Transcription factor Foxo1 is a negative regulator of natural killer cell maturation and function.

Little is known about the role of negative regulators in controlling natural killer (NK) cell development and effector functions. Foxo1 is a multifunctional transcription factor of the forkhead family. Using a mouse model of conditional deletion in NK cells, we found that Foxo1 negatively controlled NK cell differentiation and function. Immature NK cells expressed abundant Foxo1 and little Tbx21 relative to mature NK cells, but these two transcription factors reversed their expression as NK cells proceeded through development. Foxo1 promoted NK cell homing to lymph nodes by upregulating CD62L expression and inhibited late-stage maturation and effector functions by repressing Tbx21 expression. Loss of Foxo1 rescued the defect in late-stage NK cell maturation in heterozygous Tbx21(+/-) mice. Collectively, our data reveal a regulatory pathway by which the negative regulator Foxo1 and the positive regulator Tbx21 play opposing roles in controlling NK cell development and effector functions.

Numerous multinucleated giant cells in cutaneous epithelioid angiosarcoma and pulmonary metastasis: A unique observation with potential diagnostic pitfalls.

The histopathologic diagnosis of poorly differentiated cutaneous angiosarcoma can be challenging. We report a case of cutaneous epithelioid angiosarcoma with numerous multinucleated giant cells (MGCs) developing pulmonary metastasis. A 79-year-old man presented with a red-purple plaque on the scalp. A skin biopsy revealed epithelioid cell proliferation, admixed with numerous MGCs, and background hemorrhage. Vascular spaces were focally present and lined by atypical endothelial cells, including MGCs. Immunohistochemically, tumor cells, including MGCs, were positive for CD31, D2-40, and ERG. The patient received radiation therapy and chemotherapy, after which a follow-up CT scan revealed symptomless pneumothorax and pulmonary metastases. The patient received palliative partial lung resection, and the specimen revealed histopathological and immunohistochemical features similar to the primary cutaneous lesion. Our report expands the morphologic spectrum of cutaneous epithelioid angiosarcoma. Cutaneous angiosarcoma is an aggressive neoplasm; thus, awareness of this rare manifestation is important.

Utility of next-generation sequencing in the diagnosis of metastatic melanoma: A case report.

During routine dermatologic examination, a 77-year-old male was noted to have a firm blue subcutaneous nodule on his right lateral upper back. His past medical history included metastatic melanoma of unknown primary involving right and left axillary lymph nodes, treated with ipilimumab/nivolumab with complete response, and subsequent primary uveal melanoma. The subcutaneous nodule was located near his previous right axillary scar for metastatic melanoma. Excision of the nodule showed a plexiform neoplasm involving mid and deep dermis composed of spindle and epithelioid atypical cells admixed with numerous melanophages. Central necrosis was present. Immunohistochemical studies revealed the tumor cells to be diffusely positive for HMB45, with retained expression of BAP1 and p16. The tumor cells were negative for PRAME, nuclear expression of ß-catenin, LEF1, and BRAF V600E. Molecular studies demonstrated BAP1 and GNA11 somatic mutations, a profile different from that exhibited by his prior melanoma. Collectively, these data were interpreted as a metastasis from uveal melanoma and not a recurrence of his metastatic likely cutaneous melanoma after complete response to immunotherapy. This case emphasizes the importance of molecular studies for definitive diagnosis in challenging clinical situations, especially when there is discordance among histopathological, immunohistochemical, and molecular studies. Integration of clinical, histopathological, and molecular features is warranted.

Early Organ Metastasis in Granulomatous Mycosis Fungoides: A Systematic Review.

BACKGROUND: Granulomatous mycosis fungoides (GMF) is a rare form of cutaneous T-cell lymphoma characterized by a granulomatous inflammatory infiltrate. OBJECTIVE: The impact of granulomatous inflammation on the prognosis of the disease remains controversial as there have been both favorable and unfavorable outcomes documented. METHODS: We performed a systematic review of 116 GMF cases previously described in the literature. RESULTS: In contrast to the classic Alibert-Bazin type of mycosis fungoides (MF), cutaneous lesions in GMF tend to involve distal extremities (lower legs, feet, hands) early in the disease course. In the literature, 30% of GMF patients developed organ metastasis, most frequently to the lung. The median time to stage progression was 25 months. CONCLUSION: GMF is an aggressive form of MF. Therefore, screening for distant metastases should be considered at presentation and repeated during follow-up.

