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PURPOSE: The combination of trastuzumab and pertuzumab (HP) as part of a taxane-based regimen has shown benefit in the adjuvant and metastatic HER2 + breast cancer setting. In the CLEOPATRA trial, pruritus was reported in 11-17.6% of patients. The clinical phenotype and potential treatment strategies for this event have not been reported. METHODS: A retrospective review of 2583 patients receiving trastuzumab and pertuzumab for the treatment of HER2 + breast cancer from 11/23/2011 to 6/21/2021 was performed at Memorial Sloan Kettering Cancer Center (MSKCC). Patient demographics, pruritus characteristics, and treatments as documented in the electronic medical record (EMR) were included in this analysis. RESULTS: Of 2583 pts treated with HP, 122 (4.72%) with pruritus were identified. On average, patients experienced pruritus 319.0 days (8-3171) after initiation of HP. The upper extremities (67.4%), back (29.3%), lower extremities (17.4%), and shoulders (14.1%) were the most commonly affected regions. Grade 1/2 pruritus (97.6%) occurred in most cases. Patients responded primarily to treatment with topical steroids (52.2%), antihistamines (29.9%), emollients (20.9%), and gabapentinoids (16.4%). Of those with pruritus, 4 patients (3.3%) required treatment interruption or discontinuation. CONCLUSIONS: Pruritus is uncommon in patients on trastuzumab and pertuzumab, generally a chronic condition, with gabapentinoids or antihistamines representing effective therapies.
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Anticorpos Monoclonais Humanizados , Neoplasias da Mama , Humanos , Feminino , Trastuzumab , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2 , Antagonistas dos Receptores Histamínicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
ABSTRACT: The conventional morphological characteristics of Wnt-activated deep penetrating/plexiform melanocytomas/nevi (DPN) are those of large spindled or epithelioid melanocytes with distinctive voluminous amphophilic cytoplasm, fine pigmented granules, and surrounding melanophages. The central molecular hallmark is the activation of the Wnt-pathway predominantly driven by mutations in the beta-catenin ( CTNNB1 ) gene. Although typically lacking a junctional component, a lesser-known superficial variant with a junctional component has been identified, which could potentially lead to diagnostic challenges. This study presents a cohort of 11 such cases displaying a junctional component of DPN from 10 patients (5 women and 5 men; age range: 27-78 years; median age: 51 years). The nevi were distributed as follows: 1 conjunctival, 1 scalp, 2 lower limb, and 6 truncal lesions. Eight cases were combined with a conventional nevus, 2 cases displayed pure DPN cytology exhibiting only a junctional element, and 9 cases exhibited some degree of lentiginous architecture. All cases demonstrated a low mitotic index (<1 mitosis/mm 2 ). Immunohistochemistry revealed positive BRAF V600E staining in 8 cases (8/11), whereas all cases tested (11/11) were PRAME negative. Nuclear beta-catenin and LEF1 staining was consistently strong and diffuse with DPN cytology (11/11), along with robust cyclin D1 staining in all cases tested (11/11). By contrast, all 9 conventional nevi showed an absence of nuclear beta-catenin staining (0/9) and weaker, mosaic-type LEF1 and cyclin D1 staining was observed. This study emphasizes the diagnostic challenge these nevi can pose in the absence of a conventional, deeper DPN component, which can potentially be misdiagnosed as melanoma.
