Response and outcome of patients with melanoma skin metastases and immune checkpoint inhibition.

It is known, that different metastatic organ systems respond differently to immune checkpoint inhibitors (ICIs). In this study, we aimed to investigate the extent to which skin/subcutaneous metastases respond to ICI or targeted therapies (TTs) and whether the response rate differs from that of distant metastases in the same patient. Patients with melanoma diagnosed between January 2021 and September 2023 with at least one skin/subcutaneous metastasis who had received therapy with ICI or TT in an advanced setting were included in the analysis. Best overall response (BOR) was classified according to the revised response evaluation criteria in solid tumors (RECIST). The BOR of skin metastases and visceral metastases to ICI and TT was compared using the chi-square test. Skin metastases treated with ICI a first-line setting showed an overall response rate (ORR) of 44.1%. In contrast, visceral metastases had a higher ORR of 51.1%. However, the difference was not statistically significant (p = .77). Regarding TT, the ORR for skin metastases was 57.1%, compared to 38.5% for visceral metastases (p = .59). Interestingly, the ORR for skin/subcutaneous metastases was notably lower with ICI compared to visceral metastases, in contrast to patients who underwent TT. Skin metastases showed a poorer response to ICI than visceral metastases. Therefore, careful monitoring is recommended to detect non-response early in patients with skin metastases as skin metastases may have a worse response than TT. A larger cohort is needed for a comprehensive analysis and confirmation of our results.

Impact of electrochemotherapy in metastatic cutaneous melanoma: a contemporary systematic review and meta-analysis.

BACKGROUND: Electrochemotherapy (ECT) harnesses electric pulses to enhance cytotoxic drug delivery into tumors and has entered the armamentarium to treat superficially metastatic melanoma. We performed a systematic review and meta-analysis to assess treatment patterns and patient outcomes. METHODS: PubMed, Medline, Embase, and the Cochrane Library databases were queried for publication from inception to September 2020. Primary outcome measures were overall and complete response rate (ORR and CRR); secondary outcomes included local control rate (LCR) and overall survival (OS). RESULTS: Twenty-seven studies met the selection criteria for a total of 1161 individuals (mean age 71 years) and 5308 tumors (weighted mean size 14 mm). The majority of patients (n = 1124) underwent bleomycin-ECT. Aggregate ORR was 77.6% (95% confidence interval [CI] 71.0 - 83.2%) and CRR 48% (95% CI 42 - 54%), with no significant difference between the route of bleomycin administration (ORR, 69.2 vs. 81.9% following intravenous or intratumoral bleomycin, p = .37) and tumor size (p = .69). When reported (n = 8 studies), 1- and 2-year LCR ranged from 54 to 89% and 72 to 74%, respectively, and 1-year OS (n = 3 studies) from 67 to 89%. CONCLUSIONS: ECT with either intratumoral or intravenous bleomycin confers a high therapeutic response in cutaneous metastatic melanoma. Moderate evidence supports its low toxicity and durability of local control.HighlightsElectrochemotherapy (ECT) is associated with a 77% overall response rate (ORR).Intravenous and intratumoral bleomycin are equally effective.There are no relevant toxicity concerns.One-year local tumor control rate ranges from 54 to 89%.Current literature has significant variation in reporting.

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.

Cutaneous metastases of endometrial carcinoma: report of an unusual case and literature review.

PURPOSE: Cutaneous metastases of endometrial carcinoma are rare. We report a case of a 54-year-old woman who developed cutaneous metastases from an endometrial carcinoma, and review the related literature to offer insight into this rare and serious condition. METHODS: The clinical and pathological data and therapy delivered to a patient from Peking University People's Hospital, were retrieved from her medical records. A systematic literature search regarding this unusual disease progression was conducted through PubMed/MEDLINE. RESULTS: A postmenopausal patient diagnosed with stage IB endometrioid carcinoma rapidly developed cutaneous metastases. 10 months postoperatively, the patient developed multiple lymph node metastases, and 22 months later, cutaneous metastases appeared on both breasts. She was then treated with chemotherapy, immunotherapy and hormone therapy. The skin lesions eased temporarily but deteriorated quickly. Ultimately, she died in 7 months subsequent to the appearance of cutaneous lesions. CONCLUSION: Cutaneous metastases from endometrial carcinoma have usually been incurable and associated with a limited prognosis.

