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Orphanet Journal of Rare Diseases Jun 2024Extramammary Paget's disease (EMPD) is a rare cancer that occurs within the epithelium of the skin, arising predominantly in areas with high apocrine gland concentration...
BACKGROUND
Extramammary Paget's disease (EMPD) is a rare cancer that occurs within the epithelium of the skin, arising predominantly in areas with high apocrine gland concentration such as the vulva, scrotum, penis and perianal regions. Here, we aim to integrate clinicopathological data with genomic analysis of aggressive, rapidly-progressing de novo metastatic EMPD responding to HER2-directed treatment in combination with other agents, to attain a more comprehensive understanding of the disease landscape.
METHODS
Immunohistochemical staining on the scrotal wall tumor and bone marrow metastasis demonstrated HER2 overexpression. Whole genome sequencing of the tumor and matched blood was performed.
RESULTS
Notable copy number gains (logFC > 0.9) on chromosomes 7 and 8 were detected (n = 81), with 92.6% of these unique genes specifically located on chromosome 8. Prominent cancer-associated genes include ZNF703, HOOK3, DDHD2, LSM1, NSD3, ADAM9, BRF2, KAT6A and FGFR1. Interestingly, ERBB2 gene did not exhibit high copy number gain (logFC = 0.4) although 90% of tumor cells stained HER2-positive. Enrichment in pathways associated with transforming growth factor-beta (TGFβ) (FDR = 0.0376, Enrichment Ratio = 8.12) and fibroblast growth factor receptor (FGFR1) signaling (FDR = 0.0082, Enrichment Ratio = 2.3) was detected. Amplicon structure analysis revealed that this was a simple-linear amplification event.
CONCLUSION
Whole genome sequencing revealed the underlying copy number variation landscape in HER2-positive metastatic EMPD. The presence of alternative signalling pathways and genetic variants suggests potential interactions with HER2 signalling, which possibly contributed to the HER2 overexpression and observed response to HER2-directed therapy combined with other agents in a comprehensive treatment regimen.
Topics: Humans; Paget Disease, Extramammary; Whole Genome Sequencing; Male; Receptor, ErbB-2; Aged; DNA Copy Number Variations
PubMed: 38831459
DOI: 10.1186/s13023-024-03169-y -
Case Reports in Women's Health Jun 2024Angiomyofibroblastoma (AMFB) represents a rare, benign mesenchymal tumor with a predilection for the vulvovaginal region. It is usually diagnosed in middle-aged women....
Angiomyofibroblastoma (AMFB) represents a rare, benign mesenchymal tumor with a predilection for the vulvovaginal region. It is usually diagnosed in middle-aged women. Histopathology and immunohistochemical study remain the key to diagnosis. Like other benign mesenchymal vulval tumors, AMFB shows indolent behavior and rarely recurs after complete surgical excision. Herein, we present a case of vulvar AMFB in a 51-year-old woman to highlight the diagnostic difficulties when considering this rare entity.
PubMed: 38827183
DOI: 10.1016/j.crwh.2024.e00617 -
Experimental and Molecular Pathology Jun 2024Shallow whole genome sequencing (Shallow-seq) is used to determine the copy number aberrations (CNA) in tissue samples and circulating tumor DNA. However, costs of NGS...
BACKGROUND
Shallow whole genome sequencing (Shallow-seq) is used to determine the copy number aberrations (CNA) in tissue samples and circulating tumor DNA. However, costs of NGS and challenges of small biopsies ask for an alternative to the untargeted NGS approaches. The mFAST-SeqS approach, relying on LINE-1 repeat amplification, showed a good correlation with Shallow-seq to detect CNA in blood samples. In the present study, we evaluated whether mFAST-SeqS is suitable to assess CNA in small formalin-fixed paraffin-embedded (FFPE) tissue specimens, using vulva and anal HPV-related lesions.