Pigmented Villonodular Synovitis: A Metastatic Melanoma Imitator.

ABSTRACT: A 45-year-old woman with a history of previously treated left plantar foot melanoma presented with a left thigh mass. Fine needle aspiration findings were concerning for metastatic melanoma (MM). Imaging was remarkable for PET-avidity of both the biopsied thigh mass and of a left posterior knee nodule. The knee nodule was also enhancing on MRI, concerning for a site of metastasis. Resection of the thigh mass and intra-articular nodule was performed. The thigh lesion was positive for MM. The specimen obtained from the knee demonstrated a proliferation of spindle and epithelioid cells associated with focal fibrosis and scattered giant cells with brown pigment, raising the possibility of melanoma metastasis with treatment effect. Additional immunohistochemical studies with anti-SOX10 failed to demonstrate melanoma cells in the lesion. The final diagnosis for the knee nodule was pigmented villonodular synovitis. This case highlights the potential for pigmented villonodular synovitis to mimic MM, requiring additional pathologic analysis to yield an accurate diagnosis.

Rare Presentation of Melanoma Recurrences With Diffuse Subcutaneous Intravascular Lesions: A Novel In-Transit Metastases Pattern.

ABSTRACT: In 4%-11% of cases, melanoma recurrences present as in-transit (IT) metastases, and their prognosis is quite poor. Consequently, an early diagnosis and treatment of IT metastasis assume paramount significance. Despite this, the diagnosis of cutaneous IT metastases persistently presents a formidable challenge due to the diversity in clinical and dermoscopic characteristics. We provide a novel melanoma IT metastases pattern with interesting dermoscopic features and magnetic resonance imaging via presenting an unusual case characterized by diffuse subcutaneous intravascular lesions to supplement the understanding of cutaneous melanoma IT metastases.

Metastatic Tonsil Squamous Cell Carcinoma: An Important Consideration in the Differential Diagnosis of Malignant Basaloid Neoplasms in the Skin: Case Report and Review of the Literature.

ABSTRACT: Malignant basaloid neoplasms of the skin are frequent, and their accurate diagnosis holds paramount importance for treatment and prognosis. However, these neoplasms can present diagnostic challenges because of their extensive differential diagnosis, which encompasses cutaneous metastasis among many other possibilities. We present a case of a 74-year-old man with a history of p16-positive palatine tonsil squamous cell carcinoma (SCC) treated with surgery and adjuvant radiation with no prior evidence of recurrence who presented to the dermatologist with 2 chin papules. The initial histopathologic evaluation of these lesions showed poorly differentiated malignant basaloid neoplasms. Subsequently, these biopsies were compared with the previous biopsies from his tonsil and lymph node, which showed similar findings including positive p16 staining and positive molecular testing for human papillomavirus-16, confirming the diagnosis of cutaneous metastasis from his previously diagnosed human papillomavirus-related tonsil SCC. Additional imaging studies found metastases to internal organs including the brain, and he was started on chemotherapy, immunotherapy, and radiation therapy. Cutaneous metastases from tonsil SCC are exceedingly rare, and only 5 cases have been described. Furthermore, this is the first case confirming the presence of high-risk human papillomavirus by molecular studies within the cutaneous metastases. The presented case underscores the importance of recognizing this unusual manifestation of tonsil SCC metastatic to the skin along with a good clinical patient history, ensuring accurate and prompt diagnosis and treatment of this condition.

A Case of Gallbladder Metastasis of Malignant Melanoma.

