Complete removal of individual dysplastic nevi (DN) is often accomplished by a second surgical procedure after the initial biopsy. The choice to perform the second procedure is strongly influenced by histopathologic margin status of the initial biopsy specimen.To evaluate the clinical and histopathologic outcomes of in toto biopsy of DN using a predetermined margin of normal skin.We conducted a prospective study of a saucerization method using a defined 2-mm margin in patients undergoing biopsy of a pigmented skin lesion.We performed 151 biopsies in 138 patients. Overall, 137 of 151 lesions subjected to biopsy (90.7%) were melanocytic: 86 DN (57.0%), 40 nevi without atypia (26.5%), and 11 melanomas (7.3%). Of 78 DN, 68 (87.2%) were removed with clear histopathologic margins (8 DN were excluded because of inadequate processing). There was no clinical evidence of recurrence at any of the biopsy sites that were simply observed (i.e., not re-excised) over a median of 16.9 months.There were few biopsies performed on the face.The complete histopathologic removal of nearly 9 of 10 DN using a peripheral margin of 2 mm of normal skin and a depth at the dermis and subcutaneous fat junction has the potential to decrease second procedures at DN biopsy sites, thereby decreasing patient morbidity and saving health care dollars.
Basal cell carcinoma (BCC) is the most commonly diagnosed malignancy worldwide. Fortunately, it is often diagnosed while still localized and can be effectively treated with simple excision or Mohs micrographic surgery. However, a subset of patients are diagnosed with locally advanced, metastatic, or recurrent disease. As our understanding of the molecular pathogenesis of BCC and the Hedgehog signaling pathway has increased, Hedgehog inhibitors such as vismodegib and sonidegib have been introduced to improve the survival rates in this patient population. However, even with these advances, a significant proportion of patients will not respond to current therapies and remain at risk of developing either resistance during therapy or disease recurrence. This review paper discusses currently approved therapies in the treatment of localized, locally advanced, and metastatic BCC and the possible contribution that immune checkpoint inhibitors might add to the treatment of this malignancy.
Leishmaniasis, a widely prevalent disease throughout tropical and subtropical regions of the world, is a chronic protozoan infection of humans and mammals that remains grossly underreported and causes significant global morbidity and mortality. Different species of the intracellular protozoan parasites of the genus Leishmania can cause human leishmaniasis, resulting in various visceral, cutaneous, and mucocutaneous manifestations. The risk of leishmaniasis manifesting as a more severe entity is dependent on the infecting parasites' immune evasion potential. Some causal associations between leishmaniasis and malignancy have been evidenced in experimental animals and humans. Leishmania spp. infection can play a significant, direct or indirect, role in the pathogenesis and prognosis of some malignant disorders through numerous pathophysiologic cascades. Aging, chronic ultraviolet radiation exposure, and popular treatment abuse (eg, chameleon saliva, cactus recipes, corrosive chemicals, and topical steroids) have been proposed as the principal triggering factors. Malignancy should be considered in the differential diagnosis of leishmaniasis in endemic regions, such as Yemen. Understanding this relationship could enrich the provision of early diagnosis, proper management, and prompt control of cancer.
Treatment strategies in metastatic melanoma have attempted to use the immune system to target cancer since the 1980s. Adoptive cell transfer using autologous tumor-infiltrating lymphocytes (TILs) extracted from a patient tumor and cultured in vitro was pioneered in the 1980s and has been developed over the past 30 years through multiple clinical trials. Infusion of ex vivo expanded TILs is performed after completion of nonmyeloablative chemotherapy administered to suppress host regulatory T cells. Systemic interleukin (IL)-2 is administered post-infusion to allow T-cell persistence and activation. Toxicities to treatment are primarily related to pre-infusion chemotherapy and IL-2. Clinical predictors of response to TIL have been assessed but factors have not been elucidated to select patients with high likelihood of response to treatment. Ongoing trials aim to minimize toxicities, guide patient selection, and improve rates and duration of response.