The role of topical imiquimod in melanoma cutaneous metastases: A critical review of the literature.

Despite of the emerging new systemic and local oncologic treatments (immunotherapy and checkpoint inhibitors, oncolytic viral treatments and injected immunostimulants) the management of skin melanoma metastasis can be still challenging. The main aim of this review was to assess the efficacy and the role of imiquimod in local metastatic melanoma disease. An extensive literature review was performed from September 2000 to March 2020 using PubMed, MEDLINE, Embase, and Cochrane Library databases. Selected articles regarded topical imiquimod, its mode of action as an antitumoral agent and its applications in melanoma metastases treatment. We analyzed a total of 18 published article of clinical cases and small case series and five studies: two retrospective large case series, two Phase I and II clinical trials and one cohort non randomized study. Generally, the treatment is safe and well tolerated. Imiquimod lead to an unstable locoregional control. The use of topical imiquimod for the treatment of MM cutaneous metastases should be considered in selected cases and in palliative settings.

Dose optimization of total or partial skin electron irradiation by thermoluminescent dosimetry.

BACKGROUND: Due to the complex surface of the human body, total or partial skin irradiation using large electron fields is challenging. The aim of the present study was to quantify the magnitude of dose optimization required after the application of standard fields. METHODS: Total skin electron irradiation (TSEI) was applied using the Stanford technique with six dual-fields. Patients presenting with localized lesions were treated with partial skin electron irradiation (PSEI) using large electron fields, which were individually adapted. In order to verify and validate the dose distribution, in vivo dosimetry with thermoluminescent dosimeters (TLD) was performed during the first treatment fraction to detect potential dose heterogeneity and to allow for an individual dose optimization with adjustment of the monitor units (MU). RESULTS: Between 1984 and 2017, a total of 58 patients were treated: 31 patients received TSEI using 12 treatment fields, while 27 patients underwent PSEI and were treated with 4-8 treatment fields. After evaluation of the dosimetric results, an individual dose optimization was necessary in 21 patients. Of these, 7 patients received TSEI (7/31). Monitor units (MU) needed to be corrected by a mean value of 117 MU (±105, range 18-290) uniformly for all 12 treatment fields, corresponding to a mean relative change of 12% of the prescribed MU. In comparison, the other 14 patients received PSEI (14/27) and the mean adjustment of monitor units was 282 MU (±144, range 59-500) to single or multiple fields, corresponding to a mean relative change of 22% of the prescribed MU. A second dose optimization to obtain a satisfying dose at the prescription point was need in 5 patients. CONCLUSIONS: Thermoluminescent dosimetry allows an individual dose optimization in TSEI and PSEI to enable a reliable adjustment of the MUs to obtain the prescription dose. Especially in PSEI in vivo dosimetry is of fundamental importance.

Klinefelter syndrome and cutaneous localization of diffuse large B cell lymphoma: a real connection or a casual association?

Diffuse large B cell lymphoma (DLBCL) is a common aggressive subtype of non-Hodgkin lymphoma, accounting for nearly 30-40% of all cases. This condition can affect the skin both primarily and secondarily. Herein we report a clinical and dermoscopic case of skin metastasis of DLBCL in a patient with Klinefelter Syndrome.

Dermoscopy of skin metastases in advanced cancer-systemic (visceral, hematologic) and cutaneous.

