Dermal Invasion Research Articles

Identification of two molecularly and prognostically distinct subtypes in acral melanoma using network prediction method.

Acral melanoma, characterized by its aggressiveness and poor prognosis compared to other melanoma subtypes, poses significant challenges in clinical management. However, the molecular underpinnings driving the biological and clinical features of this disease remain poorly understood. In this study, our aim was to elucidate the molecular landscape and the correlation between subtypes and clinical features of acral melanoma. We conducted comprehensive analyses to dissect the molecular characteristics of acral melanoma, employing a combination of multi-omics data analysis and network-based disease gene prediction algorithms. Single-cell RNA-Seq data were utilized to investigate the contribution of immunocytes to the molecular classification of acral melanoma. Additionally, we used clinical samples to validate the correlation between new subtypes and the prognosis of acral melanoma and the expression of subtype markers and verified the interaction between macrophages and acral melanoma cells at cellular level. Our study reveals the existence of two distinct subtypes of acral melanoma exhibiting marked differences in clinical behaviour, cellular and molecular mechanisms. We identified a robust biomarker panel (EREG, VSIG4, FCGR3A and RAB20) that accurately distinguishes these two subtypes with an impressive AUC of 0.946, validated using clinical samples. Subtype I, characterized by thinner Breslow thickness, demonstrates a favourable prognosis, whereas Subtype II represents a high-risk subtype with a propensity for dermal invasion. Notably, the signature gene EREG of Subtype I is enriched in FCN1+ macrophages, known for promoting inflammatory and immune responses. Conversely, signature genes VSIG4 and FCGR3A of Subtype II are enriched in SPP1+ macrophages, which exhibit significant crosstalk with tumour cells. Our findings significantly enhance the understanding of the molecular landscape of acral melanoma and offer novel insights into its clinical management by identifying distinct subtypes and potential therapeutic targets. The findings have to be confirmed in different cohorts in the future for full validation.

Rare Intravascular Involvement of Pleomorphic Dermal Sarcoma Seen During Mohs Micrographic Surgery.

Pleomorphic dermal sarcoma (PDS) and atypical fibroxanthoma (AFX) are rare mesenchymal tumors that share similar clinical, histological, and immunohistochemical characteristics. Careful histopathological examination of a biopsy specimen that includes subcutaneous fat remains the preferred way to differentiate between these tumors. AFX is limited to dermal invasion, whereas PDS demonstrates deeper invasion. Moreover, PDS may present with tumor necrosis and high-grade histological findings, such as lymphovascular and perineural invasion, features absent in AFX. However, like PDS, AFX is a diagnosis of exclusion, and an exhaustive immunohistochemistry panel is recommended to distinguish these tumors from other spindled cell tumors in the differential diagnosis. The authors present the case of an 86-year-old man with biopsy-suspected AFX who was referred for Mohs micrographic surgery for tumor excision. During Mohs, the tumor was observed to have invaded deeply into the subcutaneous tissue and galeal aponeurosis, aligning more closely with a PDS. The diagnosis of PDS was confirmed using en face processing during Mohs surgery, which captured the intravascular involvement of a solitary vessel. Differentiating between PDS and AFX is important because PDS is a more aggressive tumor, with a higher rate of local recurrence and metastasis, and requires closer monitoring.

Lentigo maligna: a comprehensive review on diagnosis and treatment.

Lentigo maligna (LM), a form of melanoma in situ, and LM melanoma (LMM), its invasive counterpart, exhibit distinctive epidemiology, risk factors, and clinical features compared to other melanoma subtypes. Notably, LM occurs on chronically sun-damaged skin presenting as a slow-growing, ill-defined patch which makes it difficult to diagnose and to treat. Additionally, while LM generally presents a favourable prognosis, it can also lead to dermal invasion and behave similarly to other melanomas with the same Breslow thickness. Hence, surgery continues to be the cornerstone treatment. Wide excisions are often necessary, but challenges arise when these lesions manifest in cosmetically sensitive regions, limiting the feasibility and desirability of large excisions. Specialized approaches, including margin-controlled surgery and image-guided treatment with reflectance confocal microscopy, have been developed to address these issues. Other non-surgical treatments such as cryosurgery, imiquimod, radiotherapy, or photodynamic therapy, may also be used but commonly present with recurrent/persistent disease. Herein we comprehensively review the existing literature on the management of LM/LMM, and discus the potential new advances on managing this challenging skin cancer.