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Nevo Pigmentado , Neoplasias Cutâneas , Via de Sinalização Wnt , beta Catenina , Humanos , Pessoa de Meia-Idade , Nevo Pigmentado/patologia , Nevo Pigmentado/metabolismo , Nevo Pigmentado/genética , Feminino , Masculino , Adulto , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Idoso , beta Catenina/metabolismo , beta Catenina/genética , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Imuno-Histoquímica , Melanoma/patologia , Melanoma/genética , Melanoma/metabolismoRESUMO
INTRODUCTION: Sweet syndrome (SS) is well-known to be associated with underlying hematologic malignancies. The incidence and qualities of SS among novel targeted therapies for acute myeloid leukemia (AML) have not yet been described. METHODS: Through retrospective review of 19432 patients diagnosed with acute/chronic leukemia or myelodysplastic syndromes/ myeloproliferative neoplasms (MDS+/-MPN) over 28 years, we calculated the incidence of SS in the setting of select hematologic malignancies and described the clinicopathologic characteristics of SS in patients with onset of SS after initiation of novel AML-targeted therapies. RESULTS: Overall incidence of SS was 0.36% (95% CI: 0.27% - 0.45%), which was significantly higher among patients with AML (50/5248, 0.94%; 95% CI: 0.71% - 1.25%). Nine AML patients were on 4 classes of novel targeted treatments - IDH1/2 inhibitor alone, FLT3 inhibitor, IDH2 and DOT1L inhibitor, and anti-CD33 therapy. In therapies inducing myeloid blast differentiation, SS occurred at later onset following treatment. CONCLUSIONS: In AML patients with fever and unusual skin lesions, physicians may consider SS earlier which may shorten time to diagnosis. Future assessments of SS among patients treated with novel therapies for AML and molecular studies of biopsies may help further explain this dermatologic adverse event with earlier diagnosis and management of neutrophilic dermatoses in these patients.
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Digital papillary adenocarcinoma (DPAC) is a rare tumor of sweat gland origin that preferentially affects the digits and has the potential to metastasize. Its tumor diagnosis can be difficult. Well-differentiated variants of DPAC can be confused with a benign sweat gland tumor, in particular nodular hidradenoma. With the recent detection of HPV42 DNA in DPAC by next-generation sequence analysis, we reasoned that this association could be used for diagnostic purposes. To this end, we performed in situ hybridization for HPV42 on 10 tumors diagnosed as DPAC as well as 30 sweat gland tumors of various histology types, including 8 acral hidradenomas. All DPAC were positive for HPV42. Positive hybridization signals for HPV42 were seen in both primary and metastatic DPACs. All other tumors and normal tissues were negative. This study confirms the association of HPV42 with the tumor cells of DPAC through in situ hybridization. The positive test result in all lesions of DPAC and lack of detection of HPV42 in any of the acral hidradenomas or other sweat gland tumors examined in this series is encouraging for the potential diagnostic utility of the assay. As documented by two scrotal tumors of DPAC, the in situ hybridization test for HPV42 can also help support the rare occurrence of this tumor at a non-acral site.
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Acrospiroma , Adenocarcinoma de Células Claras , Adenocarcinoma Papilar , Adenoma de Glândula Sudorípara , Neoplasias Ósseas , Neoplasias da Mama , Neoplasias de Tecido Conjuntivo , Neoplasias das Glândulas Sudoríparas , Acrospiroma/diagnóstico , Acrospiroma/genética , Acrospiroma/patologia , Adenocarcinoma Papilar/patologia , Adenoma de Glândula Sudorípara/diagnóstico , Adenoma de Glândula Sudorípara/patologia , Feminino , Humanos , Hibridização In Situ , Neoplasias das Glândulas Sudoríparas/diagnóstico , Neoplasias das Glândulas Sudoríparas/genética , Neoplasias das Glândulas Sudoríparas/patologiaRESUMO
Immune checkpoint inhibitors have emerged as a pillar in the management of advanced malignancies. However, nonspecific immune activation may lead to immune-related adverse events, wherein the skin and its appendages are the most frequent targets. Cutaneous immune-related adverse events include a diverse group of inflammatory reactions, with maculopapular rash, pruritus, psoriasiform and lichenoid eruptions being the most prevalent subtypes. Cutaneous immune-related adverse events occur early, with maculopapular rash presenting within the first 6 weeks after the initial immune checkpoint inhibitor dose. Management involves the use of topical corticosteroids for mild to moderate (grades 1-2) rash, addition of systemic corticosteroids for severe (grade 3) rash, and discontinuation of immunotherapy with grade 4 rash. Bullous pemphigoid eruptions, vitiligo-like skin hypopigmentation/depigmentation, and psoriasiform rash are more often attributed to programmed cell death-1/programmed cell death ligand-1 inhibitors. The treatment of bullous pemphigoid eruptions is similar to the treatment of maculopapular rash and lichenoid eruptions, with the addition of rituximab in grade 3-4 rash. Skin hypopigmentation/depigmentation does not require specific dermatologic treatment aside from photoprotective measures. In addition to topical corticosteroids, psoriasiform rash may be managed with vitamin D3 analogues, narrowband ultraviolet B light phototherapy, retinoids, or immunomodulatory biologic agents. Stevens-Johnson syndrome and other severe cutaneous immune-related adverse events, although rare, have also been associated with checkpoint blockade and require inpatient care as well as urgent dermatology consultation.