METHODS
Seventy-two FFPE samples, including 36 control samples (19 vulva;17 anal) for threshold setting and 36 samples (24 vulva; 12 anal) for clinical evaluation, were analyzed by mFAST-SeqS. CNA in vulva and anal lesions were determined by calculating genome-wide and chromosome arm-specific z-scores in comparison with the respective control samples. Sixteen samples were also analyzed with the conventional Shallow-seq approach.
RESULTS
Genome-wide z-scores increased with the severity of disease, with highest values being found in cancers. In vulva samples median and inter quartile ranges [IQR] were 1[0-2] in normal tissues (n = 4), 3[1-7] in premalignant lesions (n = 9) and 21[13-48] in cancers (n = 10). In anal samples, median [IQR] were 0[0-1] in normal tissues (n = 4), 14[6-38] in premalignant lesions (n = 4) and 18[9-31] in cancers (n = 4). At threshold 4, all controls were CNA negative, while 8/13 premalignant lesions and 12/14 cancers were CNA positive. CNA captured by mFAST-SeqS were mostly also found by Shallow-seq.
CONCLUSION
mFAST-SeqS is easy to perform, requires less DNA and less sequencing reads reducing costs, thereby providing a good alternative for Shallow-seq to determine CNA in small FFPE samples.
Topics: Humans; Female; DNA Copy Number Variations; Paraffin Embedding; High-Throughput Nucleotide Sequencing; Formaldehyde; Tissue Fixation; Whole Genome Sequencing; Vulvar Neoplasms; Papillomavirus Infections; Anus Neoplasms
PubMed: 38820761
DOI: 10.1016/j.yexmp.2024.104906 -
Dermatology Practical & Conceptual Apr 2024
PubMed: 38810034
DOI: 10.5826/dpc.1402a72 -
SAGE Open Medical Case Reports 2024Birt-Hogg-Dubé syndrome, an extremely rare genetic disorder, is characterized by the development of fibrofolliculomas, lung cysts and subsequent recurrent pneumothorax,...
Birt-Hogg-Dubé syndrome, an extremely rare genetic disorder, is characterized by the development of fibrofolliculomas, lung cysts and subsequent recurrent pneumothorax, and kidney neoplasia. This report highlights the case of a 56-year-old female with a history of right vestibular schwannoma status post stereotactic radiotherapy and vulva bartholin's gland carcinoma who was initially evaluated by primary care for a 6-month history of intermittent, red, raised, widespread rash accompanied by fever, chills, and body aches. A punch biopsy of the rash was performed, which was notable for an urticarial tissue reaction with focal changes of leukocytoclasia and negative direct immunofluorescence. Laboratory tests, which included an autoimmune genetic and periodic fever panel, were unremarkable. Whole genome sequencing returned positive for a pathogenic variant in folliculin gene, consistent with a diagnosis of Birt-Hogg-Dubé syndrome.
PubMed: 38803360
DOI: 10.1177/2050313X241251759 -
Journal of Clinical Medicine May 2024: Data on the incidence and comorbidity of Lichen sclerosus (LS), based on validated nationwide population-based registries, remains scarce. : To explore the incidence...
: Data on the incidence and comorbidity of Lichen sclerosus (LS), based on validated nationwide population-based registries, remains scarce. : To explore the incidence and association of comorbidities with LS in Sweden, emphasizing its potential links to malignancies and autoimmune disorders. : A population-based retrospective open cohort study was conducted using the National Patient Register to identify all individuals diagnosed with LS (ICD-10 code L90.0) from 1 January 2001 to 1 January 2021. The study included 154,424 LS patients and a sex and age matched control group of 463,273 individuals to assess the incidence and odds ratios for various cancers and premalignant conditions. : The incidence of LS in Sweden was 80.9 per 100,000 person per year, with higher incidence in females (114.4) than in males (47.2). LS patients showed an increased odds ratio for vulvar cancer (OR = 8.3; 95% CI = 7.5-9.0), penile cancer (OR = 8.9; 95% CI = 7.3-11.0), prostate cancer (OR = 1.2; 95% CI = 1.1-1.2), testicular cancer (OR = 1.4; 95% CI = 1.1-1.7), bladder cancer (OR = 1.1; 95% CI = 1.1-1.2), breast cancer (OR = 1.4; 95% CI = 1.3-1.4), leukoplakia of the vulva (OR = 253.5; 95% CI = 221.9-289.6), and leukoplakia of the penis (OR = 5.1; 95% CI = 4.9-5.4). : This study underscores the significantly increased association of various cancers and premalignant conditions in LS patients, highlighting the critical need for efficacious treatment and diligent follow-up. The association between LS and autoimmune diseases further necessitates comprehensive investigation to understand the underlying mechanisms and clinical management implications. Future research is essential to confirm these findings and elucidate the role of LS in cancer development.