The goal of the present study was to assess the factors linked to the spread of malignant cutaneous melanoma to the lower limbs in patients without previously known or suspected primary or metastatic melanoma lesions in the lower extremities. We retrospectively reviewed 461 consecutive whole-body 2-(18F)fluoro-2-deoxy-d-glucose (18F-FDG) positron emission tomography with computed tomography (PET/CT) scans performed during a 5-year period for adult patients with histopathologically proven cutaneous primary melanoma but without previously known or suspected lower limb melanoma lesions. All PET/CT scans were correlated with the patient records covering a period of ≥ 6 months after study end, including detailed pathology reports and follow-up imaging results. Only 21 PET/CT scans (4.6%; 95% confidence interval, 3.00%-6.86%) showed lower limb lesions attributable to melanoma during the follow-up period, with most scans showing extensive metastases elsewhere. However, no scan revealed melanoma lesions solely in the lower extremities (0%; 95% confidence interval, 0%-0.83%). The time that had elapsed since primary lesion resection was significantly linked statistically to the spread of melanoma to the lower extremities (P = .03). The presence of metastatic regional lymph nodes during initial staging was also significantly linked statistically to lower limb melanoma lesions later in the disease course (P = .006). For adults with cutaneous melanoma but without previously known or suspected melanoma lesions in the lower extremities, metastatic spread to the lower limbs is infrequent. Thus, imaging can be stopped at the proximal thighs without affecting clinical management. More clinical attention should be devoted to the lower extremities as time passes and if metastases have been documented elsewhere.
Immunotherapy targeting the PD-1 negative regulatory pathway has revolutionized the treatment of melanoma. The median survival for metastatic melanoma has dramatically improved over the last 5 years, from 9 months to longer than 2 years. This improvement is largely the result of to the development of anti–PD-1 targeted immunotherapy. In melanoma, durable responses have now been observed lasting many years. The field of immune checkpoint therapy, or “cutting the brakes” on antitumor immune response, is rapidly evolving, and new challenges continue to emerge in the optimal clinical use of these drugs. We review the discovery and development of anti–PD-1 therapies and the clinical successes and difficulties that have manifested with widespread use. The emergence of autoimmune toxicities and their management is a critical area of study going forward, as these toxicities can often limit the utility of these therapies in patients who otherwise would benefit. Anti–PD-1 therapy has undoubtedly been the most dramatic shift in cancer therapy in this decade, with US Food and Drug Administration approvals in melanoma and over half a dozen other cancers. Large preclinical and clinical research efforts are now aimed at understanding the immune biology driving resistance to anti–PD-1 therapy in patients with tumors that do not respond. The future is bright, but rational approaches will be necessary to have the greatest impact on the lives of melanoma patients.
Inguinofemoral lymph node dissection is the standard of care for stage III melanoma of the lower extremity with regional lymph node metastasis. Seroma is one of the most common and burdensome postoperative complications after inguinofemoral lymph node dissection. Many measures have been taken to reduce the development of seroma, none with definite success. We reviewed the effects of TachoSil patch sealing on the formation of seroma. In the present prospective one-arm single-stage pilot study, 20 patients were scheduled to undergo inguinofemoral lymph node dissection (ILND) with TachoSil application and placement of a standard closed suction drain (CSD) to investigate the effects of TachoSil on the formation of seroma. The presence of seroma after a standard protocol, which included CSD removal 3 days after surgery and the number of aspirations after CSD removal were recorded. In addition, the number and severity of surgical site infections were recorded. A preplanned futility analysis after the inclusion of 11 patients showed that all patients developed postoperative seroma. The median number of aspirations after CSD removal was 3. This resulted in premature termination of the study. In addition, 10 of the 11 patients developed a surgical site infection. No evidence of a positive effect of TachoSil application on seroma formation after ILND was seen in the present study, and 10 of the 11 patients developed a surgical site infection. ILND remains a surgical procedure with a high incidence of postoperative complications, including seroma. New morbidity-reducing strategies are eagerly awaited, because the TachoSil patches do not seem to have a role in the management of seroma prevention after ILND.
Cutaneous surgery carries the risk of injury to nerves and other anatomical structures, which can cause significant morbidity. In this article we provide an overview of common pitfalls and ‘danger zones’ to be aware of during skin procedures, including how to identify and avoid specific key landmarks. General techniques such as positioning, lighting, preoperative marking, and appropriate use of local anesthesia can help to optimize surgical outcomes. Keloid scarring is most common on the neck and upper torso. The head and neck is a common site for skin lesions, but includes numerous danger zones. Nerve plexuses, joints, and flexor surfaces are other high-risk sites. Appropriate preparation and a detailed understanding of relevant surface anatomy are necessary for practitioners to perform safe cutaneous surgery.
