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Chinese Clinical Oncology Apr 2021Tracers and corresponding detection devices for the mapping of sentinel lymph nodes have been evolving since the first use of lymphangiogram methods in 1977 in penile... (Review)
Review
Tracers and corresponding detection devices for the mapping of sentinel lymph nodes have been evolving since the first use of lymphangiogram methods in 1977 in penile carcinoma. Nowadays a variety of dyes and radiotracers have been validated for use in breast, vulvar and cervical cancer as well as melanoma. Each tumor site with its anatomical conditions requires different mapping protocol. While the combination of radiotracer and blue dye or radiotracer alone is an established method for breast surgery, vulvar cancer and melanoma, in pelvic sentinel lymph node mapping indocyanine green is currently gaining popularity. Near infrared fluorescence imaging is an emerging technique that enables a real-time image-guided procedure and is currently approved by the Food and Drug Administration as a sentinel lymph node mapping substance with standard of care. New tracers and devices are constantly under investigation to better understand the pathway of lymphatic drainage and increase the sensibility and sensitivity of the method. In the present review the evolution of available tracers and detection devices is discussed. An exhaustive review of current clinical indications of each method, its particularities and adverse effects is made. Finally, an update on ongoing clinical studies in sentinel lymph node mapping methods is presented.
Topics: Colloids; Coloring Agents; Female; Humans; Lymph Nodes; Lymphatic Metastasis; Radiopharmaceuticals; Sentinel Lymph Node Biopsy; Technetium
PubMed: 33951916
DOI: 10.21037/cco-20-252 -
Modern Pathology : An Official Journal... Dec 2022Though uncommon in melanoma, gene fusions may have therapeutic implications. Next generation sequencing-based clinical assays, designed to detect relevant gene fusions,...
Though uncommon in melanoma, gene fusions may have therapeutic implications. Next generation sequencing-based clinical assays, designed to detect relevant gene fusions, mutations, and copy number changes, were performed on 750 melanomas (375 primary and 375 metastases) at our institution from 2014-2021. These included 599 (80%) cutaneous, 38 (5%) acral, 11 (1.5%) anorectal, 23 (3%) sinonasal, 27 (3.6%) eye (uveal/ conjunctiva), 11 (1.5%) genital (vulva/penile), and 41 (5.5%) melanomas of unknown primary. Sixteen fusions (2%) were detected in samples from 16 patients: 12/599 (2%) cutaneous, 2/38 (5%) acral, 1/9 (11%) vulva, 1/23(4.3%) sinonasal; and 12/16 (75%) fusions were potentially targetable. We identified two novel rearrangements: NAGS::MAST2 and NOTCH1::GNB1; and two fusions that have been reported in other malignancies but not in melanoma: CANT1::ETV4 (prostate cancer) and CCDC6::RET (thyroid cancer). Additional fusions, previously reported in melanoma, included: EML4::ALK, MLPH::ALK, AGAP3::BRAF, AGK::BRAF, CDH3::BRAF, CCT8::BRAF, DIP2B::BRAF, EFNB1::RAF1, LRCH3::RAF1, MAP4::RAF1, RUFY1::RAF1, and ADCY2::TERT. Fusion positive melanomas harbored recurrent alterations in TERT and CDKN2A, among others. Gene fusions were exceedingly rare (0.2%) in BRAF/RAS/NF1-mutant tumors and were detected in 5.6% of triple wild-type melanomas. Interestingly, gene rearrangements were significantly enriched within the subset of triple wild-type melanomas that harbor TERT promoter mutations (18% versus 2%, p < 0.0001). Thirteen (81%) patients were treated with immunotherapy for metastatic disease or in the adjuvant setting. Six of 12 (50%) patients with potentially actionable fusions progressed on immunotherapy, and 3/6 (50%) were treated with targeted agents (ALK and MEK inhibitors), 2 off-label and 1 as part of a clinical trial. One patient with an AGAP3::BRAF fusion positive melanoma experienced a 30-month long response to trametinib. We show that, detecting fusions, especially in triple wild-type melanomas with TERT promoter mutations, may have a clinically significant impact in patients with advanced disease who have failed front-line immunotherapy.
