromal invasion. Radiation therapy given to five patients who either had multiple positive surgical margins or experienced disease recurrence and refused additional surgery resulted in complete response with no further recurrences. On the last day of follow-up 24 patients (43%) had no evidence of disease, 24 patients (43%) were dead of other causes, 5 patients (9%) were alive with disease, 2 patients (3%) were lost to follow-up, and 1 (2%) died due to vulvar Paget disease with invasive adenocarcinoma. CONCLUSIONS Vulvar Paget disease only rarely results in a patients death, but long term follow-up is required, as recurrences are common and can be noted many years after the initial treatment.

Frontal fibrosing alopecia: A retrospective review of 19 patients seen at Duke University

BACKGROUND Frontal fibrosing alopecia (FFA) is a type of scarring hair loss primarily observed in postmenopausal women and characterized by fronto-tempero-parietal hairline recession, perifollicular erythema, and loss of eyebrows. The incidence is unknown, but the number of women presenting with this condition has significantly increased in recent years. No effective therapy has been established. OBJECTIVE The purpose of this study is to present pertinent demographic and clinical findings of patients with FFA seen at an academic hair loss clinic and their responses to various therapeutic interventions. METHODS Patients seen at the Duke University Hair Disorders Research and Treatment Center, Durham, NC, between 2004 and 2011 who met FFA inclusion criteria and signed an informed consent form for participation in the Duke University Hair Disorders Research and Treatment Center database were included in this review. RESULTS Nineteen female patients with FFA met our inclusion criteria, the majority of whom were white and postmenopausal. A number of treatments, including topical and intralesional steroids, antibiotics, and immunomodulators, were used with disappointing results in most patients. However, the majority of patients on dutasteride experienced disease stabilization. LIMITATIONS This was a retrospective review and outside clinic records were occasionally incomplete. CONCLUSIONS FFA is an increasingly common form of scarring hair loss, but the origin remains unknown. Without clear understanding of the pathogenesis and evolution of this condition, it is not surprising that treatments to date have been minimally or not effective. At our institution, dutasteride was most effective in halting disease progression, although no therapy was associated with significant hair regrowth.

Sorafenib, a Multikinase Inhibitor, Enhances the Response of Melanoma to Regional Chemotherapy

Melanoma responds poorly to standard chemotherapy due to its intrinsic chemoresistance. Multiple genetic and molecular defects, including an activating mutation in the BRaf kinase gene, are associated with melanoma, and the resulting alterations in signal transduction pathways regulating proliferation and apoptosis are thought to contribute to its chemoresistance. Sorafenib, a multikinase inhibitor that targets BRaf kinase, is Food and Drug Administration approved for use in advanced renal cell and hepatocellular carcinomas. Although sorafenib has shown little promise as a single agent in melanoma patients, recent clinical trials suggest that, when combined with chemotherapy, it may have more benefit. We evaluated the ability of sorafenib to augment the cytotoxic effects of melphalan, a regional chemotherapeutic agent, and temozolomide, used in systemic and regional treatment of melanoma, on a panel of 24 human melanoma-derived cell lines and in an animal model of melanoma. Marked differences in response to 10 μmol/L sorafenib alone were observed in vitro across cell lines. Response to sorafenib significantly correlated with extracellular signal-regulated kinase (ERK) downregulation and loss of Mcl-1 expression (P < 0.05). Experiments with the mitogen-activated protein kinase/ERK kinase inhibitor U0126 suggest a unique role for ERK downregulation in the observed effects. Sorafenib in combination with melphalan or temozolomide led to significantly improved responses in vitro (P < 0.05). In the animal model of melanoma, sorafenib in combination with regional melphalan or regional temozolomide was more effective than either treatment alone in slowing tumor growth. These results show that sorafenib in combination with chemotherapy provides a novel approach to enhance chemotherapeutic efficacy in the regional treatment of in-transit melanoma. Mol Cancer Ther; 9(7); 2090–101. ©2010 AACR.

CD34 expression in desmoplastic melanoma.

Background: Primary and metastatic malignant melanoma can simulate various soft tissue tumors, including dermatofibrosarcoma protuberans (DFSP). Expression of CD34, a marker characteristic of DFSP, as well as other spindle cell tumors, has not been previously documented in malignant melanoma.

Defining regional infusion treatment strategies for extremity melanoma: Comparative analysis of melphalan and temozolomide as regional chemotherapeutic agents

Five different human melanoma xenografts were used in a xenograft model of extremity melanoma to evaluate the variability of tumor response to regionally administered melphalan or temozolomide and to determine if various components of pertinent drug resistance pathways for melphalan [glutathione S-transferase (GST)/glutathione] and temozolomide [O6-alkylguanine DNA alkyltranferase (AGT)/mismatch repair (MMR)] could be predictive of tumor response. Xenograft-bearing rats underwent regional isolated limb infusion with either melphalan (90 mg/kg) or temozolomide (2,000 mg/kg). The levels of AGT activity, GST activity, glutathione level, and GST/AGT expression were examined in this group of xenografts and found to be quite heterogeneous. No correlation was identified between melphalan sensitivity and the GST/glutathione cellular detoxification pathway. In contrast, a strong correlation between the levels of AGT activity and percentage increase in tumor volume on day 30 (r = 0.88) was noted for tumors treated with temozolomide. Regional therapy with temozolomide was more effective when compared with melphalan for the xenograft with the lowest AGT activity, whereas melphalan was more effective than temozolomide in another xenograft that had the highest AGT activity. In three other xenografts, there was no significant difference in response between the two chemotherapy agents. This study shows that AGT activity may be useful in predicting the utility of temozolomide-based regional therapy for advanced extremity melanoma tumors. Our observations also point out the limited ability of analysis of the GST/glutathione pathway to predict response to chemotherapies like melphalan whose resistance is primarily mediated through a complex mechanism of detoxification. [Mol Cancer Ther 2007;6(5):1492–500]

Pediatric melanoma: a single-institution experience of 150 patients

PURPOSE Differentiating pigmented skin lesions from malignant melanoma in the pediatric population has been a challenge. Despite guidelines describing clinical features and histopathologic criteria to distinguish these lesions, misdiagnoses still occur. We report our experience over 30 years in a pediatric population with malignant melanoma. METHODS We performed a retrospective review of 150 pediatric patients treated for malignant melanoma between 1973 and 2007 at our institution. Outcomes measured included age, Breslow thickness, Clark level of invasion, tumor location, local and distant failure rates, and overall survival. RESULTS One hundred fifty pediatric patients were evaluated. The mean age was 15.1 years. The mean Breslow thickness was 2.05 mm and corresponding Clark level of invasion was 3.47. There were 43 known recurrences (29%); 29 distant, 14 nodal, and 7 local. Overall survival was 84% with a mean follow-up of 8.5 years. Sixteen patients (10.7%) were incorrectly diagnosed on initial pathologic examination. Overall survival in the misdiagnosed group was 66%. CONCLUSION Pigmented skin lesions in the pediatric population represent a diagnostic challenge to pathologists and clinicians. Improvements in diagnostic techniques with rigorous characterization, as well as increased physician awareness, should lead to a reduction in errors of diagnosis.