Introduction: Skin metastases arise in 10% of cancer patients, but standardized dermoscopy diagnostic criteria for skin metastases remain poor. This study's objective was to analyze the dermoscopy features of skin metastases from advanced systemic and cutaneous cancers. Methods: A retrospective study on 715 dermoscopy images of skin metastases from 33 patients with various primary cancers (breast, ovary, melanoma, non-melanoma skin cancer, and chronic leukemia) attending two academic centers between 2013 and 2023 was performed. Four independent observers blindly analyzed patterns, colors, vessels, and elementary lesions for each metastasis (30 parameters in total). Results: The structureless white pattern was the most prominent indicator of cutaneous metastasis (81.26%, p < 0.001). Regardless of the primary tumor, colors pink, red, white, and tan were identified. Elementary lesions were infrequent, except for melanoma metastases that displayed dots (13.23%) and globules (11.11%). Breast cancer metastases presented: blue (41.48%) and red (34.32%) colors, irregular vessels (13.58%), and a blue-naevus pattern (22.22%). Melanoma metastases displayed: a blue-naevus pattern (61.38%), a blue color (85.71%), and a structureless-blue combination pattern (79.37%). Non-melanoma skin cancer metastases were characterized by vascular (42.11%) and angioma-like (31.58%) patterns, pink (57.89%) and red (57.89%) colors, irregular (57.89%), thin hairpin (47.37%), comma (47, 37%), and thick hairpin (26, 32%) vessels and a red, white and irregular vessels combination pattern (52, 63%). A pink structureless combination pattern was frequent (61.05%) in chronic leukemia metastases. Ovarian cancer metastases displayed a white and tan structureless combination pattern (100%) and frequently had dotted vessels (42.85%). Conclusion: Papules and nodules with a white structureless pattern suggest skin metastases, regardless of the primary tumor. A blue structureless lesion is indicative of melanoma metastasis and a vascular pattern with irregular vessels indicates a non-melanoma skin cancer metastasis. Dermoscopy stands as a reliable non-invasive diagnostic method for suspected cutaneous metastases in patients with a known cancer history.

Thyroid Cancer With Cutaneous Metastases.

Objectives: Thyroid carcinoma with cutaneous metastases is a rare clinical finding. Cutaneous metastases from thyroid carcinoma have been associated with a poor prognosis, but these data are limited to case reports. The exact mechanism of cutaneous metastases from thyroid carcinoma is not clear. Our study aims to report the demographic, clinical, and histologic findings of patients with cutaneous metastases from thyroid carcinoma. Methods: A review was conducted using the Medline/PubMed, Cochrane, and Scopus databases to review literature from inception to May 2023. Data extracted included patient age at diagnosis of cutaneous metastases, patient sex, thyroid carcinoma histotype, location of metastases, the time interval between diagnoses of thyroid carcinoma and cutaneous metastases, and overall survival (OS) from the time of cutaneous metastases. Results: One hundred thirty-six patients were identified and 75 were female. The most common types of thyroid carcinoma with cutaneous metastases were papillary (47.79%), followed by follicular (30.15%), and medullary (11.03%). In addition, 11 cases of anaplastic carcinoma, 2 cases of oncocytic carcinoma, and 2 cases of poorly differentiated thyroid carcinoma were reported. The average age at diagnosis of cutaneous metastases was 63.13 years, and the average time interval between the diagnoses of primary thyroid carcinoma and cutaneous metastases was 48.27 months. The most common location of metastases was the scalp (n = 48). Other common locations included the neck, chest, and face. The OS after diagnosis of metastases was only available in 34 patients with an average of 13.07 months. Of these 34 cases, 10 were medullary, 10 were papillary, 9 were anaplastic, and 5 had follicular carcinoma. Conclusions: This study represents an up-to-date review of the cases of thyroid carcinoma with cutaneous metastases. While cutaneous metastasis remains a rare finding, one needs a high index of suspicion, and their presence portends a poor prognosis.

A clown nose-like nodule revealing a metastatic lung carcinoma.

Clown nose-like lesion can be the manifestation of inflammatory, infectious or neoplasm-related diseases, and some genetic syndromes. Lung carcinoma metastasize rarely to the skin. To our knowledge, 16 cases of lung cancer metastasis with clown nose-like lesions have been reported. Here, we describe a new case. Abstract: Cutaneous metastases of small-cell-lung carcinoma are rare, and nose involvement is much rarer. However, it can be the first warning sign of lung cancer. We describe the case of a patient who presented with a red nodule of the nasal tip reminding a clown-nose.