Genomic progression for local invasion of cutaneous squamous cell carcinoma from the superficial to the deep portion.

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer. While many treatments exist, our understanding of its genomic progression, especially from the epidermis to the deep dermis, remains limited. This study aims to identify genetic mutations associated with the progression of cSCC into the deep dermis, providing insights into its aggressive behavior and high-risk features. We performed high-depth whole-exome sequencing on 12 cSCC tissues, along with paired normal tissues from six patients, using microdissection techniques. The mutational analysis focused on identifying alterations enriched during cSCC progression. Gene Ontology enrichment analysis, immunohistochemical assays, and external single-cell RNA data were utilized for validation. A total of 8863 non-synonymous somatic mutations were identified in 4092 genes across the superficial and deep portions of cSCCs. Analysis of deep portion mutations revealed a significant correlation with gene ontology biological processes, particularly cell junction organization, and cell-cell adhesion. Clonal mutations in these processes were more prevalent in the deep portions, indicating their impact on the cSCC mutation landscape. Genetic evolution analysis identified 29 causal genes associated with dermal invasion in cSCC. We highlight somatic mutations in cSCC, revealing heterogeneity between superficial and deep regions. Altered genes in cell junction organization and cell-cell adhesion emerged as pivotal in dermal invasion. We identified 29 causal genes primarily in deep tumor regions. Our findings emphasize analyzing multiple tumor regions to capture varied mutational landscapes. These insights advance our understanding of cSCC progression, emphasizing genetic and cellular changes during tumor evolution.

The 2-tier grading system identifies canine cutaneous and/or subcutaneous mast cell tumors with aggressive biological behavior regardless of growth model.

Histologic grading of canine cutaneous mast cell tumors (cMCTs) has prognostic and therapeutic implications, yet validation for subcutaneous MCTs (scMCTs) is lacking. For scMCTs with or without dermal invasion, determining their biological behavior remains poorly standardized and sometimes sparks controversy. This prospective study aimed to assess the prognostic utility of the 2-tier histologic grading system in MCTs with different growth models (GMs) and explore the prognostic impact of the GM itself. We assessed 6 histologic GM categories: solely cMCT (C-SC0), cMCT with superficial (C-SC1) or deep subcutaneous (C-SC2) involvement, solely scMCT (SC-C0), and scMCT with deep (SC-C1) or superficial (SC-C2) infiltration of the dermis. Ninety-one MCTs from 76 dogs undergoing excision and regional/sentinel lymphadenectomy were examined. GM classification identified 11 (12%) C-SC0 tumors, 12 (13%) C-SC1, 15 (16%) C-SC2, 21 (23%) SC-C0, 15 (16%) SC-C1, and 17 (19%) SC-C2. Mitotic count, 2-tier grade, nodal involvement, surgical margins, and outcome were stratified according to GM. scMCTs lacking dermal invasion, historically associated with a benign clinical course, had a poor prognosis in 10% of cases. cMCTs exhibiting deep subcutaneous involvement included the largest percentage of high-grade tumors (33%), had the highest occurrence of overt nodal metastases (33%), and had the lowest 1-year survival rate (86%). Histologic grade was confirmed as a relevant prognostic factor, surpassing nodal involvement and histologic margin status. The 2-tier histologic grading enabled the identification of all MCTs with aggressive biological behavior, regardless of their cutaneous or subcutaneous location.

Upregulated expression of glucose transporter isoform 1 in invasive and metastatic extramammary Paget's disease.