Splenic marginal zone lymphoma (SMZL) is an extremely rare low-grade malignancy of the B-cells, comprising < 2% of all non-Hodgkin lymphoma (NHL). SMZL occurs at a median age of 65 years while the median survival has been recorded to be approximately 10.5 years. Clinically, it is associated with splenomegaly, moderate lymphocytosis and sometimes autoimmune thrombocytopenia and/or anemia; also cytopenias and are frequently observed.The pathogenesis of SMZL still remains unclear. Approximately 70–80% of cases have been reported to exhibit detectable cytogenetic and/or molecular genetic abnormalities. The most frequent cytogenetic abnormalities are deletions in 7q22–q32, followed by gain of chromosomes 3/3q, 5q, 9q, 12q and 20q, and deletion in 17p. Complex karyotypes are common: the most frequently involved chromosomes are 1, 3, 7, 8, and 14. However, the incidence of specific recurrent clonal cytogenetic abnormalities in SMZL has not been established yet.Bone marrow of a 78-year-old male patient with a 1 month history of umbilical abdominal pain, cough, pallor, vomiting, fever, pancytopenia, anemia and enhanced serum lactate dehydrogenase (LDH) level was studied by banding cytogenetics, refined by fluorescence in situ hybridization including array-proven multicolor banding. A complex karyotype involving, among others both chromosomes 13, was detected. An unbalanced translocation der(13)t(1;13)(q21;p11.2) led to partial trisomy of 1q21-qter and a dicentric dic(13)t(3;13)(p11.2;p11.2) caused partial trisomy of 3q11.2-qter. Besides there were inversion inv(1)(p12q12) and a balanced translocation t(9;14)(p13;q32.3) as yet unreported abnormalities in an adult SMZL case at diagnosis. The immunophenotype was consistent with marginal zone lymphoma according to World Health Organization (WHO) recommendations.To the best of our knowledge, a comparable adult SMZL case with complex karyotype, anemia and elevated LDH was not previously reported. Besides the involvement of yet unreported genetic regions in SMZL, also this case is one of the rare examples for a malignancy with a stable dicentric chromosome.
Immune checkpoint inhibitors (IO) have changed the landscape of treatment of advanced cancer. Substantial and durable responses may be experienced in patients who previously had few or no efficacious systemic treatment options available to them. IO are often well tolerated; however, uncontrolled and unexpected off-target effects can occur, resulting in wide-ranging and varied toxicities. This review discusses the current management of organ-specific IO-associated toxicity in metastatic melanoma, with a focus on skin toxicity, colitis, endocrinopathies, and IO-induced kidney injury. Furthermore, we describe the immunology behind IO-induced toxicity, propose improvements on current practice, and highlight areas in need of further research.
The use of immunotherapy in the form of monoclonal antibodies that target proteins involved in the modulation of the immune response, or checkpoints, is among the standard treatment options for patients with advanced melanoma. Ipilimumab, an anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) agent, was the first monoclonal antibody to be approved for clinical use as monotherapy to treat this disease. Significant advances were witnessed as a result of Programmed Death Receptor 1 (PD-1) blockade with pembrolizumab and nivolumab, agents that resulted in improved outcomes and reduced toxicity when compared with ipilimumab or cytotoxic chemotherapy. More recently, robust antitumor effect was demonstrated in the setting of combined CTLA-4 and PD-1 blockade with ipilimumab and nivolumab, albeit at a cost more pronounced in immune-related adverse events and unclear benefits in terms of overall survival in comparison to single-agent anti-PD-1 therapy. As a result, the optimal first-line therapy for patients with advanced melanoma remains debatable, and clearly not all patients are candidates for combined checkpoint blockade. In this review, we revisit the available literature that interrogated the efficacy of single-agent anti-PD-1 treatment and the combination of ipilimumab and nivolumab as well as aspects that may help guide treatment decisions in a scenario in which the standard of care remains unclear.