Metastasis of ovarian cancer to nasal skin and skin on the trunk: a rare case report.

Cutaneous metastases of ovarian cancer are rare and often have poor prognosis. We report a case of a 62-year-old woman with recurrent low-grade serous ovarian cancer, who presented with lung, brain, and multiple skin (nasal and anterior chest wall) metastases approximately six months after the initial diagnosis. In this case, Nijmegen breakage syndrome carrier status caused by RAD50 heterozygous mutation and previous bevacizumab therapy could be the predisposing factor for cutaneous metastases. The patient was treated with local radiotherapy (nasal skin and brain, 30Gy/6f/1.2W) and three courses of chemotherapy with albumin-bound paclitaxel and carboplatin, resulting in drastic remission of the cutaneous metastases. Unfortunately, treatment interruption resulted in rapid tumor progression, followed by death. This case represents an interesting example of cutaneous metastasis of ovarian cancer with rare clinical manifestations, unique genetic mutations, and reasonable response to treatment. Chemoradiotherapy might be an appropriate option for cutaneous metastases of ovarian cancer. Nevertheless, we still hope to find out the best treatment strategy after collecting and reviewing more cases in the future.

Metastatic Renal Cell Carcinoma to the Scalp: A Case Report With Review of Literature.

Renal cell carcinoma (RCC) is the most common type of renal neoplasm. It accounts for 3% of solid tumors in adults and mostly affects men with the peak incidence between the fifth and seventh decades. It metastasizes mainly through the hematogenous spread, and the lung is the most common site of metastasis followed by bone, lymph node, liver, brain, and adrenal glands. Skin metastasis is extremely rare and accounts for <7% of RCC metastases, with the scalp and face being the most reported sites. Skin metastases are usually diagnosed at a later stage of the disease, commonly post-nephrectomy, and are regarded as a poor prognostic factor. Here we report a case of a 54-year-old male who presented with a red, pedunculated, bleeding, and nontender scalp lesion (2x2cm in size) found on the right parietal area. with a history of left radical nephrectomy and adjuvant chemotherapy for clear cell RCC 17 years ago, as well as laminectomy and radiotherapy for bone metastases in C5 and C6 in 2015. After surgical excision of the scalp lesion, histology revealed metastatic clear cell RCC. The patient was doing well post-surgical excision and was referred back to oncology where palliative care and supportive treatment were initiated. In the span of five months post-resection, he developed several conditions where his health further deteriorated. He was announced dead in September 2022 due to cardiac arrest. This case highlights the occurrence of scalp metastases long after the surgical resection of RCC.

Late Cutaneous Metastases of Bladder Urothelial Carcinoma: A Case Report.

Cutaneous metastatic disease from bladder urothelial carcinoma is a rare but serious complication of advanced bladder cancer. It occurs when malignant cells from the primary bladder tumor spread to the skin. The most common sites for cutaneous metastases from bladder cancer are the abdomen, chest, and pelvis. We report a case of a 69-year-old patient who was diagnosed with infiltrative urothelial carcinoma of the bladder (pT2) and underwent a radical cystoprostatectomy. After one year, the patient developed two ulcerative-bourgeous lesions, which were later identified as cutaneous metastases from bladder urothelial carcinoma through histological examination. Unfortunately, the patient passed away a few weeks later.

Electrochemotherapy of skin metastases from malignant melanoma: a PRISMA-compliant systematic review.

