Indeterminate dendritic cell neoplasm of the skin: A 2-case report and review of the literature.

Indeterminate dendritic cell neoplasm (IDCN) is an exceedingly rare and mostly cutaneous histiocytosis, frequently associated with other hematopoietic malignancies. We report 2 cases of multilesional cutaneous IDCN. A 55-year-old male with no associated malignancy and complete response to ultraviolet phototherapy; and a 72-year-old male with chronic myelomonocytic leukemia (CMML). Both cases showed histiocytoid cytology, positivity for CD1a and no expression of langerin or BRAFV600E . With our patients, the literature describes 79 cases of IDCNs, including 65 (82%) with only skin involvement, 7 cases (9%) with involvement of skin and a second site, 5 cases (6%) involving lymph nodes only, 1 splenic lesion and 1 systemic disease. Seventeen cases (22%) were associated with other hematopoietic malignancies, most commonly CMML (6 cases), follicular lymphoma (4 cases) and acute myeloid leukemia (3 cases). All IDCNs associated with myeloid malignancies were limited to the skin, while most cases associated with lymphoma were limited to lymph nodes. Reported responses of cutaneous lesions to ultraviolet phototherapy are encouraging, while systemic chemotherapy is appropriate for clinically aggressive cases and treatment of associated malignancies. Recognition of the clinico-morphologic spectrum of IDCNs should prevent misdiagnoses and prompt investigation of possible associated neoplasms.

Basal Cell Skin Cancer, Version 1.2016, NCCN Clinical Practice Guidelines in Oncology.

Basal cell carcinoma (BCC) of the skin is the most common cancer, with a higher incidence than all other malignancies combined. Although it is rare to metastasize, patients with multiple or frequently recurring BCC can suffer substantial comorbidity and be difficult to manage. Assessment of risk is a key element of management needed to inform treatment selection. The overall management of BCC primarily consists of surgical approaches, with radiation therapy as an alternate or adjuvant option. Many superficial therapies for BCC have been explored and continue to be developed, including topicals, cryosurgery, and photodynamic therapy. Two hedgehog pathway inhibitors were recently approved by the FDA for systemic treatment of advanced and metastatic BCC, and others are in development. The NCCN Guidelines for Basal Cell Skin Cancer, published in full herein, include recommendations for selecting among the various surgical approaches based on patient-, lesion-, and disease-specific factors, as well as guidance on when to use radiation therapy, superficial therapies, and hedgehog pathway inhibitors.

Flow cytometric identification of immunophenotypically aberrant T-cell clusters on skin shave biopsy specimens from patients with mycosis fungoides.

OBJECTIVES: To assess the ability of flow cytometry (FC) to detect putative neoplastic T-cell subsets on skin shave biopsy (SSB) specimens from patients with mycosis fungoides (MF) and to study the immunophenotype of skin-infiltrating tumor cells in MF. METHODS: SSB specimens from patients with suspected MF were bisected and submitted for both FC and routine histopathology. Six-dimensional gating strategies were applied to identify putative neoplastic cells, independently from their expected immunophenotype. RESULTS: Aberrant T cells were detected by FC in 18 of 33 SBB specimens, of which all had clinicomorphologic features of MF. Of the remaining 15 SSB specimens, six had clinicomorphologic features of MF and nine were diagnosed with benign inflammatory dermatoses. Unexpectedly, CD26 was aberrantly overexpressed in 11 (73%) and lost in three (20%) of 15 SSB specimens from patients with MF where this antigen was evaluated. Other detected aberrancies included CD3 dim- (13/18 [72%]), CD7 dim- (15/18 [83%]), and CD4-/CD8- (3/18 [17%]). CONCLUSIONS: FC is capable of identifying putative neoplastic cells on SSB specimens from patients with MF. Bright homogeneous CD26 expression is a common and previously undescribed immunophenotypic aberrancy on MF skin infiltrates.

Dermatofibrosarcoma protuberans, version 1.2014.