Paradoxical oncogenesis was observed as early as one decade ago with pan-RAF inhibitors. The list of proliferative disorders has become even longer with the advent of selective BRAF inhibitors and includes not only skin premalignancies and malignancies, but also various epithelial, melanocytic, and vascular benign proliferations and, even now, non-skin malignancies. From the experimental side, the findings from an increasing number of important studies support a widely accepted mechanistic model of paradoxical oncogenesis. In the present review, we discuss the extent to which this model can be used to understand the variety of BRAF inhibitor-induced proliferative disorders. We also discuss a wider clinical and mechanistic definition of the paradoxical response to BRAF inhibitors, its links to the adaptive resistance to BRAF inhibition in melanoma, and its consequences for upcoming therapeutic developments.
BackgroundMelanoma and Merkel Cell Carcinoma (MCC) are rare but aggressive skin cancers that (partly) share etiologies. Locoregional melanoma and MCC are managed with surgery, with or without post-operative radiotherapy. Patients with advanced melanoma and MCC are treated differently; targeted therapy and/or immunotherapy for melanoma and chemotherapy +/- immunotherapy for MCC. In this case series, we present patients with both malignancies, discuss treatment challenges and highlight the role of PD-1 inhibition in disease management.ResultsWe describe 8 patients (6 males) with a median age at diagnosis of 65 years for melanoma and 76 years for MCC. In 3 cases melanoma and MCC were diagnosed simultaneously, in others there was a significant time interval (14-30 years). In case of locoregional disease patients underwent local excision and/or lymph node dissection. One patient received adjuvant radiotherapy. Patients with distant melanoma metastases (n=2) were treated with immunotherapy (PD-1 inhibition), while patients with distant MCC metastases (n=2) received chemotherapy. In 3 cases we describe in detail, simultaneous occurrence of both malignancies and comorbidity presented a management challenge. Our strategy was to treat the most aggressive malignancy the most aggressively, while accounting for patients’ comorbidities.ConclusionsPatients with concurrent MCC and melanoma present a management challenge. By aggressively treating the malignancy with the greatest impact on survival first, both diseases can be managed. Recent trials show that PD-1 inhibition is a promising option for patients with metastatic MCC. This could prevent conflicts of treatment strategies in patients with advanced MCC and melanoma in the future.
In this study the effect of oxidative modification on micellar and drug delivery properties of copolymers of ethylene oxide (EO) and propylene oxide (PO) was investigated. Carboxylated trifunctional copolymers were synthesized in the reaction with chromium(VI) oxide. We found that carboxylation significantly improved the uniformity and stability of polymeric micelles by inhibiting the microphase transition. The cytotoxicity of copolymers was studied in relation to their aggregative state on two cell types (cancer line vs. primary fibroblasts). The accumulation of rhodamine 123 in neuroblastoma SH-SY5Y cells was dramatically increased in the presence of the oxidized block copolymer with the number of PO and EO units of 83.5 and 24.2, respectively. The copolymer was also tested as an enhancer for topical drug delivery to the spinal cord when applied subdurally. The oxidized copolymer facilitated the penetration of rhodamine 123 across spinal cord tissues and increased its intraspinal accumulation. These results show the potential of using oxidized EO/PO based polymers for non-invasive delivery of protective drugs after spinal cord injury.
High-risk cutaneous squamous cell carcinoma includes recurrent disease, a tumor diameter > 2 cm, T4 stage, perineural or lymphovascular invasion, tumor depth of ≥ 4 mm, and high-grade histologic features. All have been implicated in an increased risk of occult regional lymph node involvement. Among a large group of patients with nonmucosal, cutaneous squamous cell carcinoma seen at our center, 30 patients with high-risk inclusion criteria were prospectively evaluated to undergo wide local excision and sentinel lymph node mapping. With a median follow-up period of 56 months, 4 patients (13%) had regional lymph nodal involvement. The patients identified with lymph node-positive disease underwent adjuvant therapy. Five patients (17%), none of whom had nodal disease at diagnosis, developed locally recurrent disease requiring additional therapy. On multivariate analysis, a statistically significant correlation was found between the depth of tumor invasion and occult sentinel lymph node involvement. In the present prospective analysis, sentinel lymph node mapping resulted in upstaging in 13% of the patients. The tumor depth was independently associated with an increased risk of nodal involvement. Given the association between a depth of tumor invasion of ≥ 4 mm and occult nodal disease in cutaneous squamous cell carcinoma, sentinel lymph node mapping could be considered an integral part of surgical staging for patients with high-risk features.