Glucose transporter isoform 1 (GLUT1), which is upregulated in a variety of malignant tumors, facilitates cellular glucose uptake to boost rapid tumor growth and progression. In several types of cancer, inhibition of GLUT1 suppresses tumor proliferation and metastasis, indicating that GLUT1 is a potential target of anticancer therapy. The present study performed immunohistochemistry to analyze GLUT1 expression levels in 51 patients with extramammary Paget's disease (EMPD), including 23 with only intraepidermal lesions and 28 with dermal-invasive lesions. Of the 28 patients with dermal invasion, nine had available samples of lymph node metastasis. GLUT1 staining scores were significantly higher in dermal-invasive (P<0.0001) and metastatic lesions (P=0.0008) compared with in intraepidermal lesions. GLUT1 is upregulated during the transition from preinvasive to invasive or metastatic tumor in EMPD. Moreover, GLUT1 staining scores were statistically higher in intraepidermal tumor cells of dermal-invasive EMPD compared with tumor cells of only in situ EMPD (P=0.0338). GLUT1 is upregulated even during the preinvasive phase in patients with invasive EMPD, suggesting that GLUT1 immunostaining can predict the risk of dermal invasion. The present study provides novel evidence to pursue in vitro and in vivo studies to confirm that upregulated expression of GLUT1 enhances tumor aggressiveness in EMPD.

Abstract 2593: Spatial multi-omics profiling of tumor cell phenotypes in primary cutaneous melanoma at single-cell resolution

Abstract Primary cutaneous melanomas develop in stages from melanoma precursor cells that may progress to melanoma in situ (MIS) and eventually to invasive disease. Molecular changes, such as tumor cell state switches from melanocytic to undifferentiated and neural-crest-like phenotypes, have been associated with the development of melanoma metastases and therapeutic resistance. However, it is unknown whether cell states or gene expression changes enriched in advanced tumors exist at the premalignant stage and if they can elicit tumor-infiltrating lymphocytes (TILs). To address this gap, we analyzed a cohort of clinical samples from 43 patients with primary cutaneous melanoma using whole-slide cyclic multiplex immunofluorescence imaging (CyCIF), morphology-guided micro-regional RNA sequencing, and high-resolution 3D imaging. Each specimen contained multiple histologically-distinct regions representing a progression axis from normal to precursor to melanoma in situ to invasion. Subsequently, we examined the molecular profiles of both atypical melanocytes and tumor cells, and the gene expression and tumor microenvironmental (TME) changes that occurred during these progression stages. We identified major intra- and inter-specimen heterogeneity in the tumor intrinsic and extrinsic features across progression stages. Multiple tumor samples contained regions where publicly available gene signatures linked to both melanocytic and undifferentiated cell phenotypes were enriched. CyCIF analysis confirmed that various tumor cell phenotypes can coexist in close proximity to each other in early-stage untreated melanomas, and that the majority of undifferentiated tumor cells were located within regions of dermal invasion. Moreover, the cellular neighborhoods around undifferentiated tumor cells had a higher proportion of CD8+ T cells and cells of myeloid lineage compared to the neighborhoods around melanocytic tumor cell phenotypes. When assessing the localization and abundance of various tumor cell phenotypes, the levels of spatial and regional heterogeneity increased proportionally along normal to premalignant to malignant progression. Furthermore, the regional entropy of tumor cell phenotypes decreased along tumor depth in the majority (63%) of the samples, and even the melanoma in situ regions showed varying levels of spatial heterogeneity. Our in-depth multimodal molecular analyses highlight the presence of spatial heterogeneity among tumor cell phenotypes as well as the organization of early-stage primary melanomas, and are suggestive of tumor cell adaptation to the local environment. Citation Format: Tuulia Vallius, Edward Novikov, Ajit Nirmal Johnson, Shi Yingxiao, Roxanne Pelletier, Shishir Pant, Zoltan Maliga, Alyce Chen, Clarence Yapp, Sabrina Chan, Christine Lian, George F. Murphy, Sandro Santagata, Peter Sorger. Spatial multi-omics profiling of tumor cell phenotypes in primary cutaneous melanoma at single-cell resolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2593.

