Extramammary Paget disease (EMPD) is a locally aggressive cutaneous malignancy that usually arises in anogenital or axillary skin. Immune checkpoint inhibitors targeting programmed cell death receptor (PD-1) and/or its ligand (PD-L1) are approved for the treatment of several types of cancer, and response to these generally correlates with increased PD-L1 expression by tumor cells. The expression of PD-L1 and composition and density of the tumor-associated immune infiltrate in EMPD have been little studied. To determine whether EMPD might be amenable to immune checkpoint blockade, we analyzed the expression of PD-1 and PD-L1 and the composition and density of the tumor-associated immune infiltrate in EMPD and evaluated associations between biomarker expression and clinicopathologic parameters. Twenty-one EMPD tumors were evaluated for tumor cell PD-L1 expression and for relative expression and distribution of CD3, CD8, PD-1, and PD-L1 in the tumor-associated immune infiltrate by using a combination of visual and image analysis (Aperio ImageScope). In addition, PD-L1 expression was assessed in 10 cases of mammary Paget disease (MPD). In EMPD cases, PD-L1 was expressed by tumor cells (3/21; 14%) and the tumor-associated immune infiltrate (15/21; 71%), and PD-1 was expressed by the tumor-associated immune infiltrate in all cases analyzed (18/18). However, PD-L1 expression by EMPD tumor cells did not correlate with the density of CD3-, CD8-, or PD-1-positive cells in the tumor-associated immune infiltrate or other clinicopathologic parameters. Furthermore, the density of CD3, CD8, PD-1, and PD-L1 in the tumor-associated immune infiltrate did not correlate with any clinicopathologic parameters evaluated with the exception that CD3 positive values were significantly higher in patients who were still alive (median, 1310 cells/mm2; range, 543-2115;) than in those who died (median, 611 cells/mm2; range, 481-908; p = 0.049). In all MPD cases, PD-L1 was absent in tumor cells but present in the tumor-associated immune infiltrate, and PD-L1 expression in lymphocytes was lower in patients with HER2/neu-positive than in those with HER2/neu-negative disease (p = 0.07). Our findings raise the possibility of therapeutic targeting of the PD-1/PD-L1 axis in EMPD.
Epithelioid cells with foamy cytoplasm (histiocytoid features) are typical histopathologic findings among benign and malignant histiocytic neoplasms such as xanthoma and atypical fibroxanthoma. However, these changes are unusual in melanoma, which is typically composed of nested and variably pigmented atypical epithelioid cells. Here, we report a patient with metastatic melanoma in lymph nodes presenting with prominent balloon cell/histiocytoid features expressing melanocytic markers, after treatment with nivolumab. This report suggests that the spectrum of neoplasms with histiocytoid features should be expanded to include melanoma, a pattern that, to the best of our knowledge, is uncommon, especially in the setting of post‐neoadjuvant therapy.
<p>(A, B, C) We first assigned patients with PVM to a T-category according to the AJCC for PCM (7th Edition). (A) Shows the AJCC schema and the number of patients assigned to each category. (B) Kaplan Meier DSS curves for patients stratified by AJCC T-categories demonstrate robust prognostic differences for patients with PVM and pT1 and to an extent pT2 disease from those with pT3 and pT4 disease, but less robust stratification among those patients with PVMs {less than or equal to}2.00 mm; pT1 versus pT2 (isolated in C) or >2.0 mm; pT3 and pT4. (D, E, F) Because both tumor thickness and mitotic rate were independent prognostic factors for DSS and because mitotic rate showed a natural prognostic separation at 2 mitotic figures/mm2 (as shown in Figure 1D), we first asked whether a T-category according to the conventional AJCC cut-offs ({less than or equal to}1.0, 1.01-2.0, 2.01-4.0 and >4.0 mm) subsequently modified by mitotic rate (a: <2/mm2 and b: {greater than or equal to}2/mm2) instead of ulceration (as in the AJCC) would effectively stratify patient outcomes. (D) Shows this initial 'alternative T-category' schema and the number of patients assigned to each category. (E) Kaplan Meier DSS curves for patients assigned to the alternative T-categories demonstrate longer DSS for patients with pT1a and pT2a PVM compared to all other patients in the schema. In particular, patients with PVM >2.0 mm (pT3 and pT4) had a short DSS independent of mitotic rate. More importantly, among patients with a tumor thickness {less than or equal to}2.0 mm (pT1 or pT2), only those with mitotic rate {greater than or equal to}2/mm2 had a short DSS, which was essentially superimposable with patients with pT3 and pT4 PVM in this schema. (F) Kaplan-Meier survival curve for patients with pT1 and pT2 PVMs show striking differences in survival according to mitotic rate (<2/mm2 for pT1a or pT2a versus {greater than or equal to}2/mm2 for pT1b and pT2b). (G, H) Combining the above observations together, we concluded that tumor thickness of 2.0 mm represented the ideal cut off to combine with mitotic rate (with <2/mm2 versus {greater than or equal to}2/mm2 as the cut off) to most effectively delineate DSS among patients with PVM. (G) Schema for the proposed T-category and (H) Kaplan-Meier plots of disease-specific survival according to proposed T-categories. (Note: part G and H are identical to Figure 3C and 3D and are only shown here for direct comparison).</p>