The medial cortico-striatal-thalamo-cortical (CSTC) motor circuit is a core system that exerts control over interval timing and action. A common network generates these behaviors possibly owing to cellular coding of temporal and non-temporal information, which in turn promotes reconfiguration of functional connectivity in accord with behavioral goals. At the neuroanatomical level, support for flexible CSTC reconfiguration comes from studies of temporal illusions demonstrating that this system calibrates the experience of time through functional interactions with various context-sensitive brain regions. Revelations that CSTC effective connectivity is pivotal for context-dependent facets of voluntary actions, namely action planning, complement its role in predictive processes such as timing. These observations suggest that the CSTC is positioned to represent high-level information about ‘what to do’ and ‘when to do it’ by dynamically reconfiguring effective connectivity as circumstances arise.
Angiosarcomas represent a family of malignant vascular tumors arising from the endothelial lining of blood vessels. Vascular tumors arising in the chest wall are rare, and primary chest wall angiosarcomas (PACW) are even rarer. They have high propensity to metastasize to distant organs, but metastatic colonization of the skin by primary chest wall tumors has never been reported. Presented is a systematic review of the literature to identify cases of PACW reporting skin metastasis. A systematic review was conducted in accordance with PRISMA guidelines. A PubMed, Scopus, Web of Science, and manual search through references of relevant publications was used to identify all published case reports of PACW. Data extracted from each case included age, sex, symptomatology, immunohistochemistry markers, metastasis, management, follow-up, and outcome. The systematic review identified 9 publications reporting 11 cases of PACW. Mean age at presentation was 35 years (range, 8-84 years). Treatment strategies included surgical excision alone (n = 5), surgical excision and adjuvant radiotherapy and chemotherapy (n = 3), and radiotherapy and chemotherapy alone (n = 2). Death was the final outcome in 44.44% of patients. There was no report of cutaneous metastasis in any of the included cases; however, nonskin metastasis was reported in 2 cases. Based on this systematic review, there was no case found of PACW metastasizing to the skin.
Treatment of refractory, unresectable cutaneous squamous cell carcinoma presents a great challenge in head and neck oncology with poor prognosis. Prior case reports have shown off-label pembrolizumab, a programed cell death receptor antagonist, can be effective in unresectable cutaneous squamous cell carcinoma. Furthermore, prior reports have suggested enhanced efficacy when high mutational burden is present. In this study we present a severe case of unresectable cutaneous squamous cell carcinoma invading the orbit and cavernous sinus with documented tumor MLH1 mutation. The patient had a complete response to palliative, off-label pembrolizumab therapy.
Melanoma is the most aggressive form of skin cancer. Targeted antimelanoma therapies such as BRAF V600 inhibitors have shown spectacular results. However, these therapies are restricted to BRAF V600 mutated melanoma and display both adverse effects and resistance outbreaks. A high-content screening campaign identified compounds that displayed antimelanoma activities that can potentiate anti–BRAF V600 inhibitors. We identified ivermectin, a US Food and Drug Administration (FDA)-approved macrocyclic lactone widely used as an anthelmintic and insecticidal agent. Macrocyclic lactones possess in vitro cytotoxicity against either BRAF wild type (wt) or BRAF V600 mutated melanoma cells lines. Daily intraperitoneal injections of ivermectin strongly reduce pulmonary metastasis implantation in vivo in murine and melanoma models. Interestingly, these macrocyclic lactones are also able to trigger vemurafenib-dependent cytotoxicity in vitro in BRAF-wt melanoma cells, although vemurafenib action was thought to be restricted to melanoma bearing the BRAF V600 mutation. These macrocyclic lactones are also able to increase the in vitro antimelanoma activity of another BRAF V600 clinical inhibitor, dabrafenib. Serine/threonine p21-activated protein kinase 1 (PAK1) is the key target of ivermectin responsible for its antimelanoma activity. Ivermectin is a promising agent that could strongly increase melanoma therapy efficiency because it is cytotoxic for BRAF-wt and BRAF mutated melanomas and because it increases the efficiency of antimutated BRAF inhibitors independent of the BRAF status of tumors. Because ivermectin is FDA approved and a study of ivermectin would be able to include all patients in the same protocol, this combination treatment should be next investigated in clinical studies.