Cancer Cell Biomechanical Properties Accompany Tspan8-Dependent Cutaneous Melanoma Invasion.

The intrinsic biomechanical properties of cancer cells remain poorly understood. To decipher whether cell stiffness modulation could increase melanoma cells' invasive capacity, we performed both in vitro and in vivo experiments exploring cell stiffness by atomic force microscopy (AFM). We correlated stiffness properties with cell morphology adaptation and the molecular mechanisms underlying epithelial-to-mesenchymal (EMT)-like phenotype switching. We found that melanoma cell stiffness reduction was systematically associated with the acquisition of invasive properties in cutaneous melanoma cell lines, human skin reconstructs, and Medaka fish developing spontaneous MAP-kinase-induced melanomas. We observed a systematic correlation of stiffness modulation with cell morphological changes towards mesenchymal characteristic gains. We accordingly found that inducing melanoma EMT switching by overexpressing the ZEB1 transcription factor, a major regulator of melanoma cell plasticity, was sufficient to decrease cell stiffness and transcriptionally induce tetraspanin-8-mediated dermal invasion. Moreover, ZEB1 expression correlated with Tspan8 expression in patient melanoma lesions. Our data suggest that intrinsic cell stiffness could be a highly relevant marker for human cutaneous melanoma development.

Invasive Paget disease of the breast: two unique cases with diagnostic conundrum

Abstract Introduction/Objective Invasive Paget disease of the breast is a rare entity with diagnostic challenges. It has been reported in 4-8% of cases of mammary Paget disease, while Paget disease itself represents only 1-4% of all breast carcinomas. The pigmented variant of this entity brings even greater diagnostic challenge. Herein, we present two patients with Paget disease of the breast with dermal invasion, one case with associated ulceration and another with pigmentation. Methods/Case Report Patient 1 is a 47-year-old female with a 9 mm right breast mass with a lobulated margins and calcifications. Simple mastectomy was grossly notable for nipple ulceration. Patient 2 is a 54-year-old female with a cm irregular mass in the right breast. Grossly, the nipple appeared blackened and mildly everted. Results (if a Case Study enter NA) Histopathologic evaluation of the nipple sections from patient 1 show invasive Paget disease with associated ulceration, with a depth of invasion of 4.5 mm. The breast biomarkers on the nipple section show tumor cells are negative for ER (0%) and PR (0%), and positive for HER2/neu (3+). Additionally, there was a separate 1.5 cm invasive ductal carcinoma, combined Nottingham histologic grade 3, pathologic stage of pT1c. The nipple sections from patient 2 show pigmented, invasive Paget disease, with a 1.5 mm depth of invasion. The tumor cells are positive for CK7 (weak), ER and PR, and negative for HER2/neu (1+). HMB45 and MART1 show increased reactivity in melanocytes. She also had a separate 2.5 cm invasive ductal carcinoma, combined Nottingham histologic grade 3, pathologic stage of pT2. Conclusion We present two unique cases of breast invasive Paget disease: one with associated ulceration, which brings challenges with tumor staging; and another one with pigmentation, which can be mistaken as melanoma. Invasive Paget disease must be distinguished from locally advanced breast cancer presenting as satellite skin nodules or skin ulceration, as it can lead to erroneous tumor over-staging as pT4b. It is important to recognize these two variations of invasive Paget disease so as to avoid over-staging or misdiagnosis, respectively, and to be cognizant of the fact that the treatment and prognosis differ.