PubMed: 38792303
DOI: 10.3390/jcm13102761 -
Journal of Clinical Medicine May 2024Gender-affirming vaginoplasty (GAV) comprises the construction of a vulva and a neovaginal canal. Although technical nuances of vulvar construction vary between... (Review)
Review
Gender-affirming vaginoplasty (GAV) comprises the construction of a vulva and a neovaginal canal. Although technical nuances of vulvar construction vary between surgeons, vulvar construction is always performed using the homologous penile and scrotal tissues to construct the corresponding vulvar structures. Therefore, the main differentiating factor across gender-affirming vaginoplasty techniques is the tissue that is utilized to construct the neovaginal canal. These tissue types vary markedly in their availability, histology, and ease of harvest and have different advantages and disadvantages to their use as neovaginal lining. In this narrative review, the authors provide a comprehensive overview of the tissue types and associated operative approaches used for construction of the neovagina in GAV. Tissue choice is guided by several factors, such as histological similarity to natal vaginal mucosa, tissue availability, lubrication potential, additional donor site morbidity, and the specific goals of each patient. Skin is used to construct the neovagina in most cases with a combination of pedicled penile skin flaps and scrotal and extra-genital skin grafts. However, skin alternatives such as peritoneum and intestine are increasing in use. Peritoneum and intestine are emerging as options for primary vaginoplasty in cases of limited genital skin or revision vaginoplasty procedures. The increasing number of gender-affirming vaginoplasty procedures performed and the changing patient demographics from factors such as pubertal suppression have resulted in rapidly evolving indications for the use of these differing vaginoplasty techniques. This review sheds light on the use of less frequently utilized tissue types described for construction of the neovaginal canal, including mucosal tissues such as urethral and buccal mucosa, the tunica vaginalis, and dermal matrix allografts and xenografts. Although the body of evidence for each vaginoplasty technique is growing, there is a need for large prospective comparison studies of outcomes between these techniques and the tissue types used to line the neovaginal canal to better define indications and limitations.
PubMed: 38792302
DOI: 10.3390/jcm13102760 -
Nuklearmedizin. Nuclear Medicine May 2024The authors present a procedure guideline for scintigraphic detection of sentinel lymph nodes in malignant melanoma, in breast cancer, in penile and vulva tumors, in...
The authors present a procedure guideline for scintigraphic detection of sentinel lymph nodes in malignant melanoma, in breast cancer, in penile and vulva tumors, in head and neck cancer, and in prostate carcinoma. Important goals of sentinel lymph node scintigraphy comprise reduction of the extent of surgery, lower postoperative morbidity and optimization of histopathological examination focussing on relevant lymph nodes. Sentinel lymph node scintigraphy itself does not diagnose tumorous lymph node involvement and is not indicated when lymph node or distant metastases have been definitely diagnosed before sentinel lymph node scintigraphy. Procedures are compiled with the aim to reliably localise sentinel lymph nodes with a high detection rate typically in early tumour stages. New aspects in this guideline are new radiopharmaceuticals such as tilmanocept and Tc-99m-PSMA and SPECT/CT allowing an easier anatomical orientation. Initial dynamic lymphoscintigraphy in breast cancer is of little significance nowadays. Radiation exposure is low so that pregnancy is not a contraindication for sentinel lymph node scintigraphy. A one-day protocol should preferentially be used. Even with high volumes of scintigraphic sentinel lymph node procedures surgeons, theatre staff and pathologists receive a radiation exposure < 1 mSv/year so that they do not require occupational radiation surveillance. Aspects of quality control were included (scintigraphy, quality control of gamma probe, 6 h SLN course for surgeons, certified breast centers, medical surveillance center).
