Melanoma trials that defined surgical management.

Treatment of regional lymph nodes in melanoma has been controversial for more than a century. A series of clinical trials evaluating elective lymph node dissection and then sentinel lymph node biopsy have helped define the current standard of care. These trials resulted in increasingly selective application of surgical intervention for regional lymph nodes in melanoma. First by focusing on optimal candidates for elective lymph node dissection and then by identifying patients through sentinel lymph node biopsy. The current standard of sentinel lymph node biopsy for appropriately selected patients and nodal observation for many patients, even with involved sentinel nodes is both more accurate in staging and much less morbid than what came before.

Melanoma trials that defined surgical management: Overview of trials that established NCCN margin guidelines.

Since the observation that clearance of all visible and microscopic tumors from cutaneous melanoma is critical to prevent a recurrence, wide surgical margins have been central to surgical dogma. In the last several decades, more conservative margin widths have been vigorously studied by surgical investigators to lessen wound complications, the need for reconstruction, and healthcare costs. This review summarizes surgeon-led clinical trials that define current guidelines and highlights the challenges to initiate and perform trials today.

Spatiotemporal trends of the global burden of melanoma in 204 countries and territories from 1990 to 2019: Results from the 2019 global burden of disease study.

This study aimed to estimate the latest magnitudes and temporal trends of melanoma burden at the national, regional, and global levels. The data on melanoma incidence, deaths, and disability-adjusted life-years (DALYs) in 204 countries and territories between 1990 and 2019 came from the Global Burden of Disease 2019 Study. Estimated annual percentage change (EAPC) was calculated to depict the temporal trends and Spearman rank correlation was used to analyze the influential factors of EAPC. From 1990 to 2019, the incident cases of melanoma increased by 170% to 289,950, death increased by 90% to 62,840, and DALYs increased by 67% to 1,707,800 globally. The age-standardized incidence rate (ASIR) of melanoma increased globally by an average of 1.13 [95% confidence interval (CI): 0.93-1.32], while the age-standardized rates of death and DALYs both declined with the EAPC of -0.27 (95% CI: -0.36 to -0.19) and -0.49 (95% CI: -0.57 to -0.41). In 2019, the highest burden of melanoma was observed in Australasia, followed by high-income North America and Europe regions, which all presented an incremental growth in ASIR. The positive association between the EAPC in ASIR and socio-demographic index (SDI) in 2019 (ρ = 0.600, P < 0.001) suggested that countries with higher SDI have experienced a more rapid increase in ASIR of melanoma. In conclusion, the burden of melanoma is increasing globally but differed greatly across the world. Notably, the high burden areas are facing a continuing increase in incidence, which implies more targeted strategies should be taken for reducing the increasing melanoma burden.

State of Melanoma: An Historic Overview of a Field in Transition.

The management of melanoma significantly improved within the last 25 years. Chemotherapy was the first approved systemic therapeutic approach and resulted in a median overall of survival less than 1 year, without survival improvement in phase III trials. High-dose interferon α2b and IL-2 were introduced for resectable high-risk and advanced disease, respectively, resulting in improved survival and response rates. The anti-CTLA4 and anti-programmed death 1 monoclonal antibodies along with BRAF/MEK targeted therapies are the dominant therapeutic classes of agent for melanoma. This article provides an historic overview of the evolution of melanoma management.

From Breslow to BRAF and immunotherapy: evolving concepts in melanoma pathogenesis and disease progression and their implications for changing management over the last 50 years.

Since it was first recognized as a disease entity more than two centuries ago, advanced melanoma has, until recently, followed a very aggressive and almost universally fatal clinical course. However, over the past 50 years crucial ground breaking research has greatly enhanced our understanding of the etiology, risk factors, genomic pathogenesis, immunological interactions, prognostic features and management of melanoma. It is this combined body of work which has culminated in the exciting improvements in patient outcomes for those with advanced melanoma over the last ten years. In this the 50th anniversary of Human Pathology, we highlight the key developments in melanoma over this period.

Modifications of Callender's Classification of Uveal Melanoma at the Armed Forces Institute of Pathology.

One hundred well-documented cases of uveal melanoma accessioned at the Armed Forces Institute of Pathology before 1970 were reviewed and reclassified to identify changes made in the Callender classification. We compared the new classification with the original classification to determine the effect of the changes on the prediction of outcome for the patient after enucleation. Staff pathologists had originally classified 52 of the 100 cases as spindle-cell type melanoma. Only 31 of the 100 cases were reclassified as spindle-cell types (two spindle-cell nevi and 29 spindle-cell melanomas). Tumors classified as mixed-cell type were further subdivided into groups based on the percentage and size of the epithelioid cells. Tumors formerly classified as spindle-cell type that contained small or rare epithelioid cells were reclassified as mixed-cell type. This improved the prediction of outcome for the patient. We found that nucleolar size and pleomorphism are important variables that should be considered in the classification of uveal melanomas.

Detection of melanoma metastases with the sentinel node biopsy: the legacy of Donald L. Morton, MD (1934-2014).