Therapeutic outcomes and survival analysis of Extramammary Paget's disease: A multicentre retrospective study of 249 patients

Evidence regarding long-term therapeutic outcomes and disease-specific survival (DSS) in Extramammary Paget's disease (EMPD) is limited. To assess the DSS and outcomes of surgical and nonsurgical therapeutic modalities in a large cohort of EMPD patients. Retrospective chart review of EMPD patients from 20 Spanish tertiary care hospitals. Data on 249 patients with a median follow-up of 60months were analyzed. The estimated 5-, 10-, and 15-year DSS was 95.9%, 92.9%, and 88.5%, respectively. A significantly lower DSS was observed in patients showing deep dermal invasion (≥1mm) or metastatic disease (P<.05). A ≥50% reduction in EMPD lesion size was achieved in 100% and 75.3% of patients treated with surgery and topical therapies, respectively. Tumor-free resection margins were obtained in 42.4% of the patients after wide local excision (WLE). The 5-year recurrence-free survival after Mohs micrographic surgery (MMS), WLE with tumor-free margins, WLE with positive margins, radiotherapy, and topical treatments was 63.0%, 51.4%, 20.4%, 30.1%, and 20.8%, respectively. Retrospective design. EMPD is usually a chronic condition with favorable prognosis. MMS represents the therapeutic alternative with the greatest efficacy for the disease. Recurrence rates in patients with positive margins after WLE are similar to the ones observed in patients treated with topical agents.

Cutaneous Malignant Melanoma with Testicular Metastases in a Wild Rabbit (Oryctolagus cuniculus).

Melanocytic skin tumours have been rarely described in pet rabbits, and exposure to UV light in sparsely haired areas has been hypothesised to play a cancerogenic role. Here, we describe a case of cutaneous malignant melanoma arising from the skin of the scrotum in an 8-year-old male wild rabbit, with testicular metastases as an unusual metastatic site for melanoma reported in humans to date. The tumour was nearly 5 cm in size, firm, and highly pigmented, with multifocal superficial ulcerations and large areas of intratumoural necrosis. The adjacent testis was 1.5 cm, multinodular, and black, obscuring tissue morphology. Histologically, the dermis was expanded by an infiltrative, densely cellular neoplasm composed of nests and sheets of polygonal to spindle neoplastic melanocytes, supported by scant fibrovascular stroma. Neoplastic cells showed intermediate N/C ratio, moderate basophilic cytoplasm, often obscured by abundant brownish granular pigment, and eccentric nuclei with prominent nucleoli. Cellular pleomorphism and nuclear atypia were severe, and high mitotic activity was observed. Diffuse dermal lymphovascular invasion was also observed. The testis was delimited by a thin tunica albuginea, and the parenchyma was largely obscured in its morphology by densely packed neoplastic cells. Seminiferous tubules, lined with a thin basement membrane and containing neoplastic and scattered spermatogenic cells, were occasionally observed. Neoplastic cells within the skin and the testis were positive for HMB-45, Melan-A, and S-100. The growing popularity of rabbits as pets allows for a greater ability to accumulate data on the spontaneous occurrence of tumours in these animals. Furthermore, descriptions of the biological aspects of spontaneously occurring tumours may serve to improve current knowledge in animal species and humans in which the same neoplasm may occur.

A Reconstructed Human Melanoma-in-Skin Model to Study Immune Modulatory and Angiogenic Mechanisms Facilitating Initial Melanoma Growth and Invasion.

Invasion, immune modulation, and angiogenesis are crucial in melanoma progression. Studies based on animals or two-dimensional cultures poorly recapitulate the tumor-microenvironmental cross-talk found in humans. This highlights a need for more physiological human models to better study melanoma features. Here, six melanoma cell lines (A375, COLO829, G361, MeWo, RPMI-7951, and SK-MEL-28) were used to generate an in vitro three-dimensional human melanoma-in-skin (Mel-RhS) model and were compared in terms of dermal invasion and immune modulatory and pro-angiogenic capabilities. A375 displayed the most invasive phenotype by clearly expanding into the dermal compartment, whereas COLO829, G361, MeWo, and SK-MEL-28 recapitulated to different extent the initial stages of melanoma invasion. No nest formation was observed for RPMI-7951. Notably, the integration of A375 and SK-MEL-28 cells into the model resulted in an increased secretion of immune modulatory factors (e.g., M-CSF, IL-10, and TGFβ) and pro-angiogenic factors (e.g., Flt-1 and VEGF). Mel-RhS-derived supernatants induced endothelial cell sprouting in vitro. In addition, observed A375-RhS tissue contraction was correlated to increased TGFβ release and α-SMA expression, all indicative of differentiation of fibroblasts into cancer-associated fibroblast-like cells and reminiscent of epithelial-to-mesenchymal transition, consistent with A375's most prominent invasive behavior. In conclusion, we successfully generated several Mel-RhS models mimicking different stages of melanoma progression, which can be further tailored for future studies to investigate individual aspects of the disease and serve as three-dimensional models to assess efficacy of therapeutic strategies.