The main treatment of MM metastases are systemic therapies, surgery, limb perfusion, and intralesional talimogene laherparepvec. Electrochemotherapy (ECT) is potentially useful also due to the high response rates recorded in cancers of any histology. No randomized studies comparing ECT with other local therapies have been published on this topic. We analyzed the available evidence on efficacy and toxicity of ECT in this setting. PubMed, Scopus, and Cochrane databases were screened for paper about ECT on MM skin metastases. Data about tumor response, mainly in terms of overall response rate (ORR), toxicity (both for ECT alone and in combination with systemic treatments), local control (LC), and overall survival (OS) were collected. The methodological quality was assessed using a 20-item validated quality appraisal tool for case series. Overall, 18 studies were included in our analysis. In studies reporting "per patient" tumor response the pooled complete response (CR) was 35.7% (95%CI 26.0-46.0%), and the pooled ORR was 80.6% (95%CI 68.7-90.1%). Regarding "per lesion" response, the pooled CR was 53.5% (95%CI 42.1-64.7%) and the pooled ORR was 77.0% (95%CI 56.0-92.6%). One-year LC rate was 80%, and 1-year OS was 67-86.2%. Pain (24.2-92.0%) and erythema (16.6-42.0%) were the most frequent toxicities. Two studies reported 29.2% and 41.6% incidence of necrosis. ECT is effective in terms of tumor response and tolerated in patients with skin metastases from MM, albeit with a wide variability of reported results. Therefore, prospective trials in this setting are warranted.

Skin metastases in the clinical and dermoscopic aspects.

According to the literature, skin metastases affect 0.7%-10.4% of patients with malignant neoplasms of internal organs and may be 1 presentation of systemic spread of the cancer. Skin metastases may be the first sign of relapse after treatment and about 30% of cases of skin metastases are diagnosed before the diagnosis of internal organ cancer. Cutaneous metastases most often come from breast cancer and melanoma. They can present synchronous or metachronous. Adequate vigilance, combined with knowledge of the clinical picture and epidemiology, can contribute to accurate diagnosis and treatment. Clinically, skin metastases occur in the form of atypical solitary, painless nodules, or tumors. Lumps or infiltrating foci do not show clinical features that help in making a diagnosis. Skin changes are more accessible during physical examination, and it is easier to do a biopsy and provide histological assessment. Dermoscopy, a useful initial tool for the assessment of skin metastases, can lead to a rapid accurate diagnosis and treatment. Ultimately, the diagnosis of a metastatic malignancy is confirmed by histopathological examination.

Delayed presentation of inflammatory breast carcinoma during the COVID-19 pandemic.

Background: Breast cancer may present with distinct cutaneous manifestations that may be paraneoplastic or secondary to direct skin infiltration, distant skin metastases, or dermal lymphatic tumor embolization (inflammatory breast carcinoma). Case report: A 51-year-old Asian woman visited the emergency care department during the outbreak of COVID-19 in Northern Italy. About 6 months before, she had noted the onset of right breast swelling accompanied by skin redness and itching. She never consulted a physician, and, over time, the local skin condition progressed to a large scaly plaque covering the entire breast surface including the nipple. At presentation, abduction of the right upper limb was impaired due to severe shoulder pain. CT scan showed the presence of bilateral breast masses with necrotic and colliquative features, and multiple skeletal, nodal, pulmonary, and brain images suggestive of metastases. An ultrasound-guided core biopsy of the contralateral breast showed grade 2 non-special type infiltrating carcinoma. The patient was referred to the breast oncology unit and is currently being treated with aromatase inhibitors and chemotherapy. Conclusion: The COVID-19 pandemic has disrupted the entire spectrum of oncological care including breast cancer. Hopefully, telemedicine will contribute to increase patients' confidence and will provide earlier diagnosis and treatment while minimizing the risk of contagion.

Squamous cell carcinoma of the lung presenting as a fungating ulcerated skin lesion: a case report.