Topics: Male; Female; Humans; Proto-Oncogene Proteins B-raf; Melanoma; Gene Fusion; Mutation; Receptor Protein-Tyrosine Kinases; Nerve Tissue Proteins
PubMed: 35871080
DOI: 10.1038/s41379-022-01138-z -
Gynecologic Oncology Apr 2021To identify clinicopathological characteristics, treatment patterns, clinical outcomes and prognostic factors in patients with vulvar melanoma (VM).
OBJECTIVE
To identify clinicopathological characteristics, treatment patterns, clinical outcomes and prognostic factors in patients with vulvar melanoma (VM).
MATERIALS & METHODS
This retrospective multicentre cohort study included 198 women with VM treated in eight cancer centres in the Netherlands and UK between 1990 and 2017. Clinicopathological features, treatment, recurrence, and survival data were collected. Overall and recurrence-free survival was estimated with the Kaplan-Meier method. Prognostic parameters were identified with multivariable Cox regression analysis.
RESULTS
The majority of patients (75.8%) had localized disease at diagnosis. VM was significantly associated with high-risk clinicopathological features, including age, tumour thickness, ulceration, positive resection margins and involved lymph nodes. Overall survival was 48% (95% CI 40-56%) and 31% (95% CI 23-39%) after 2 and 5 years respectively and did not improve in patients diagnosed after 2010 compared to patients diagnosed between 1990 and 2009. Recurrence occurred in 66.7% of patients, of which two-third was non-local. In multivariable analysis, age and tumour size were independent prognostic factors for worse survival. Prognostic factors for recurrence were tumour size and tumour type. Only the minority of patients were treated with immuno- or targeted therapy.
CONCLUSION
Our results show that even clinically early-stage VM is an aggressive disease associated with poor clinical outcome due to distant metastases. Further investigation into the genomic landscape and the immune microenvironment in VM may pave the way to novel therapies to improve clinical outcomes in these aggressive tumours. Clinical trials with immunotherapy or targeted therapy in patients with high-risk, advanced or metastatic disease are highly needed.
Topics: Aged; Cohort Studies; Disease-Free Survival; Female; Humans; Immune Checkpoint Inhibitors; Melanoma; Middle Aged; Molecular Targeted Therapy; Neoplasm Staging; Netherlands; Prognosis; Retrospective Studies; Survival Rate; United Kingdom; Vulvar Neoplasms
PubMed: 33514483
DOI: 10.1016/j.ygyno.2021.01.018 -
Cancer Communications (London, England) Jun 2018Although the most commonly recommended treatment for melanoma and extramammary Paget's disease (EMPD) of the genital region is wide surgical excision of the lesion, the... (Clinical Trial)
Clinical Trial
BACKGROUND
Although the most commonly recommended treatment for melanoma and extramammary Paget's disease (EMPD) of the genital region is wide surgical excision of the lesion, the procedure is highly invasive and can lead to functional and sexual problems. Alternative treatments have been used for local control when wide local excision was not feasible. Here, we describe four patients with genital malignancies who were treated with boron neutron capture therapy (BNCT).
METHODS
The four patients included one patient with vulvar melanoma (VM) and three with genital EMPD. They underwent BNCT at the Kyoto University Research Reactor between 2005 and 2014 using para-boronophenylalanine as the boron delivery agent. They were irradiated with an epithermal neutron beam between the curative tumor dose and the tolerable skin/mucosal doses.
RESULTS
All patients showed similar tumor and normal tissue responses following BNCT and achieved complete responses within 6 months. The most severe normal tissue response was moderate skin erosion during the first 2 months, which diminished gradually thereafter. Dysuria or contact pain persisted for 2 months and resolved completely by 4 months.
CONCLUSIONS
Treating VM and EMPD with BNCT resulted in complete local tumor control. Based on our clinical experience, we conclude that BNCT is a promising treatment for primary VM and EMPD of the genital region. Trial registration numbers UMIN000005124.