In the clinical course of malignant melanoma, which can metastasize to multiple organs, gallbladder metastases are rarely detected. A 69-year-old man who underwent resection of a primary malignant melanoma was subsequently treated with nivolumab for lung metastases and achieved complete response. Seven years after surgery, multiple nodules were found in the gallbladder, and he underwent laparoscopic cholecystectomy. The postoperative diagnosis was metastases of malignant melanoma. He has been recurrence-free 8 months after surgery. If radical resection is possible, such surgery should be performed for gallbladder metastases found in patients with other controlled lesions of malignant melanoma.

Cutaneous metastases: From epidemiology to therapy.

Cutaneous metastases are seen in up to 10% of all oncology patients and can occur in different locations depending on the entity. Cutaneous metastases are often associated with a high psychological burden and, especially in the case of exulceration, with shame and social withdrawal. This review discusses the diagnostic and therapeutic options. The most common tumor entities in which cutaneous metastases are observed are discussed, and local and systemic treatment options are presented according to the current state of research.

Beyond the Surface: A Case Report of a Patient with Small Bowel Metastasis and Melanoma History. Diagnosis and Management.

Background: Malignant melanoma (MM) is one of the most prevalent and deadliest forms of skin cancer, resulting from the malignant transformation of melanocytes. It accounts for approximately 1.7% of global cancer diagnoses and is the fifth most common cancer in the US. MM can metastasize to almost any part of the body, with early detection significantly improving prognosis. Case presentation: We report the case of an 81-year-old female with a history of malignant melanoma (primary lesion on the left calf) and various comorbidities. She presented with severe anemia of unknown origin. A CT scan was performed due to her medical history, revealing a circumferential, asymmetrical parietal thickening at the level of a hypogastric ileal loop. The lesion suggested a tumoral substrate. Subsequent colonoscopy showed no metastatic lesions, but surgical intervention confirmed a malignant melanoma ileal metastasis. The patient underwent laparoscopic segmental resection with favorable post-surgery outcomes. Histopathological examination of the resected tissue confirmed the diagnosis of small intestine secondary lesions from the malignant melanoma. Conclusion: This case underscores the necessity of considering metastatic melanoma in patients with a history of MM and vague gastrointestinal symptoms. Early and accurate diagnosis through advanced imaging and endoscopic techniques can significantly improve patient outcomes.

Novel EWSR1::UBP1 fusion expands the spectrum of spindle cell rhabdomyosarcomas.

Over the last decade, the development of next-generation sequencing techniques has led to the molecular dismantlement of adult and pediatric sarcoma, with the identification of multiple gene fusions associated with specific subtypes and currently integrated into diagnostic classifications. In this report, we describe and discuss the identification of a novel EWSR1-UBP1 gene fusion in an adult patient presenting with multi-metastatic sarcoma. Extensive pathological, transcriptomic, and genomic characterization of this tumor in comparison with a cohort of different subtypes of pediatric and adult sarcoma revealed that this fusion represents a novel variant of spindle cell rhabdomyosarcoma with features of TFCP2-rearranged subfamily.

Generalized Reddish Skin Nodules.