Histopathological survey of free-ranging neotropical bats with dermatitis.

Bats have a fundamental ecological role, and no wildlife disease has decimated more individuals than white-nose syndrome (WNS). This impactful mycosis has raised the importance of monitoring disease threats to bat populations. In this study, we aimed to investigate gross skin lesions in neotropical bats by histopathology to survey the occurrence of dermatitis that could resemble WNS cases in Brazil. Eleven species of free-ranging bats were sampled from the rabies surveillance program in 9 municipalities of Northern Paraná. Members of the Molossidae family were the most frequent ones among the 126 analyzed individuals, and 4 cases of dermatitis in 2 black mastiff bats (Molossus rufus), 1 great fruit-eating bat (Artibeus lituratus), and a big free-tailed bat (Nyctinomops macrotis) were detected. Gross lesions included alopecia, macules, discoloration, and hyperkeratosis. Among the bats with gross lesions, dermal thickening and mild inflammation were observed histologically. Two M. rufus bats had dermal fungal invasion; however, none resembled WNS.

Transcription factor activating enhancer-binding protein 2B expression correlates with invasiveness and prognosis of extramammary Paget's disease.

Extramammary Paget's disease (EMPD) is a slowly advancing malignancy that sometimes progresses to the invasion of the dermis, systemic metastases, and death. Although there have been reports that dermal invasion is associated with poor prognosis, no molecular markers of this invasion have been identified thus far. The aim of this study was to identify key molecules for predicting the risk of EMPD dermis invasion. We performed microarray screening for three cases of in-situ EMPDs, three cases of invasive EMPDs, and three cases of normal epidermis. We identified a molecule that exhibited a stepwise increase in expression. Further, we analyzed 47 cases of EMPD using immunohistochemical staining (IHC) and examined the correlated clinicopathological findings, including prognosis. We examined molecules that showed stepwise differences with invasion. We focused on transcription factor activating enhancer-binding protein 2 B (TFAP2B). Of the 47 EMPD patients, 38 (80.9%) and 9 (19.1%) had low and high TFAP2B expression, respectively. TFAP2B expression was significantly correlated with invasion into the dermis, mass formation, and preoperative lymph node metastasis (p=0.001, 0.042, and 0.033, respectively). The cumulative postoperative recurrence-free rate in the TFAP2B-high expression group was significantly lower than that in the TFAP2B-low expression group (P<0.001). In univariate analysis of recurrence-free survival, TFAP2B expression was found to be a significant factor (p=0.006). The expression of TFAP2B, which was comprehensively found by microarray screening, may correlate with the invasiveness of EMPD and may be an unfavorable prognostic factor.

Inflammatory breast cancer and the importance of skin punch biopsy

BackgroundThe oncologic outcomes of patients diagnosed with inflammatory breast cancer (IBC) based on clinical exam only versus those with dermal lymphatic invasion on skin punch biopsy may be different and are worth further investigation. MethodsPatients diagnosed from 2006 to 2021 with IBC at our institution were grouped according to clinical diagnosis or skin biopsy performed. Oncologic and survival outcomes among groups were compared. ResultsA total of 72 IBC patients were identified and grouped into 3 categories based on method of diagnosis: skin biopsy positive (n = 24), skin biopsy negative (n = 10) and no biopsy performed (n = 38). Skin biopsy positive patients had a higher incidence of lymphovascular invasion identified on final pathology and were more likely to experience a chest wall recurrence. At 5.1 yrs of follow-up, 40% of patients experienced recurrence, with 61% overall survival. ConclusionClinical diagnosis remains diagnostic for IBC, but skin punch biopsy allows for improved oncologic insight.