Topics: Aged; Boron Neutron Capture Therapy; Female; Humans; Male; Melanoma; Paget Disease, Extramammary; Penile Neoplasms; Radiotherapy Dosage; Skin Neoplasms; Time Factors; Treatment Outcome; Vulvar Neoplasms; Melanoma, Cutaneous Malignant
PubMed: 29914570
DOI: 10.1186/s40880-018-0297-9 -
Vestnik Rossiiskoi Akademii... 2016Melanoma is one of the most aggressive human malignant tumors. Its incidence and mortality are growing steadily. Ultraviolet irradiation is the main risk factor for... (Review)
Review
Melanoma is one of the most aggressive human malignant tumors. Its incidence and mortality are growing steadily. Ultraviolet irradiation is the main risk factor for melanoma involved in melanomagenesis. The probability of viral etiology of melanoma has been discussed. Human papillomaviruses (HPV) have been mentioned among candidates for its etiologic agents because some HPV types are the powerful carcinogens causing cervical cancer and other cancers. The review analyses the literature data on the association of melanoma with HPV Several groupsfound HPVin skin melanomas as well as in mucosa; viruses of high oncogenic risk were detected in some cases. For some organs the etiological role of high-risk HPV as inducers of invasive carcinomas is confirmed. These organs require special mention: cervix uteri, vulva, vagina, penis, anal region, and oral cavity. However in the majority of the studies in which viral DNA-positive melanomas were found, testing for viral genome expression was not done while this is the fact of primary importance. HPVare found in normal skin and mucous membranes thus creating justifiable threat of tumor specimen contamination with viral DNA in vivo. There are limited data on aggravation of the disease prognosis in papillomavirus-positive melanomas. However, any systematic observation of a sizeable patient group distinguished by that tumor type has not been performed yet. Viral E6 and E7 oncogenes of high-risk papillomaviruses were shown to be able to transform normal human melanocytes in vitro experiments. Thus, we can assume the presence of the association of melanoma with oncogenic HPV. The clinical significance of this problem is indisputable under the conditions of the steady increase in melanoma incidence and mortality rates in Russia and abroad. The problem requires further study.
Topics: DNA, Viral; Humans; Melanoma; Papillomaviridae; Papillomavirus E7 Proteins
PubMed: 27522713
DOI: 10.15690/vramn654 -
Seminars in Diagnostic Pathology Jan 2021Malignancies of the vulva in the pediatric population are exceptionally rare, which makes it difficult to gain any insight into their clinicopathologic profile. In this... (Review)
Review
Malignancies of the vulva in the pediatric population are exceptionally rare, which makes it difficult to gain any insight into their clinicopathologic profile. In this review, we summarize all published cases of a vulva malignancy in pediatric patients (≤21 years) reported in the English language literature for the 50-year period between 1970 and 2020. We estimate that less than 100 malignancies have been reported in total, approximately 50% of which were rhabdomyosarcomas. Invasive squamous cell carcinomas, yolk sac tumors, Ewing sarcoma/primitive neuroectodermal tumors (ES/PNET) and melanomas each represented approximately 10% of reported cases. For rhabdomyosarcoma, the alveolar and embryonal subtypes were reported with equal frequency, with both representing 70% of cases combined. The average patient age was 9.8 years. 48% and 35% were Intergroup Rhabdomyosarcoma Study clinical groupings I and III respectively. Managements were generally multimodal, and overall outcomes for the group were favorable. For invasive squamous cell carcinoma, the patients were all in their teenage years, with an average age at diagnosis of 15.2 years. A small subset of cases were associated with human papillomavirus and immunosuppression, and it is possible that immunosuppression has a role in vulvar squamous carcinogenesis in this population. One case was associated with lichen sclerosus. The patients with yolk sac tumors ranged in age from less than 1 year to 20 years (mean 12) and 67% of cases were stage I at presentation. An insufficient number of cases have been reported to define their prognosis, although some cases were notably aggressive. The few reported cases of melanoma are distinctive only because they were all associated with lichen sclerosus, suggestive of some role for the latter in their pathogenesis. The average age of patients reported with ES/PNET was 15 years (range 3.3 to 20). At least half of the reported cases were advanced stage at presentation, and patient outcomes were notably poor: 62.5% were dead of disease at follow-up. Pediatric vulvar malignancies are rare and are mostly comprised of 5 entities. Their accurate pathologic classification is necessary to facilitate optimal management.