Dermatofibrosarcoma protuberans (DFSP) is an uncommon soft tissue tumor characterized by a relatively high risk of local recurrence and low risk of metastasis. The NCCN Guidelines for DFSP provide multidisciplinary recommendations on the management of patients with this rare disease. These NCCN Guidelines Insights highlight the addition of the Principles of Pathology section, which provides recommendations on the pathologic assessment of DFSP. Because DFSP can mimic other lesions, immunohistochemical studies are often required to establish diagnosis. Cytogenetic testing for the characteristic translocation t(17;22)(q22;q13) can also be valuable in the differential diagnosis of DFSP with other histologically similar tumors.

Merkel cell carcinoma, version 1.2014.

Merkel cell carcinoma is a rare, aggressive cutaneous tumor that combines the local recurrence rates of infiltrative nonmelanoma skin cancer with the regional and distant metastatic rates of thick melanoma. The NCCN Guidelines for Merkel Cell Carcinoma provide recommendations on the diagnosis and management of this aggressive disease based on clinical evidence and expert consensus. This version includes revisions regarding the use of PET/CT imaging and the addition of a new section on the principles of pathology to provide guidance on the analysis, interpretation, and reporting of pathology results.

Unanswered questions in the management of stage I-III Merkel cell carcinoma.

Many unanswered questions remain about what constitutes appropriate guidelines for treatment of Merkel cell carcinoma (MCC). In this review, we address current uncertainty surrounding optimal management of MCC. These areas of uncertainty include early recognition features; clinical and histopathologic prognostic factors; optimum margins of excision of the primary tumor; indications for and value of surgical staging of the clinically negative regional nodes; optimum management of the patient with pathologically positive regional nodes; and indications for and value of radiation to the primary and regional nodes. Through identifying and elaborating on these areas of uncertainty, the authors hope to foster additional research and ultimately improve the evidence base for future iterations of the NCCN Clinical Practice Guidelines in Oncology in this rare but increasingly encountered cutaneous malignancy. The intent, however, is not to exhaustively identify all areas of controversy, but rather to highlight clinically relevant questions that further studies could address to improve the standard of care for MCC.

Quantitative flow cytometric identification of aberrant T cell clusters in erythrodermic cutaneous T cell lymphoma. Implications for staging and prognosis.

AIMS: Assessment of peripheral blood tumour burden for staging of cutaneous T cells lymphoma is most often accomplished by flow cytometry (FC) using various non-standarised strategies. We report the results of calculating absolute Sezary cell counts (SCCs) by FC, based on the identification of aberrant T cell clusters on a virtual 6-dimensional space and independently of the expected immunophenotype (6D-FC SCC). METHODS: 6D-FC SCCs were calculated on 65 peripheral blood specimens from 28 patients with erythrodermic cutaneous T cells lymphoma (stage III or IV). Comparisons were made with recommended FC strategies and correlations with overall mortality were studied. RESULTS: At first visit, 17 of 28 patients (61%) had 6D-FC SCCs meeting current criteria for Stage IV disease (≥1000 SC/µL); while only 2 patients (7%) met Stage IV criteria on other tissues. As defined by comprehensive staging using clinicomorphological criteria and 6D-FC SCCs, Stage IV disease identified a subgroup of patients with worse overall survival (p=0.0227). Residual non-aberrant CD4 T cells were markedly decreased in Stage IV disease (p=0.018). Among 65 specimens, discrepancies were observed between 6D-FC SCCs and usual FC thresholds for Stage IV disease, namely a CD4:CD8 ratio ≥10:1 (9 discrepancies, 14%), and ≥40% aberrant CD4 T cells (4 discrepancies, 6%). Surprisingly, 8 cases (12%) from 6 patients exhibited two distinctively separate clusters of aberrant CD4 T cells with different CD7 and/or CD26 expression. CONCLUSIONS: Visual 6-dimensional identification of aberrant T cell clusters by FC allows for the calculation of clinically significant SCCs. Simplified gating strategies and relative quantitative values might underestimate the immunophenotypical complexity of Sezary cells.

Composite hemangioendothelioma and its classification as a low-grade malignancy.