Verrucous Carcinoma of the Toenail: A Case Report and Review of Literature

Verrucous carcinoma (VC) is a rare, highly keratinized, well-differentiated, low-grade squamous cell carcinoma. A 58-year-old male presented with a 5-year history of a recurrent growing hyperkeratotic mass with intermittent bloody discharge, ulceration and dystrophic nail change on the right fifth toe. Since multiple dermatologic treatments were yielding no response, punch biopsy was performed for a more accurate diagnosis and the result was consistent with verruca vulgaris. As the lesion was responding poorly despite further dermatologic treatments for verruca vulgaris, radical surgical resection was performed. Microscopic examination of the excised lesion revealed epidermis with hyperkeratosis, hypergranulosis, papillomatosis, and reticular dermis invasion, consistent with VC. Since the diagnosis changed to VC, and the resection margin was involved by the carcinoma, the patient underwent an amputation procedure at the proximal phalangeal base. This case report highlights the importance of diagnosing VC. In cases of lesions such as verruca vulgaris or onychomycosis that are not responsive to general treatment, physicians should consider VC as a differential diagnosis, to prevent delaying a proper diagnosis and progression of disease.

A Phase I Study of Adjuvant Niraparib Administered Concurrently with Postoperative Radiation Therapy in Patients with Localized Triple Negative Breast Cancer

<h3>Purpose/Objective(s)</h3> Residual disease after neoadjuvant therapy (NAT) is associated with higher risk of recurrence, including local failure (25%) in triple negative breast cancer (TNBC). Novel combinations that increase the efficacy of standard-of-care treatments on locoregional control are warranted. PARP inhibitors (PARPi) target the DNA damage repair pathway, which is often altered in TNBC, and show promise as radiosensitizers. The objective of this phase I trial (NCT03945721) was to determine the maximum tolerated dose (MTD) of a PARPi, niraparib, in pts with high risk TNBC receiving postoperative radiotherapy (RT). <h3>Materials/Methods</h3> Eligible pts had stage I-III TNBC with residual invasive disease following NAT or primary tumor ≥1 cm after upfront surgery. A 3+3 escalation design was used to test 2 dose levels of QD niraparib (100mg, 200mg) with concurrent RT to the chest wall or breast +/- regional lymph nodes over 4-6 weeks. Dose expansion followed at the MTD. A boost was delivered in pts who had lumpectomy. 2 pts received proton beam RT. Bolus was administered in postmastectomy RT or in cases of dermal lymphatic invasion. Circulating tumor DNA (ctDNA) was collected at baseline, mid-RT, end of RT, and 30 days post-RT to assess the kinetics of ctDNA levels during RT and the association with clinical outcomes. Adverse events (AEs) were assessed using CTCAE v5.0. <h3>Results</h3> 21 pts were enrolled from July 2019 – October 2021. The median age was 49 (31-69). 19/21 pts had residual disease after NAT (6 RCB I, 7 RCB II, 6 RCB III); among them, 2 underwent adjuvant chemotherapy prior to enrolling. The remaining 2/21 pts (pT2N0; pT1cN0) received upfront breast conserving surgery followed by adjuvant chemotherapy. In dose escalation, 6 pts received 100mg niraparib + RT and 2 pts received 200mg niraparib + RT. One DLT in the 100mg cohort (G3 dermatitis) was attributed to RT. Two DLTs in the 200mg cohort (G3 thrombocytopenia) were attributed to niraparib and study drug was discontinued. In dose expansion, 13 pts received 100mg niraparib + RT. G3 AEs were dermatitis (4/21), hematologic (4/21), consisting of thrombocytopenia, anemia & lymphopenia, and elevated alkaline phosphatase (1/21). There was one G4 thrombocytopenia. All skin AEs were attributed to RT and were not exacerbated by niraparib. No pts in dose expansion discontinued treatment due to toxicity. 20/21 went on to standard-of-care capecitabine after completing RT. Results of ctDNA will be reported at the meeting. <h3>Conclusion</h3> The MTD of niraparib + postop RT was determined to be 100mg QD and was associated with a 24% rate of G3-4 hematologic toxicities and 19% rate of G3 radiation dermatitis in pts with localized TNBC, which is within upper limits of normal for pts in whom chest wall/skin is targeted. These results will be informative for a future larger study testing the efficacy of niraparib + postop RT in high risk TNBC.