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Toxidermias/etiologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias/tratamento farmacológico , Toxidermias/epidemiologia , Toxidermias/imunologia , Toxidermias/patologia , HumanosAssuntos
Carcinoma de Célula de Merkel , Neoplasias Cutâneas , Humanos , Carcinoma de Célula de Merkel/epidemiologia , Carcinoma de Célula de Merkel/patologia , Carcinoma de Célula de Merkel/etnologia , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/etnologia , Estudos Retrospectivos , Masculino , Feminino , Estudos de Casos e Controles , Idoso , Pessoa de Meia-Idade , Idoso de 80 Anos ou maisAssuntos
Dermatite , Linfoma Cutâneo de Células T , Neoplasias Cutâneas , Humanos , Imuno-Histoquímica , Estudos Retrospectivos , Linfoma Cutâneo de Células T/diagnóstico , Linfoma Cutâneo de Células T/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Dermatite/diagnóstico , Dermatite/etiologiaRESUMO
BACKGROUND: Angiotropism is the histopathological correlate of pericytic mimicry and extravascular migratory metastasis (EVMM), a mechanism of melanoma spread by migration along the external surface of blood and lymphatic vessels. The frequency of angiotropism in primary cutaneous melanoma and the clinical utility of its detection remain unclear. METHODS: We investigated angiotropism in 179 primary cutaneous melanomas by hematoxylin and eosin (H&E), CD31, and S100/D240 stains. RESULTS: We detected angiotropism in 31 cases (17%) by H&E. CD31 immunohistochemistry increased detection to 59 cases (33%). When lymphatic vessels were included by using S100/D240 stains, 67 cases (37%) cases were positive. Angiotropism was associated with lymphatic invasion and mitotic rate with all detection methods. There was an association with increased tumor thickness when detected by H&E and CD31. No association with sentinel lymph node status was seen. By H&E and CD31 staining, angiotropism was associated with disease progression and distant metastases by univariate, but not multivariate analysis. Overall survival was not affected by the presence of angiotropism. CONCLUSIONS: Angiotropism is relatively common in primary melanoma when immunohistochemical stains are used for detection and associated with mitotic rate and intravascular lymphatic invasion. The association with disease progression and distant metastasis suggests that it represents an alternative pathway of metastasis, that is, EVMM/pericytic mimicry vs intravascular spread.