Diagnosis of nodular red lesions is challenging. The differential diagnosis includes dermal nevus, angioma, pyogenic granuloma, amelanotic melanoma, eccrine poroma, Kaposi's sarcoma, skin malignancy or metastasis. Erythema nodosum is one of the common consideration of the red skin nodules, however fully work up should be done to find the right diagnosis.A 60 years old female admitted to our hospital due to pain dark reddish skin nodules since one month. She had continuously high grade fever of 39 Celsius accompanied by arthralgia and fatigue since two months prior to admission and she lost 6 kg of weight in 2 months. On admission, physical examination revealed slight fever, pale conjunctiva, mild hepatosplenomegaly, tender dark red nodules 0.3 to 2 cm, firm edge, at her cheek, abdominal area and both lower extremities. No lymph nodes enlargement was noticed. Her laboratory test showed haemoglobin 9,1 g/dl, WBC 3,040/mL, PLT 149,000/mL, SGOT 48 U/L, SGPT 43 U/L, urea 12.5 mg/dL, creatinine 0.67 mg/dL. She was found to be non-reactive for HBsAg, HCV, and HIV antigens. Urine routine and microscopic examination was unremarkable.Her histopathology of left foot nodule biopsy revealed cutaneous lymphoma. The immunohistochemical (IHC) stain of CD45, CD20, and CD10 were positive, Ki67 were also positive  with >70% tumor cells, while CD3,CD56, CD30, and Granzyme were negative. Her final diagnosed was Cutaneous Diffuse large B cell lymphoma.Primary cutaneous lymphomas of B-cells occur less frequently than primary cutaneous T-cells lymphomas. Primary extra-nodal diffuse large B-Cell lymphoma (DLBCL) can be seen in up to 40% of cases. However skin involvement is less common and in a large cohort of DLBCL cases, skin involvement at presentation was seen only in 3.3% of cases.It characterized by few lesions, in general showing nodules or infiltrations of relatively fast growth and have no itching. The diagnosis is made by the immunohistochemical findings, clinicopathological correlation, and molecular pathology.  The lymphomas have different clinical behaviours despite being identical in morphological appearance. The primary lymphomas presents with local recurrence in up to 68% of the cases and with rare extra-cutaneous dissemination, with an average rate of 5-year survival varying from 89 to 96%. Cutaneous lymphoma should be always become one of considered diagnosed of skin red nodules even it is rare.

Ipilimumab in a real-world population: A prospective Phase IV trial with long-term follow-up.

Ipilimumab was the first treatment that improved survival in advanced melanoma. Efficacy and toxicity in a real-world setting may differ from clinical trials, due to more liberal eligibility criteria and less intensive monitoring. Moreover, high costs and lack of biomarkers have raised cost-benefit concerns about ipilimumab in national healthcare systems and limited its use. Here, we report the prospective, interventional study, Ipi4 (NCT02068196), which aimed to investigate the toxicity and efficacy of ipilimumab in a real-world population with advanced melanoma. This national, multicentre, phase IV trial included 151 patients. Patients received ipilimumab 3 mg/kg intravenously and were followed for at least 5 years or until death. Treatment interruption or cessation occurred in 38%, most frequently due to disease progression (19%). Treatment-associated grade 3 to 4 toxicity was observed in 28% of patients, and immune-related toxicity in 56%. The overall response rate was 9%. Median overall survival was 12.1 months (95% CI: 8.3-15.9); and progression-free survival 2.7 months (95% CI: 2.6-2.8). After 5 years, 20% of patients were alive. In a landmark analysis from 6 months, improved survival was associated with objective response (HR 0.16, P = .001) and stable disease (HR 0.49, P = .005) compared to progressive disease. Poor performance status, elevated lactate dehydrogenase and C-reactive protein were identified as biomarkers. This prospective trial represents the longest reported follow-up of a real-world melanoma population treated with ipilimumab. Results indicate safety and efficacy comparable to phase III trials and suggest that the use of ipilimumab can be based on current cost-benefit estimates.

Phase 1/2 study of topical submicron particle paclitaxel for cutaneous metastases of breast cancer.

PURPOSE: This Phase 1/2 study evaluated safety and efficacy of a topical submicron particle paclitaxel (SPP) in an anhydrous ointment base (SOR007), primarily in breast cancer patients with cutaneous metastases (CM). METHODS: One of three concentrations of SOR007 SPP (0.15%, 1.0%, or 2.0%) was applied twice daily over an area of 50 cm2 under a 3 + 3 phase 1 design for up to 28 days, with the option for expansion to an additional 28 days at the highest dose under a Phase 2a once safety was established. Efficacy was analyzed by lesion measurements and photographs to determine overall response rate (ORR), complete response (CR), and progression free survival by day 28 or 56. RESULTS: Twenty-three subjects were enrolled, 21 with cutaneous metastases of breast cancer (CMOBC). Four subjects received SOR007 0.15% for a median of 28 days (range = 17-29), three at a dose of 1.0% for a median of 28 days (range = 6-29), and sixteen at 2.0% for a median of  55 days (range = 6-60). All doses were well tolerated, and 19 subjects were evaluable for efficacy. At day 28 across all dose levels, 16% (95% CI 3.4 to 39.6%) of subjects achieved an ORR and another 63% (95% CI 34.9-96.8%) had stable disease (SD). The proportion of patients being progression free at 28 days across all treatments was 79% (95 CI 54-94%). CONCLUSION: Application of SOR007 0.15%, 1.0%, and 2.0% to CM was safe and well tolerated with some reduction in lesion pain, and minimal systemic absorption of paclitaxel. Lesion stabilization was observed in most subjects over the study period. A randomized, placebo-controlled trial to confirm these findings is warranted. GOV IDENTIFIER: NCT03101358.