Extramammary Paget’s Disease Arising in the Scrotum of an Elderly Male

Extramammary Paget’s disease (EMPD) is a rare form of primary or secondary intraepithelial adenocarcinoma typically presenting within the fifth through seventh decades of life. Though cases of EMPD localized to the scrotum are typically not associated with underlying malignancy, evaluation of dermal and angiolymphatic invasion in conjunction with pertinent laboratory investigations, e.g., serum CEA, is essential to rule out malignancy and metastatic disease. We present a case of EMPD in an elderly male that presented with a history of a longstanding asymptomatic scrotal lesion that was ultimately managed with excision and skin grafting.

Cyclin D1 and PRAME expression in distinguishing melanoma in situ from benign melanocytic proliferation of the nail unit

BackgroundDistinguishing benign lesion from early malignancy in melanocytic lesions of the nail unit still remains a diagnostic challenge, both clinically and histopathologically. While several immunohistochemistry (IHC) stainings have been suggested to help discriminate benign subungual melanocytic proliferation (SMP) and subungual melanoma in situ (MIS), the diagnostic utility of IHC staining for cyclin D1 and PRAME has not been thoroughly investigated in melanocytic lesions of nail unit.MethodsThis retrospective study included cases of benign SMP and subungual MIS confirmed by biopsy at Asan Medical Center from January 2016 to December 2020. Cases of melanocytic activation without proliferation and melanoma where dermal invasion was identified were excluded. Cyclin D1 and PRAME expression was assessed by counting proportion of melanocytes with nuclear positivity under 200x magnification.ResultsA total of 14 patients with benign SMP and 13 patients with subungual MIS were included in this study. 11 patients with benign SMP (71.4%) and 5 patients with subungual MIS (38.5%) showed > 60% nuclear immunostaining for cyclin D1, respectively. While 13 patients with benign SMP (92.9%) showed totally negative staining for PRAME, 10 patients with subungual MIS (76.9%) exhibited > 50% nuclear immunostaining for PRAME. Using the cutoff of 10%, PRAME exhibited good overall discrimination between benign SMP and subungual MIS (AUC = 0.849, 95% CI = 0.659–0.957).ConclusionsThis study suggests that PRAME IHC staining as a reliable discriminator in distinguishing subungual MIS from benign SMP.

Subungual melanoma with blue naevus-like morphological features: a clinicopathological retrospective analysis of nine cases

Melanocytic lesions in the nail apparatus are often challenging. Both subungual melanomas (SUM) and blue naevus of the nail are very rare. Occasionally, melanomas may mimic blue naevus histologically. Benign and malignant blue melanocytic lesions are commonly associated with G protein mutations, a distinct abnormality not associated with conventional subungual melanomas. We describe the clinical, histological and immunohistochemical features of nine cases of SUM with blue naevus-like morphological features. Mutations in exon 4 and 5 of GNAQ and GNA11 were investigated in two cases, which showed no mutations. RNA-seq of one case revealed unknown mutations along with mutations in ATM, METK and ARID1A. Our study delineates a variant of SUM that mimics blue naevus. Awareness of this pitfall is important when evaluating heavily pigmented lesions around the nail in order to avoid misdiagnosis. Appropriate sampling of subungual lesions and clinicopathological correlation are paramount to reach the correct diagnosis.