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Progressão da Doença , Melanoma , Proteínas de Neoplasias/metabolismo , Pericitos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Neoplasias Cutâneas , Feminino , Humanos , Imuno-Histoquímica , Masculino , Melanoma/metabolismo , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Pericitos/metabolismo , Pericitos/patologia , Estudos Retrospectivos , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Melanoma Maligno CutâneoRESUMO
BACKGROUND: Calciphylaxis is a rare, painful, and debilitating disorder of vascular calcification and skin necrosis that typically affects patients with advanced kidney disease. During our routine pathology practice, we noted several missed diagnoses on calciphylaxis consultation cases originating from outside institutions and sought to explore factors associated with false-negative pathologic diagnosis of calciphylaxis. METHODS: The pathology database of a large tertiary academic medical center was retrospectively searched for "calciphylaxis" in inside reports on outside surgical consultation cases between 2007 and 2017. Inside and outside pathology reports were compared and medical records were searched for calciphylaxis clinical diagnosis and risk factors. RESULTS: Twenty-four calciphylaxis patients were identified, with median age of 63.5 years. Seven of 24 (29%) of specimens were inadequate (e.g., lack of subcutaneous adipose tissue for evaluation). Eight of 17 (47%) of adequate specimens had a first false-negative pathologic diagnosis of calciphylaxis. Histochemical staining for calcium significantly correlated with true-positive diagnosis (93% vs 55%, P = 0.004). Dermatopathology fellowship training significantly correlated with true-positive diagnosis (82% vs 38%, P = 0.047). CONCLUSIONS: Adequate sampling, dermatopathology training, and use of histochemical stains to identify calcium associate with decreased false-negative rate for calciphylaxis diagnosis. These findings need further evaluation in larger prospective studies.
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Calciofilaxia , Cálcio/metabolismo , Dermatopatias , Adulto , Idoso , Idoso de 80 Anos ou mais , Calciofilaxia/diagnóstico , Calciofilaxia/metabolismo , Calciofilaxia/patologia , Bases de Dados Factuais , Reações Falso-Negativas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Dermatopatias/diagnóstico , Dermatopatias/metabolismo , Dermatopatias/patologiaRESUMO
Access of melanoma cells to the cutaneous vasculature either via lymphatic invasion or angiotropism is a proposed mechanism for metastasis. Lymphatic invasion is believed to be a mechanism by which melanoma cells can disseminate to regional lymph nodes and to distant sites and may be predictive of adverse outcomes. Although it can be detected on hematoxylin- and eosin-stained sections, sensitivity is markedly improved by immunohistochemistry for lymphatic endothelial cells. Multiple studies have reported a significant association between the presence of lymphatic invasion and sentinel lymph node metastasis and survival. More recently, extravascular migratory metastasis has been suggested as another means by which melanoma cells can spread. Angiotropism, the histopathologic correlate of extravascular migratory metastasis, has also been associated with melanoma metastasis and disease recurrence. Although lymphatic invasion and angiotropism are not currently part of routine melanoma reporting, the detection of these attributes using ancillary immunohistochemical stains may be useful in therapeutic planning for patients with melanoma.
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Linfonodos/patologia , Melanoma/patologia , Neovascularização Patológica/patologia , Neoplasias Cutâneas/patologia , Movimento Celular , Intervalo Livre de Doença , Histocitoquímica , Humanos , Imuno-Histoquímica , Metástase Linfática , Melanoma/irrigação sanguínea , Melanoma/metabolismo , Glicoproteínas de Membrana/análise , Invasividade Neoplásica , Recidiva Local de Neoplasia , Neovascularização Patológica/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/análise , Prognóstico , Proteínas S100/análise , Biópsia de Linfonodo Sentinela , Neoplasias Cutâneas/irrigação sanguínea , Neoplasias Cutâneas/metabolismo , Proteínas de Transporte Vesicular/análiseRESUMO
BACKGROUND: Sentinel lymph node (SLN) metastasis is a powerful predictor of survival in primary cutaneous melanoma. Lymphatic invasion (LI) may correlate with increased risk of SLN metastasis. Intralymphatic metastases, often difficult to detect on hematoxylin and eosin (H&E) stained sections, are readily identified with dual immunohistochemistry for melanocytic and lymphatic markers. METHODS: We used dual S100/D240 immunohistochemistry to detect LI in 125 melanomas from patients who underwent SLN biopsy and correlated LI with melanoma staging parameters and disease status. RESULTS: Dual immunohistochemistry allowed for the identification of LI in 33 cases (26%), compared to only 2% on H&E stained sections. Melanomas with LI showed greater thickness, higher mitotic rate and more frequent ulceration. Eleven of 33 cases with LI (33%) and 10 of 92 cases without LI (11%) were associated with a positive SLN (P = .006). More patients without LI were disease-free at last follow-up (80%) than patients with LI (50%; P = .002); LI was significantly associated with decreased progression-free survival. CONCLUSION: The detection of LI is improved by dual immunohistochemistry and predicts SLN metastasis. The presence of LI may impact therapeutic planning in melanoma, such as the decision to perform a SLN biopsy.