Hemangioendotheliomas are vascular neoplasms occupying a spectrum of biological potential ranging from benign to low-grade malignancy. Composite hemangioendothelioma (CH) is one of the less commonly encountered variants exhibiting a mixture of elements of other hemangioendothelioma subtypes, such as epithelioid, retiform, and spindle cell. Some authors have identified areas histopathologically equivalent to angiosarcoma within CH, raising the question of the true nature of this neoplasm. Although CH recurs locally, there are only 3 reported cases which metastasized. To date, 26 cases (including the present case) have been described in the literature. Herein, we describe a unique case of CH arising in the background of previous radiation therapy and long-standing lymphedema (classically associated with the development of angiosarcoma-Stewart-Treves syndrome) that harbored higher grade areas but behaved as a low-grade malignant neoplasm. This, in conjunction with the many reported cases of CH-harboring angiosarcoma-like areas, and the occasional association with a history of lymphedema, raises the question of whether this variant of hemangioendothelioma may actually be an angiosarcoma that behaves prognostically better than the conventional type. After careful study of the natural disease progression of the current case and review of the literature, we discuss justification for the continued classification of CH as a low-grade malignancy.

Targeted therapy in melanoma.

Since the discovery of activating mutations in the BRAF oncogene in melanoma, there has been remarkable progress in the development of targeted therapies for unresectable and metastatic melanoma. We review the latest developments in our understanding of the role of BRAF/MEK/ERK pathway signaling in melanoma, and the development of inhibitors of this pathway. We also explore alternative mutations seen in melanoma, such as NRAS, KIT, GNAQ, and GNA11, and the drug development that is ongoing based on this biology. Strategies for the management of the vexing clinical problem of BRAF inhibitor resistance, primarily via combination therapy, are outlined. With the recent approval of the BRAF inhibitor vemurafenib for stage IV metastatic melanoma, use of this agent is expanding in the United States. Thus, management of the skin toxicities of this agent, such as squamous cell carcinomas, "acneiform" eruptions, hand-foot syndrome, and panniculitis, will be a growing problem facing dermatologists today. We discuss the toxicities of targeted agents in use for melanoma, in particular the dermatologic effects and the management of these skin toxicities.

Proliferative activity, chromosomal aberrations, and tumor-specific mutations in the differential diagnosis between blue nevi and melanoma.

Blue nevi are a clinically and pathologically heterogeneous group of benign pigmented dermal melanocytic tumors that may exhibit histologic overlap with malignant melanoma. This study evaluates the role of immunohistochemical and molecular analyses in the classification and differential diagnosis between blue nevi and melanoma. Twenty-three dermal melanocytic tumors, initially diagnosed as benign or ambiguous, were subjected to immunohistochemical staining for phosphohistone H3 and MIB-1 to evaluate mitotic activity, comparative genomic hybridization to detect chromosomal aberrations, and GNAQ, GNA11, BRAF, NRAS, and KRAS sequencing. Of 19 patients with follow-up information (median, 1.6 years), 3 developed recurrent or metastatic disease. Nevertheless, 11 of the 19 patients with follow-up had <2 years of follow-up. Nine of 23 patients showed chromosomal aberrations, including all 3 patients with tumor recurrence or progression. There was no significant correlation between mutation status (P = 0.6) or mitotic rate (P = 0.3) and outcome. In conclusion, three of nine patients with chromosomal aberrations developed tumor recurrence or progression. Patients with histologically ambiguous dermal melanocytic proliferations that exhibit copy number aberrations should undergo careful clinical follow-up.

Primary cutaneous B-cell lymphomas: recent advances in diagnosis and management.

BACKGROUND: Primary cutaneous B-cell lymphoma (PCBCL) is a heterogeneous group of rare clonal B-cell lymphoproliferative disorders with distinct clinicopathologic features from more common nodal B-cell lymphomas. METHODS: We performed a systematic review of the relevant literature in the MEDLINE database and analyzed laboratory and clinical data. This review discusses the three most common types of PCBCL: primary cutaneous marginal zone lymphoma (PCMZL), primary cutaneous follicle-center lymphoma (PCFCL), and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT). RESULTS: Skin biopsies with histology, immunohistochemistry, and molecular clonality studies are essential for a correct diagnosis of cutaneous B-cell lymphoma. Comprehensive lymphoma staging with laboratory and imaging studies and bone marrow aspiration and biopsy are important for determining the prognosis and differentiation of PCBCL from secondary skin involvement with systemic B-cell lymphomas. PCMZL and PCFCL are low-grade PCBCLs, with an estimated 5-year disease-specific survival rate of greater than 95%. Surgical excision or focal radiation therapy is sufficient to control stages T1 and T2 disease. Rituximab monotherapy is frequently used for patients with stage T3 disease. PCDLBCL, LT is an intermediate-grade B-cell lymphoma, with a 5-year disease-specific survival rate of approximately 50%. An anthracycline-based chemotherapy regimen with rituximab is usually required as initial therapy to improve outcomes. CONCLUSIONS: In less than a decade, significant progress has been made in our understanding of PCBCL. Novel classification, staging, and prognostic systems have resulted in more accurate diagnosis and prognosis. Although no randomized prospective studies have been conducted in PCBCL, therapies derived from systemic B-cell lymphomas have shown promising results.