Topics: Adolescent; Carcinoma, Squamous Cell; Child; Child, Preschool; Endodermal Sinus Tumor; Female; Humans; Infant; Lichen Sclerosus et Atrophicus; Melanoma; Neuroectodermal Tumors, Primitive; Pediatrics; Rhabdomyosarcoma; Vulva; Vulvar Neoplasms; Young Adult
PubMed: 32943238
DOI: 10.1053/j.semdp.2020.09.001 -
Dermatologic Surgery : Official... May 2021
Review
Topics: Aged; Female; Humans; Melanoma; Mohs Surgery; Skin Neoplasms; Vulvar Neoplasms
PubMed: 33905396
DOI: 10.1097/DSS.0000000000002907 -
Sentinel Node Methods in Penile Cancer - a Historical Perspective on Development of Modern Concepts.Seminars in Nuclear Medicine Jul 2022Malignant penile tumors are of squamous cell origin in more than 95% of cases and the occurrence of a distant metastasis without prior inguinal lymph node metastatic... (Review)
Review
Malignant penile tumors are of squamous cell origin in more than 95% of cases and the occurrence of a distant metastasis without prior inguinal lymph node metastatic deposits is very rare. This makes inguinal lymph node staging very reliable and of great prognostic significance since undiscovered and untreated inguinal metastases may lead to a fatal clinical course. In lack of a sufficiently accurate noninvasive lymph node staging modality, penile cancer relies on surgical lymph node removal for regional staging. In this respect sentinel node biopsy offers a favourable minimally invasive alternative to prophylactic inguinal lymph node dissection which is associated with significant surgery-related morbidity. Today sentinel node biopsy is widely used in surgical oncology within high volume cancers such as breast cancer and melanoma. In rare cancers sentinel node biopsy is also emerging as a minimal invasive staging tool in patients with no obvious lymph node involvement. At several specialized units across Europe sentinel node biopsy has been practiced by dedicated specialist within vulva and penile cancer for more than two decades. In fact, the rare disease penile cancer was a model entity for development of the original sentinel node concept as early as the 1970'es due to work by the Paraguayan penile cancer pioneer, Cabañas, the sentinel node concept was subsequently successfully adapted in breast cancer and melanoma. This turned out mutually beneficial since the sequential development of sentinel node biopsy in penile cancer in the 1990s eventually adopted new insights and added conceptual details from the experiences harvested in the broader clinical application possible in these high-volume diseases. The prerequisite to conceptualising the sentinel node approach was the gradual anatomical and functional understanding of the lymphatic system which in western medicine rooted in ancient Greece and gradually increased in details and comprehension with significant contributions from many great notabilities during the last centuries including Hippocrates, Galen, Fallopio, Malpighi, Virchow, Starling, Cabañas, Hodgkin and Horenblas. Sentinel node biopsy in penile cancer is a complex multimodality procedure involving inguinal ultrasonography by radiologists, precise tracer-injection and interpretation of nuclear images by nuclear medicine physicians, radio-tracer- and dye guided open surgical biopsies by urologists and thorough step-sectioning, immunostaining and accurate lymph node specimen analysis by pathologists. This team effort requires well-tested protocols, experience and good collaboration and in rare diseases this calls for centralization of service.