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Biomarcadores Tumorais/análise , Imuno-Histoquímica/métodos , Metástase Linfática/diagnóstico , Melanoma/patologia , Linfonodo Sentinela/patologia , Neoplasias Cutâneas/patologia , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Melanoma Maligno CutâneoRESUMO
AIMS: Bile duct adenomas may be difficult to distinguish from metastatic carcinomas, particularly well-differentiated pancreatic ductal adenocarcinoma. Prior studies have evaluated the utility of various immunohistochemical markers, although these markers are notable for low sensitivity and/or specificity. The aim of this study was to investigate the utility of albumin and BRAFV600E expression in distinguishing between metastatic pancreatic adenocarcinoma and bile duct adenoma. METHODS AND RESULTS: We studied 26 bile duct adenomas, three bile duct hamartomas, and 158 pancreatic ductal adenocarcinomas. Branched-chain in-situ hybridization (bISH) for albumin was performed; bISH is based on the branched DNA technology, wherein signal amplification is achieved via a series of sequential steps. Additionally, BRAFV600E immunohistochemistry (IHC) was performed on a subset of cases. Twenty-three of 25 (92%) bile duct adenomas were positive for albumin; 18 (72%) showed diffuse staining, and five showed focal staining (20%), including two challenging examples. Two bile duct hamartomas also stained positively. All pancreatic adenocarcinomas were negative for albumin. Seven of 16 (44%) bile duct adenomas and five of 106 (5%) pancreatic ductal adenocarcinomas were positive for BRAFV600E by IHC. The sensitivity and specificity of expression of albumin, as detected by bISH, for distinguishing bile duct adenomas from metastatic pancreatic adenocarcinomas were 92% and 100%, respectively; the sensitivity and specificity of BRAFV600E IHC for distinguishing bile duct adenomas from metastatic pancreatic adenocarcinomas were 43.8% and 95.3%, respectively. CONCLUSIONS: Diagnostically challenging examples of bile duct adenoma may be distinguished from metastatic pancreatic adenocarcinoma by the use of albumin bISH.
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Adenocarcinoma/diagnóstico , Adenoma de Ducto Biliar/diagnóstico , Albuminas/biossíntese , Neoplasias dos Ductos Biliares/diagnóstico , Biomarcadores Tumorais/análise , Adulto , Idoso , Albuminas/análise , Ductos Biliares Intra-Hepáticos/patologia , Carcinoma Ductal Pancreático/diagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/diagnóstico , Proteínas Proto-Oncogênicas B-raf/biossíntese , Estudos Retrospectivos , Sensibilidade e Especificidade , Análise Serial de TecidosRESUMO
BACKGROUND: Chronic urticaria is a condition with many inciting factors and often presents a therapeutic challenge to clinicians. In addition to a central role for mast cells, an immune dysregulated state related to cytokine/chemokine alterations is increasingly being recognized. METHODS: Biopsies of chronic urticaria (n = 11) and normal skin (n = 5) were evaluated with immunostains for CD117, CD3 and dual stains for CD4/T-bet, GATA-3, STAT-3 or BNC-2 (transcription factors specific and mutually exclusive for Th1, Th2, Th17 and Th22 cells, respectively). Clinical data, including autoantibodies and thyroid function tests, and the number of CD117+ mast cells and percent of Th1, Th2, Th17 and Th22 of CD3+ T-cells were compared. RESULTS: Th2 cells and Th17 cells were significantly more frequent in chronic urticaria than controls. In contrast, there was no significant difference in mast cells, Th1 cells or Th22 cells. Three of nine chronic urticaria patients had evidence of autoimmune disease; biopsies from these patients trended toward a greater number of mast cells and decreased percent of Th-cell subtypes as compared with those without autoimmunity markers, with significantly less Th22 cells. CONCLUSIONS: These findings provide novel insight into the role of Th2 and Th17 in chronic urticaria pathophysiology and may impact therapy.