PubMed: 38788776
DOI: 10.1055/a-2319-8306 -
Medicine May 2024The human papillomavirus (HPV) belongs to the Papillomaviridae family of viruses which includes small, double-stranded DNA viral agents. Approximately 90% of HPV... (Review)
Review
The human papillomavirus (HPV) belongs to the Papillomaviridae family of viruses which includes small, double-stranded DNA viral agents. Approximately 90% of HPV infections occur asymptomatically and resolve spontaneously. However, infection with high-risk viral strains can lead to the development of preneoplastic lesions, with an increased propensity to become cancerous. The location of these malignancies includes the oral cavity, cervix, vagina, anus, and vulva, among others. The role of HPV in carcinogenesis has already been demonstrated for the aforementioned neoplasia. However, regarding skin malignancies, the mechanisms that pinpoint the role played by HPV in their initiation and progression still elude our sight. Until now, the only fully understood mechanism of viral cutaneous oncogenesis is that of human herpes virus 8 infection in Kaposi sarcoma. In the case of HPV infection, however, most data focus on the role that beta strains exhibit in the oncogenesis of cutaneous squamous cell carcinoma (cSCC), along with ultraviolet radiation (UVR) and other environmental or genetic factors. However, recent epidemiological investigations have highlighted that HPV could also trigger the onset of other non-melanocytic, for example, basal cell carcinoma (BCC), and/or melanocytic skin cancers, for example, melanoma. Herein, we provide an overview of the role played by HPV in benign and malignant skin lesions with a particular focus on the main epidemiological, pathophysiological, and molecular aspects delineating the involvement of HPV in skin cancers.
Topics: Humans; Skin Neoplasms; Papillomavirus Infections; Papillomaviridae; Carcinoma, Squamous Cell; Carcinoma, Basal Cell; Melanoma; Human Papillomavirus Viruses
PubMed: 38787972
DOI: 10.1097/MD.0000000000038202 -
BioRxiv : the Preprint Server For... May 2024Apical extracellular matrices (aECMs) are associated with all epithelia and form a protective layer against biotic and abiotic threats in the environment. Despite their...
Apical extracellular matrices (aECMs) are associated with all epithelia and form a protective layer against biotic and abiotic threats in the environment. Despite their importance, we lack a deep understanding of their structure and dynamics in development and disease. molting offers a powerful entry point to understanding developmentally programmed aECM remodeling. A transient matrix is formed in embryos and at the end of each larval stage, presumably to pattern the new cuticle. Focusing on targets of NHR-23, a key transcription factor which drives molting, we identified the Kunitz family protease inhibitor gene as an NHR-23 target. We identified NHR-23-binding sites that are necessary and sufficient for epithelial expression. is necessary to pattern every layer of the adult cuticle, suggesting a broad patterning role prior to the formation of the mature cuticle. MLT-11::mNeonGreen::3xFLAG transiently localized to the aECM in the cuticle and embryo. It was also detected in lining openings to the exterior (vulva, rectum, mouth). Reduction of function disrupted the barrier function of the cuticle. Tissue-specific RNAi suggested activity is primarily necessary in seam cells and we observed alae and seam cell fusion defects upon inactivation. Predicted null mutations caused fully penetrant embryonic lethality and elongation defects suggesting also plays an important role in patterning the embryonic sheath. Finally, we found that inactivation suppressed the blistered cuticle phenotype of mutants of mutants, a subtilisin protease gene but did not affect BLI-4::sfGFP expression. These data could suggest that MLT-11 may be necessary to assure proper levels of BLI-4 activity.
PubMed: 38766248
DOI: 10.1101/2024.05.12.593762