p63, a recently identified homologue of the p53 gene, is mainly expressed by basal and myoepithelial cells in skin. Others and we have shown the value of p63 in distinguishing primary adnexal tumors from visceral adenocarcinomas metastatic to skin. We now investigate the pattern of p63 expression in metastases from skin adnexal carcinomas and their cognate primaries and evaluate p63 expression in a larger case series of malignant cutaneous adnexal neoplasms. Immunohistochemical analysis for p63 was performed on 13 metastases of adnexal carcinomas and their corresponding primary tumors. Twenty visceral metastatic adenocarcinomas to the skin and 7 primary mucinous carcinomas with cutaneous or visceral origin were compared. The majority (90.9%) of primary adnexal tumors strongly expressed p63 and their metastases labeled similar to their cognate primary tumors. With one exception, primary or metastatic mucinous carcinomas did not express p63. Metastases from two apocrine carcinomas lacked p63 expression. All other cutaneous metastases from internal adenocarcinomas were negative for p63. Analysis of p63 expression may assist in the differential diagnosis of primary adnexal carcinomas versus metastatic visceral adenocarcinomas to the skin. Metastases from adnexal carcinomas generally retain p63 expression similar to their associated primary tumors.
Although trichorhinophalangeal syndrome type 1 (TRPS1) was initially thought to be highly sensitive and specific for carcinomas and mesenchymal tumors of mammary origin, more recent data suggest its expression is not limited to breast neoplasms but also can be seen in other cutaneous neoplasms, such as extramammary Paget disease and squamous cell carcinoma (SCC) in situ.
<div>AbstractPurpose:<p>Ocular adnexal (OA) sebaceous carcinoma is an aggressive malignancy of the eyelid and ocular adnexa that frequently recurs and metastasizes, and effective therapies beyond surgical excision are lacking. There remains a critical need to define the molecular-genetic drivers of the disease to understand carcinomagenesis and progression and to devise novel treatment strategies.</p>Experimental Design:<p>We present next-generation sequencing of a targeted panel of cancer-associated genes in 42 and whole transcriptome RNA sequencing from eight OA sebaceous carcinomas from 29 patients.</p>Results:<p>We delineate two potentially distinct molecular-genetic subtypes of OA sebaceous carcinoma. The first is defined by somatic mutations impacting <i>TP53</i> and/or <i>RB1</i> [20/29 (70%) patients, including 10 patients whose primary tumors contained coexisting <i>TP53</i> and <i>RB1</i> mutations] with frequent concomitant mutations affecting <i>NOTCH</i> genes. These tumors arise in older patients and show frequent local recurrence. The second subtype [9/29 (31%) patients] lacks mutations affecting <i>TP53, RB1</i>, or <i>NOTCH</i> family members, but in 44% (4/9) of these tumors, RNA sequencing and <i>in situ</i> hybridization studies confirm transcriptionally active high-risk human papillomavirus. These tumors arise in younger patients and have not shown local recurrence.</p>Conclusions:<p>Together, our findings establish a potential molecular-genetic framework by which to understand the development and progression of OA sebaceous carcinoma and provide key molecular-genetic insights to direct the design of novel therapeutic interventions.</p></div>
<div>Abstract<p>Point mutations in the <i>KIT</i> receptor tyrosine kinase gene have recently been identified in mucosal, acral lentiginous, and chronically sun-damaged melanomas. We have identified the first human melanoma cell line with an endogenous L576P mutation, the most common <i>KIT</i> mutation in melanoma (∼30-40%). <i>In vitro</i> testing showed that the cell viability of the L576P mutant cell line was not reduced by imatinib, nilotinib, or sorafenib small molecule KIT inhibitors effective in nonmelanoma cells with other <i>KIT</i> mutations. However, the viability of the mutant cells was reduced by dasatinib at concentrations as low as 10 nM (<i>P</i> = 0.004). Molecular modeling studies found that the L576P mutation induces structural changes in KIT that reduce the affinity for imatinib (ΔΔGbind = −2.52 kcal/mol) but not for dasatinib (ΔΔGbind = +0.32 kcal/mol). Two metastatic melanoma patients with the L576P <i>KIT</i> mutation were treated with dasatinib, including one patient previously treated with imatinib. Both patients had marked reduction (>50%) and elimination of tumor F18-fluorodeoxyglucose (FDG)-avidity by positron emission tomography (PET) imaging after dasatinib treatment. These data support the selective inhibitory effect of dasatinib against cells harboring the most common <i>KIT</i> mutation in melanoma, and thus has therapeutic implications for acrallentiginous, chronic sun-damaged, and mucosal melanomas. [Mol Cancer Ther 2009;8(8):2079–85]</p></div>