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Doenças Autoimunes , Pele , Células Th17 , Células Th2 , Doenças da Glândula Tireoide , Urticária , Adulto , Antígenos de Diferenciação/imunologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Doença Crônica , Feminino , Humanos , Masculino , Mastócitos/imunologia , Mastócitos/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Pele/imunologia , Pele/patologia , Células Th17/imunologia , Células Th17/patologia , Células Th2/imunologia , Células Th2/patologia , Doenças da Glândula Tireoide/imunologia , Doenças da Glândula Tireoide/patologia , Urticária/imunologia , Urticária/patologiaAssuntos
Vasculite por IgA/diagnóstico , Pele/patologia , Vasculite/diagnóstico , Biópsia , Doença de Crohn/complicações , Diagnóstico Diferencial , Edema/etiologia , Exantema/etiologia , Humanos , Vasculite por IgA/complicações , Vasculite por IgA/patologia , Masculino , Dor/etiologia , Púrpura/etiologia , Adulto JovemAssuntos
Cefaleia/etiologia , Hemoglobinúria Paroxística/diagnóstico , Trombose Venosa/etiologia , Dor Abdominal/etiologia , Adulto , Anemia/etiologia , Anemia Hemolítica/diagnóstico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Exame de Medula Óssea , Encéfalo/diagnóstico por imagem , Veias Cerebrais/diagnóstico por imagem , Coagulação Intravascular Disseminada/diagnóstico , Feminino , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/tratamento farmacológico , Humanos , Radiografia Abdominal , Baço/diagnóstico por imagem , Baço/patologia , Trombocitopenia/etiologia , Tomografia Computadorizada por Raios X , Trombose Venosa/diagnóstico por imagem , Transtornos da Visão/etiologiaRESUMO
BACKGROUND: For patients with melanoma, the decision to perform sentinel lymph node biopsy (SLNB) is based on the estimated risk of lymph node metastasis. We assessed 3 melanoma SLNB risk-prediction models' statistical performance and their ability to improve clinical decision making (clinical utility) on a cohort of melanoma SLNB cases. STUDY DESIGN: Melanoma patients undergoing SLNB at a single center from 2003 to 2021 were identified. The predicted probabilities of sentinel lymph node positivity using the Melanoma Institute of Australia, Memorial Sloan Kettering Cancer Center (MSK), and Friedman nomograms were calculated. Receiver operating characteristic and calibration curves were generated. Clinical utility was assessed via decision curve analysis, calculating the net SLNBs that could have been avoided had a given model guided selection at different risk thresholds. RESULTS: Of 2,464 melanoma cases that underwent SLNB, 567 (23.0%) had a positive sentinel lymph node. The areas under the receiver operating characteristic curves for the Melanoma Institute of Australia, MSK, and Friedman models were 0.726 (95% CI, 0.702 to 0.750), 0.720 (95% CI, 0.697 to 0.744), and 0.721 (95% CI, 0.699 to 0.744), respectively. For all models, calibration was best at predicted positivity rates below 30%. The MSK model underpredicted risk. At a 10% risk threshold, only the Friedman model would correctly avoid a net of 6.2 SLNBs per 100 patients. The other models did not reduce net avoidable SLNBs at risk thresholds of ≤10%. CONCLUSIONS: The tested nomograms had comparable performance in our cohort. The only model that achieved clinical utility at risk thresholds of ≤10% was the Friedman model.