Dr. Donald L. Morton was clearly the pioneer of the sentinel node biopsy, which was a major advance in oncology that has improved the management of cancer patients worldwide. He conducted a series of practice-changing clinical trials to validate the important staging role of the sentinel lymph node biopsy for melanoma, and also spawned other studies that demonstrated its staging value in multiple other cancer types, most notably in breast cancer, gastric cancer, and colorectal cancer. His many contributions in this field have provided a unique opportunity to study host/tumor relationships, since the sentinel lymph node is the first location were the host immune defenses are confronted with metastasis arising from the primary cancer.

Higher than reported adolescent and young adult clinical trial enrollment during the "Golden Age" of melanoma clinical trials.

Clinical trial enrollments in adolescents and young adults (AYA) with cancer have historically been lower than those in pediatric and older adult populations. We sought to examine therapeutic trial enrollment rates at our cancer center. We performed a retrospective evaluation of AYA patients treated before and after the first checkpoint inhibitor trial opened at our cancer center in 2007. We examined gender, stage at presentation and insurance status in terms of trial enrollment. We compared the trial participation rate of AYA patients with that of older adults. In this adult facility, 12.7% (1,831) of total patients were between age 15 and 39. Overall therapeutic clinical trial rate was 17.6% which increased to 19.8% since 2007. Both nodal disease or metastatic disease at presentation was associated with increasing odds of trial enrollment (OR = 5.36 and P < 0.001 for nodal disease and OR = 7.96 and P < 0.001 for metastatic disease). There was a nonstatistically significant trend toward improved 3-year overall survival in the AYA patients with advanced presentation that enrolled on clinical trials compared with those not enrolled on trials since 2007. AYA clinical trial enrollment at a comprehensive care center melanoma program was higher than reported in the literature overall for AYA patients. This 1,831 patient cohort may provide a foundation for more detailed investigation toward quantifying the effects of clinical trial enrollment in terms of age-specific benefits and toxicities for AYA patients with malignancies that have their peak incidence in older adults.

The first description of the complete natural history of uveal melanoma by two Scottish surgeons, Allan Burns and James Wardrop.

James Wardrop (1782-1869), a young Scottish surgeon and an early ophthalmologist in Edinburgh, is credited for describing in 1809 retinoblastoma as an entity in his treatise 'Observations on Fungus Haematodes or Soft Cancer'. His treatise also reveals that Allan Burns (1781-1813), another young Scottish surgeon and anatomist, had invited Wardrop to assist in enucleating an eye from a 41-year-old Glasgow woman who, in retrospect, had a uveal melanoma. Her eye had become blind 4 months after symptoms of exudative retinal detachment had appeared, and it had become painful after a further 2-4 months. The tumour eventually perforated the sclera, and she died within a year thereafter of hepatic metastases. Burns and Wardrop went on to publish detailed parallel accounts of the symptoms, signs, ophthalmic pathology and post-mortem findings regarding the primary, recurrent and metastatic tumour. Burns may have performed the post-mortem after exhuming the body, a common occurrence in early 19th Century Scotland, a thriving hub for teaching morbid anatomy to young surgeons at the time.

Survival of cutaneous melanoma based on sex, age, and stage in the United States, 1992-2011.

Women diagnosed with cutaneous melanoma have a survival advantage compared to men, which has been hypothesized to be due to difference in behavior and/or biology (sex hormones). It remains controversial whether this advantage is dependent on age or stage of disease. We sought to compare melanoma-specific survival between females in pre, peri, and postmenopausal age groups to males in the same age group, adjusting for stage of disease. This is a retrospective population-based cohort study using the Surveillance, Epidemiology, and End Results (SEER) database. Patients diagnosed from 1 January 1992 through 31 January 2011 with primary invasive cutaneous melanoma were included in our cohort. Melanoma-specific survival was the main outcome studied. Of the 106,511 subjects that were included, 45% were female. Females in all age groups (18-45, 46-54, and ≥55) with localized and regional disease, were less likely to die from melanoma compared to males in the same age group. Among patients with localized and regional disease, the relative risk of death due to melanoma increased with advancing age at diagnosis; this increase was more pronounced among females than males. In contrast, we observed no female survival advantage among patients with distant disease and no effect of age on relative risk of death from melanoma. Females with localized and regional melanoma have a decreased risk of death compared to males within all age groups. Our data show no differences in survival between men and women with metastatic melanoma, indicating that the influence of sex on survival is limited to early stage disease but not confined to pre or perimenopausal age groups.

Laennec's melanosis: The first published description of metastatic melanoma.

Melanomas are a common skin condition in Australia. The authors decided to examine the history of melanomas and its metastases with particular reference to the description of Laennec and the controversy between him and his teacher Dupuytren, who challenged his pupil as to who was the first to describe melanomatous metastases to the lungs. The rivalry between teacher and student continued, with each describing a similar system of pathological classification.

René-Théophile-Hyacinthe Laennec (1781-1826) and the description of metastatic pulmonary melanoma.

In 19th century, the anatomo-clinical school of Paris linked clinical signs with anatomical lesions establishing clinical medicine. One of the most enlightened promoters of this method was the French physician René-Théophile-Hyacinthe Laennec, known as the inventor of stethoscope. In our article, we reveal his work on pulmonary melanoma.