BACKGROUND: Our patient presents with a novel presentation of a fungated ulcerated skin lesion as the initial presentation of lung cancer. The literature describes skin metastases from lung cancer as nodular, papular, and zosteriform. Our case is a fungating ulcerated skin lesion which is not widely reported in literature. There is a still a need for more data on the clinical presentation and prognosis of such cases as it will elucidate the diagnostic challenges and treatment management. CASE PRESENTATION: We present a case of a 55 year old Caucasian male with a 60-pack-year smoking history initially presenting with a nodule on his right upper back that quickly fungated and ulcerated requiring surgical excision. Biopsy of both the skin lesion and the lung mass confirmed squamous cell carcinoma (SCC) and the lung mass being the primary tumor. The patient's clinical and functional status severely declined during his hospital stay and was later discharged to hospice without therapeutic intervention. He later expired a month after hospice stay. CONCLUSIONS: Although uncommon, this case clearly illustrates that skin metastases can be the initial finding of primary lung cancer and that not all patients with lung cancer will present with bronchopulmonary symptoms. It also illustrates that a fungating ulcerated lesion can be the initial presentation of lung cancer in addition to nodular, papular, and zosteriform presentations noted in the literature.

Cutaneous and Cerebral Metastases From Primary Peritoneal Clear Cell Carcinoma.

Peritoneal tumors are very uncommon and among them, primary peritoneal clear cell carcinoma is extremely rare and often misdiagnosed as others subtypes. There are only 13 cases of primary peritoneal clear cell carcinoma previously reported in the literature and there are no reports about cutaneous metastasis in this setting and only brain metastases were described to be associated with other primary peritoneal carcinoma subtypes. More information about this topic is needed and so we are presenting a new case of primary peritoneal clear cell carcinoma with cutaneous and cerebral metastases in a 34-year-old female.

Literature Review and Our Experience With Bleomycin-Based Electrochemotherapy for Cutaneous Vulvar Metastases From Endometrial Cancer.

Endometrial carcinoma is the most common gynecological malignancy and the fifth most common malignancy in women. The worldwide incidence is 15.9 new cases per 100,000 women per year, and the incidence in Europe is 22.7 new cases. Minority of cases are diagnosed at an advanced stage of the disease. Cutaneous metastases are very rare with a prevalence of 0.8%. If cutaneous metastases are present, the prognosis is poor with an overall survival of up to 12 months. In this review, we presented clinical data on treatment of gynecological cancers with electrochemotherapy, with focus on treatment of cutaneous vulvar metastases from endometrial cancer. Further, we present our data on the case of a 64-year-old woman with recurrent endometrial adenocarcinoma with vulvar skin metastases. Treatment of endometrial carcinoma metastases is multimodal with surgery, chemotherapy, radiotherapy and hormone treatment. There is still no consensus about the specific treatment of cutaneous metastases from endometrial cancer, in particular in order to release symptoms. Electrochemotherapy may be a treatment option to reduce pain and bleeding and a safe option to treat multiple skin metastases.

Combination of Pembrolizumab with Electrochemotherapy in Cutaneous Metastases from Melanoma: A Comparative Retrospective Study from the InspECT and Slovenian Cancer Registry.

Electrochemotherapy (ECT) is an effective locoregional therapy for cutaneous melanoma metastases and has been safely combined with immune checkpoint inhibitors in preliminary experiences. Since ECT is known to induce immunogenic cell death, its combination with immune checkpoint inhibitors might be beneficial. In this study, we aimed to investigate the effectiveness of ECT on cutaneous melanoma metastases in combination with pembrolizumab. We undertook a retrospective matched cohort analysis of stage IIIC-IV melanoma patients, included in the International Network for sharing practices of ECT (InspECT) and the Slovenian Cancer Registry. We compared the outcome of patients who received the following treatments: (a) pembrolizumab alone, (b) pembrolizumab plus ECT, and (c) ECT. The groups were matched for age, sex, performance status, and size of skin metastases. The local objective response rate (ORR) was higher in the pembrolizumab-ECT group than in the pembrolizumab group (78% and 39%, p < 0.001). The 1 year local progression-free survival (LPFS) rates were 86% and 51% (p < 0.001), and the 1 year systemic PFS rates were 64% and 39%, respectively (p = 0.034). The 1 year overall survival (OS) rates were 88% and 64%, respectively (p = 0.006). Our results suggest that skin-directed therapy with ECT improves superficial tumor control in melanoma patients treated with pembrolizumab. Interestingly, we observed longer PFS and OS in the pembrolizumab-ECT group than in the pembrolizumab group. These findings warrant prospective confirmation.