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Melanoma , Linfonodo Sentinela , Neoplasias Cutâneas , Humanos , Biópsia de Linfonodo Sentinela , Melanoma/patologia , Nomogramas , Metástase Linfática/patologia , Linfonodo Sentinela/patologia , Linfonodos/patologia , Neoplasias Cutâneas/cirurgia , Neoplasias Cutâneas/patologia , Estudos RetrospectivosRESUMO
The multiplexed immunofluorescence (mIF) platform enables biomarker discovery through the simultaneous detection of multiple markers on a single tissue slide, offering detailed insights into intratumor heterogeneity and the tumor-immune microenvironment at spatially resolved single cell resolution. However, current mIF image analyses are labor-intensive, requiring specialized pathology expertise which limits their scalability and clinical application. To address this challenge, we developed CellGate, a deep-learning (DL) computational pipeline that provides streamlined, end-to-end whole-slide mIF image analysis including nuclei detection, cell segmentation, cell classification, and combined immuno-phenotyping across stacked images. The model was trained on over 750,000 single cell images from 34 melanomas in a retrospective cohort of patients using whole tissue sections stained for CD3, CD8, CD68, CK-SOX10, PD-1, PD-L1, and FOXP3 with manual gating and extensive pathology review. When tested on new whole mIF slides, the model demonstrated high precision-recall AUC. Further validation on whole-slide mIF images of 9 primary melanomas from an independent cohort confirmed that CellGate can reproduce expert pathology analysis with high accuracy. We show that spatial immuno-phenotyping results using CellGate provide deep insights into the immune cell topography and differences in T cell functional states and interactions with tumor cells in patients with distinct histopathology and clinical characteristics. This pipeline offers a fully automated and parallelizable computing process with substantially improved consistency for cell type classification across images, potentially enabling high throughput whole-slide mIF tissue image analysis for large-scale clinical and research applications.
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PURPOSE: Immune-related cutaneous adverse events (ircAE) occur in ≥50% of patients treated with checkpoint inhibitors, but the underlying mechanisms for ircAEs are poorly understood. EXPERIMENTAL DESIGN: Phenotyping/biomarker analyses were conducted in 200 patients on checkpoint inhibitors [139 with ircAEs and 61 without (control group)] to characterize their clinical presentation and immunologic endotypes. Cytokines were evaluated in skin biopsies, skin tape strip extracts, and plasma using real-time PCR and Meso Scale Discovery multiplex cytokine assays. RESULTS: Eight ircAE phenotypes were identified: pruritus (26%), maculopapular rash (MPR; 21%), eczema (19%), lichenoid (11%), urticaria (8%), psoriasiform (6%), vitiligo (5%), and bullous dermatitis (4%). All phenotypes showed skin lymphocyte and eosinophil infiltrates. Skin biopsy PCR revealed the highest increase in IFNγ mRNA in patients with lichenoid (P < 0.0001) and psoriasiform dermatitis (P < 0.01) as compared with patients without ircAEs, whereas the highest IL13 mRNA levels were detected in patients with eczema (P < 0.0001, compared with control). IL17A mRNA was selectively increased in psoriasiform (P < 0.001), lichenoid (P < 0.0001), bullous dermatitis (P < 0.05), and MPR (P < 0.001) compared with control. Distinct cytokine profiles were confirmed in skin tape strip and plasma. Analysis determined increased skin/plasma IL4 cytokine in pruritus, skin IL13 in eczema, plasma IL5 and IL31 in eczema and urticaria, and mixed-cytokine pathways in MPR. Broad inhibition via corticosteroids or type 2 cytokine-targeted inhibition resulted in clinical benefit in these ircAEs. In contrast, significant skin upregulation of type 1/type 17 pathways was found in psoriasiform, lichenoid, bullous dermatitis, and type 1 activation in vitiligo. CONCLUSIONS: Distinct immunologic ircAE endotypes suggest actionable targets for precision medicine-based interventions.