Cutaneous metastasis of primary diffuse large B-cell lymphoma of the central nervous system developing 4 years after complete remission: Diagnosis confirmed by comparison of clones.

B-cell lymphoma of the central nervous system (CNS) is a rare malignancy with diffuse large B-cell lymphoma (DLBCL) variant being most common. Although DLBCL has a high propensity to relapse locally within the CNS, only a few cases of cutaneous metastasis have been described in the literature. We present a unique case of cutaneous metastasis of a primary DLBCL of the CNS in a 79-year-old man who was in clinical remission for 4 years until presenting with a lesion in the left adrenal gland and cutaneous nodules on the left flank. Skin biopsy specimen revealed a diffuse dermal infiltrate of atypical B-cell lymphocytes with expression of CD20, BCL-2, BCL-6, and MUM-1, suggestive of DLBCL. For differentiation between another primary or a recurrent process, immunoglobulin kappa (IgK) light chain gene rearrangement was performed and demonstrated that the DLBCL of the skin and CNS were of the same clonal origin. Restaging computerized tomography after initiating chemotherapy and daily ibrutinib showed complete resolution of the left adrenal mass and resolving cutaneous lesions. Our case demonstrates the rare, late cutaneous metastasis of DLBCL of the CNS and highlights the importance of genetic testing for the distinction between the primary and secondary lesions.

Sorafenib derivatives-functionalized gold nanoparticles confer protection against tumor angiogenesis and proliferation via suppression of EGFR and VEGFR-2.

Sorafenib is a multi-kinase inhibitor that has been highlighted as a tumor suppressor due to its anti-proliferative and anti-angiogenic properties, whereas the clinical application of Sorafenib is restricted by the side effects it may cause. The past decade has witnessed the development of a series of sorafenib derivatives to improve the clinical performance of sorafenib. Gold nanoparticles (AuNPs) have been widely utilized in drug delivery systems due to their unique properties, including biocompatible nature, simple preparation, and easy surface modification. Herein, this study is aimed to investigate the anti-tumor effects of new sorafenib derivatives-capped gold nanoparticles (AuNPs-New Sor) in tumor formation and metastasis as well as the underlying mechanisms. Initially, new sorafenib derivatives were constructed and combined with AuNPs to form AuNPs-New Sor, and the properties of synthesized AuNPs-New Sor were identified in a mouse model of tumorigenesis. The effect of AuNPs-New Sor on tumor vascular normalization was investigated by assessing vascular permeability and perfusion rate. Next, we evaluated the effect of AuNPs-New Sor on migration and viability of tumor cells and human umbilical vein endothelial cells (HUVECs) as well as on HUVEC angiogenesis in vitro. A melanoma mouse model was further established for in vivo substantiation of the anti-tumor effect of AuNPs-New Sor. According to the results, AuNPs could deliver new sorafenib derivatives into tumor tissues and downregulate the expression of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2), thereby suppressing tumor migration, EMT, and angiogenesis in vitro. In addition, AuNPs-New Sor displayed competitive anti-tumor activities in vivo. Taken together, AuNPs-New Sor may attenuate tumor development and angiogenesis through downregulation of EGFR and VEGFR-2.

Bilateral Hand Metastases From a Pleomorphic/Dedifferentiated Leiomyosarcoma: A Case Report.