Advances in the chemoprevention of non-melanoma skin cancer in high-risk organ transplant recipients.

Patients with a history of more than four basal cell carcinomas (BCCs) or squamous cell carcinomas (SCCs) are at high risk for developing further skin cancers. Immunosuppressed patients, especially solid organ transplantation patients, harbor a higher risk of developing SCC. Systemic retinoids have been demonstrated to possess chemoprophylactic properties in the treatment of non-melanoma skin cancer. This article reviews the efficacies of the available oral retinoid agents in the chemoprophylaxis of SCCs in high-risk solid organ transplant recipients.

Recent advances in the management of cutaneous lymphomas.

The treatment options for patients with primary cutaneous B- and T-cell lymphomas are as diverse as the diseases themselves, including both skin-directed and systemic therapies. Long-term remission can be attained in many cases; however, no treatment is curative with the possible exception of allogeneic stem cell transplant. Improved insight into the molecular biology and pathophysiology of these diseases has led to the development of novel drugs and targeted therapies, including monoclonal antibodies and antimetabolites, as well as improved radiotherapeutic techniques. We aim to summarize these new and emerging treatment modalities, and to outline how they may be integrated into the clinical management of patients with primary cutaneous lymphoma (CL).

Case-control study of smoking and non-melanoma skin cancer.

OBJECTIVE: To investigate the association between cigarette smoking and basal and squamous cell carcinomas (BCC and SCC) of the skin, a clinic-based case-control study was conducted in Tampa, FL. METHODS: Patients with histologically confirmed BCC/SCC were recruited from a university dermatology clinic (n = 215 BCC, 165 SCC). Controls were comprised of individuals with no history of skin cancer who screened negative for skin cancer upon physical examination at the affiliated cancer screening or primary care clinics (n = 315). Information on smoking and other risk factors was obtained from self-administered questionnaires. RESULTS: After adjustment for age, sex, and other skin cancer-risk factors, ever smoking was not associated with BCC (odds ratio (OR) = 1.26, 95% confidence interval (CI) = 0.83-1.92), but was statistically significantly associated with SCC (OR = 1.97, 95% CI = 1.19-3.26), with significant trends observed for SCC associated with increasing cigarettes per day (p = 0.01) and pack-years smoked (p = 0.01). Among men, smoking ≥20 pack-years was associated with non-significant increased risks of BCC (OR = 1.90, 95% CI = 0.88-4.12) and SCC (OR = 1.97, 95% CI = 0.84-4.66), whereas among women, no association was observed with BCC (OR = 0.98, 95% CI = 0.39-2.46) while a statistically significant three-fold risk was observed with SCC (OR = 3.00, 95% CI = 1.02-8.80). CONCLUSION: Cigarette smoking is more strongly associated with SCC than BCC, particularly among women.

Mohs surgery for melanoma: rationale, advances and possibilities.

Mohs surgery (MS) is an effective technique for the removal of a variety of cutaneous neoplasms by virtue of its thorough assessment of margins. It has yet to become widely accepted for melanoma because recognizing melanocytes histologically in frozen section can be problematic. Recently, 'rapid' methods of immunohistochemistry have been developed that resolve this issue by staining the melanocytes in frozen section. In addition, some of the immunohistochemistry protocols that previously required up to 1 h now take 19 min or less. These technological enhancements for MS have removed some of the obstacles towards the acceptance of MS as a legitimate option for removal of melanomas, especially poorly demarcated lesions and lesions from the head and neck, the distal extremities and the genitalia. Experience thus far with MS for melanoma has shown lower recurrence rates and improved disease-specific survival compared with historical controls for standard excision, while at the same time minimizing the sacrifice of normal tissue.