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Citocinas , Inibidores de Checkpoint Imunológico , Humanos , Masculino , Feminino , Inibidores de Checkpoint Imunológico/efeitos adversos , Pessoa de Meia-Idade , Idoso , Citocinas/metabolismo , Pele/patologia , Pele/imunologia , Pele/metabolismo , Pele/efeitos dos fármacos , Adulto , Toxidermias/etiologia , Toxidermias/patologia , Toxidermias/imunologia , Prurido/imunologia , Prurido/induzido quimicamente , Prurido/patologia , Prurido/etiologia , Prurido/genética , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Dermatopatias/induzido quimicamente , Dermatopatias/imunologia , Dermatopatias/patologia , Dermatopatias/etiologia , Exantema/induzido quimicamente , Exantema/patologia , Idoso de 80 Anos ou mais , Psoríase/tratamento farmacológico , Psoríase/imunologia , Psoríase/patologia , Psoríase/genética , Eczema/patologia , Eczema/tratamento farmacológicoRESUMO
Cutaneous lymphomas encompass a heterogeneous group of neoplasms with a wide spectrum of clinical presentations, histopathologic features, and prognosis. Because there are overlapping pathologic features among indolent and aggressive forms and with systemic lymphomas that involve the skin, clinicopathologic correlation is essential. Herein, the clinical and histopathologic features of aggressive cutaneous B- and T-cell lymphomas are reviewed. Indolent cutaneous lymphomas/lymphoproliferative disorders, systemic lymphomas, and reactive processes that may mimic these entities are also discussed. This article highlights distinctive clinical and histopathologic features, increases awareness of rare entities, and presents new and evolving developments in the field.
Assuntos
Linfoma Cutâneo de Células T , Linfoma de Células T , Neoplasias Cutâneas , Humanos , Linfoma Cutâneo de Células T/diagnóstico , Linfoma Cutâneo de Células T/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Linfoma de Células T/patologia , PrognósticoRESUMO
Background: Immune-related cutaneous adverse events (ircAEs) are frequent and may reduce quality of life and consistent dosing. IL12/23 has been implicated in psoriasis, which is reminiscent of the psoriasiform/lichenoid ircAE phenotype. We report the use of ustekinumab as a therapeutic option. Methods: Patients at Memorial Sloan Kettering Cancer Center, New York, who received immune checkpoint inhibitors and were treated with ustekinumab or had the keywords "ustekinumab" or "Stelara" in their clinical notes between 1 March 2017 and 1 December 2022 were retrospectively identified via a database query. Documentation from initial and follow-up visits was manually reviewed, and response to ustekinumab was categorized into complete cutaneous response (CcR, decrease to CTCAE grade 0), partial cutaneous response (PcR, any decrease in CTCAE grade exclusive of decrease to grade 0), and no cutaneous response (NcR, no change in CTCAE grade or worsening). Labs including complete blood count (CBC), cytokine panels, and IgE were obtained in a subset of patients as standard of care. Skin biopsies were reviewed by a dermatopathologist. Results: Fourteen patients with psoriasiform (85.7%), maculopapular (7.1%), and pyoderma gangrenosum (7.1%) ircAEs were identified. Ten (71.4%) receiving ustekinumab had a positive response to treatment. Among these 10 responders, 4 (40%) demonstrated partial cutaneous response and 6 (60%) demonstrated complete cutaneous resolution. Six patients (42.9%) experienced interruptions to their checkpoint inhibitor treatment as a result of intolerable ircAEs, and following ircAE management with ustekinumab, two (33.3%) were successfully rechallenged with their checkpoint inhibitors. On histopathology, patients primarily had findings of interface or psoriasiform dermatitis. No patients reported an adverse event related to ustekinumab. Conclusions: Ustekinumab showed a benefit in a subset of patients with psoriasiform/lichenoid ircAEs. No safety signals were identified. However, further prospective randomized controlled trials are needed to confirm our findings.