ABSTRACT: Leiomyosarcomas of the lower extremity are heterogeneous tumors with high recurrence and metastasizing rates, which, rarely, can suffer a dedifferentiation process, making them extremely aggressive and unpredictable. We report the case of a 72-year-old female patient who presented the clinical and histopathological features of a rare leiomyosarcoma of the foot that was completely excised, but because of the interruption of adjuvant oncological treatment and lack of compliance for the follow-up, the patient suffered a dedifferentiation process and the tumor metastasized in the fingers-an unprecedented site for this type. The present case proves the fact that there is still a lot we do not know about the behavior of this disease, and there is always room to learn. Also, through this report, we are emphasizing a frequently encountered and never-ending problem in our country-that of difficult and resource-consuming cases derived from disconsidering medical advice by noncompliant patients when faced with a malignant diagnosis, making all attempts to offer them a better quality of life futile.

A rare case of cutaneous metastasis of distal phalanx chondrosarcoma.

Chondrosarcoma is the second-most common primary malignant bone tumor but chondrosarcoma of small bones of the hand is extremely rare, representing less than 2% of all cases, with exceedingly rare skin metastases. Cutaneous metastases of chondrosarcoma represent less than 3% of all cutaneous metastases. According to PubMed, there are only four previous case reports of cutaneous metastases originating from chondrosarcoma of small bones of the hand. We present an additional case of cutaneous metastases of phalangeal chondrosarcoma with a unique immunophenotype.

Clinical outcome of patients with metastatic melanoma of unknown primary in the era of novel therapy.

Melanoma of unknown primary (MUP) is considered different from melanoma of known primary (MKP), and it is unclear whether these patients benefit equally from novel therapies. In the current study, characteristics and overall survival (OS) of patients with advanced and metastatic MUP and MKP were compared in the era of novel therapy. Patients were selected from the prospective nation-wide Dutch Melanoma Treatment Registry (DMTR). The following criteria were applied: diagnosis of stage IIIc unresectable or IV cutaneous MKP (cMKP) or MUP between July 2012 and July 2017 and treatment with immune checkpoint inhibition and/or targeted therapy. OS was estimated using the Kaplan-Meier method. The stratified multivariable Cox regression model was used for adjusted analysis. A total of 2706 patients were eligible including 2321 (85.8%) patients with cMKP and 385 (14.2%) with MUP. In comparative analysis, MUP patients more often presented with advanced and metastatic disease at primary diagnosis with poorer performance status, higher LDH, and central nervous system metastases. In crude analysis, median OS of cMKP or MUP patients was 12 months (interquartile range [IQR] 5 - 44) and 14 months (IQR 5 - not reached), respectively (P = 0.278). In adjusted analysis, OS in MUP patients was superior (hazard rate 0.70, 95% confidence interval 0.58-0.85; P < 0.001). As compared to patients with advanced and metastatic cMKP, MUP patients have superior survival in adjusted analysis, but usually present with poorer prognostic characteristics. In crude analysis, OS was comparable indicating that patients with MUP benefit at least equally from treatment with novel therapies.

Histopathological and molecular profiling of lung adenocarcinoma skin metastases reveals specific features.

AIMS: Little is known regarding the histopathological and molecular features of lung adenocarcinoma skin metastases. Our study is the largest, to our knowledge, to comprehensively explore these to date. METHODS AND RESULTS: We performed a retrospective cohort study analysing 42 lung adenocarcinoma skin metastasis samples obtained from a database of 2659 lung adenocarcinomas collected between 2010 and 2020. EGFR exon 19 deletion was detected in one patient and KRAS mutations were detected in 12 (33.3%) patients. The programmed cell death ligand 1 (PD-L1) tumour proportion score was <1% in 27 patients, ≥1% and <50% in eight patients, ≥50% in six patients and not assessable in one patient. We showed that the predominant histopathological subtype is different from that at other metastatic sites (P = 0.024). Thyroid transcription factor I (TTF-1) was more often negative in skin metastases compared to other sites (P < 0.001). The EGFR mutation rate tended to be lower for skin metastases compared to other sites (P = 0.079). Skin metastases were associated with a high rate of PD-L1-negative cases (P = 0.022). CONCLUSION: Our work shows that the skin metastases of lung adenocarcinoma have a specific histopathological profile.