Topics: Breast Neoplasms; Female; Humans; Lymphatic Metastasis; Male; Melanoma; Neoplasm Staging; Penile Neoplasms; Sentinel Lymph Node Biopsy
PubMed: 34933740
DOI: 10.1053/j.semnuclmed.2021.11.010 -
Gynecologic Oncology Nov 2017Melanoma originating from gynecologic sites (MOGS), including the vulva, vagina, and cervix, is a rare and aggressive form of melanoma with poor long-term clinical...
OBJECTIVE
Melanoma originating from gynecologic sites (MOGS), including the vulva, vagina, and cervix, is a rare and aggressive form of melanoma with poor long-term clinical outcome. The clinicopathologic features of vulvar and non-vulvar tumors remain relatively understudied, and in contrast to cutaneous melanomas at non-sun-exposed sites, MOGS typically do not harbor BRAF mutations. Thus, we sought to analyze the clinicopathologic and molecular features of MOGS.
METHODS
A large retrospective cohort of patients with MOGS (n=59) at a single large academic institution over a 28-year period was identified. Associations among clinicopathologic characteristics were assessed via standard statistical approaches, and clinical outcome was examined using Cox regression analysis. Sanger sequencing was utilized to identify mutations in hotspot regions of BRAF, KIT, NRAS, and CTNNB1.
RESULTS
Tumors involving the vagina and/or cervix (non-vulvar) are significantly associated with high-risk clinicopathologic features, including increased tumor thickness, ulceration, positive resection margins, lymph node metastasis, and poor long-term clinical outcome (with increased risk of death due to disease). The aggressive clinical behavior of non-vulvar tumors is independent of advanced clinical stage and lymph node metastasis in multivariate analysis. Targeted molecular analysis confirms an overall low rate of oncogenic mutations in our MOGS cohort, although KIT mutations (particularly in exon 11) are relatively enriched.
CONCLUSIONS
Overall, our results show that non-vulvar MOGS are aggressive tumors with poor long-term clinical outcome and indicate that few targeted therapeutic options are currently available to patients with MOGS.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Cohort Studies; Female; GTP Phosphohydrolases; Genital Neoplasms, Female; Humans; Melanoma; Membrane Proteins; Middle Aged; Mutation; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-kit; Retrospective Studies; Young Adult; beta Catenin
PubMed: 28844540
DOI: 10.1016/j.ygyno.2017.08.023 -
Epidemiology and Molecular Profile of Mucosal Melanoma: A Population-Based Study in Southern Europe.Cancers Feb 2022Mucosal melanoma is a rare neoplasm on which few epidemiological population-based studies have been published. A good surgical approach is the standard treatment, but...
BACKGROUND
Mucosal melanoma is a rare neoplasm on which few epidemiological population-based studies have been published. A good surgical approach is the standard treatment, but the prognosis is worse than that of skin melanoma. The analysis of mucosal melanoma's mutational profile can help to develop target therapies in advanced disease or adjuvant settings.
METHODS
We analyzed the database of the Cancer Registry of Girona, a region located in the north-east of Spain, in the period of 1994-2018. We selected cases of primary invasive melanoma, excluding those located in the skin, eye, central nervous system and an unknown primary site. Epidemiological analysis included incidence and survival. Mutational profile analysis was performed with a custom gene panel.
RESULTS
Forty-two patients were identified: 14 (33%) had vulvar-vaginal melanoma, 15 (35.7%) had rectal melanoma, 12 (28.6%) had melanoma located in the head and neck sphere and 1 male patient had a urethral melanoma. European age-standardized incidence rates for vulvar-vaginal, rectal and head and neck melanoma were 0.09, 0.1 and 0.09 cases/100,000 inhabitant-years, respectively. Five-year observed survival rates were 37.5%, 20% and 25% for these types of cancers. NRAS Q61 was the most frequent mutation found.
CONCLUSION
Our study confirms the steady incidence and low survival of mucosal melanomas in a region of southern Europe. NRAS and NF1 play a role in the molecular landscape of mucosal melanoma. MEK and PI3K/mTOR inhibitors could be reasonable treatment options and are being studied in clinical trials.
PubMed: 35159047
DOI: 10.3390/cancers14030780