Primary Melanoma of the Lacrimal Sac Treated With Pembrolizumab.

Primary melanoma of the lacrimal sac is a rare entity, with high mortality and a propensity for recurrence. This report details a patient with widely metastatic melanoma discovered after biopsy of abnormal lacrimal sac tissue during routine dacryocystorhinostomy. The patient subsequently underwent local excision and treatment with pembrolizumab. At the time of this writing, it has been 24 months since the original diagnosis with resolution of his lacrimal and orbital lesions and improvement in all metastatic lesions. This case highlights the growing use of cancer genomics and immunotherapeutic agents in orbital aspects of oncology and reinforces the role of a multidisciplinary approach in the treatment of such diseases.

Signal transduction pathway analysis in desmoid-type fibromatosis: transforming growth factor-ß, COX2 and sex steroid receptors.

Despite reports of sex steroid receptor and COX2 expression in desmoid-type fibromatosis, responses to single agent therapy with anti-estrogens and non-steroidal anti-inflammatory drugs are unpredictable. Perhaps combination pharmacotherapy might be more effective in desmoid tumors that co-express these targets. Clearly, further understanding of the signaling pathways deregulated in desmoid tumors is essential for the development of targeted molecular therapy. Transforming growth factor-ß (TGFß) and bone morphogenetic proteins (BMP) are important regulators of fibroblast proliferation and matrix deposition, but little is known about the TGFß superfamily in fibromatosis. A tissue microarray representing 27 desmoid tumors was constructed; 14 samples of healing scar and six samples of normal fibrous tissue were included for comparison. Expression of selected receptors and activated downstream transcription factors of TGFß family signaling pathways, ß-catenin, sex steroid hormone receptors and COX2 were assessed using immunohistochemistry; patterns of co-expression were explored via correlational statistical analyses. In addition to ß-catenin, immunoreactivity for phosphorylated SMAD2/3 (indicative of active TGFß signaling) and COX2 was significantly increased in desmoid tumors compared with healing scar and quiescent fibrous tissue. Low levels of phosphorylated SMAD1/5/8 were detected in only a minority of cases. Transforming growth factor-ß receptor type 1 and androgen receptor were expressed in both desmoid tumors and scar, but not in fibrous tissue. Estrogen receptor-ß was present in all cases studied. Transforming growth factor-ß signaling appears to be activated in desmoid-type fibromatosis and phosphorylated SMAD2/3 and COX2 immunoreactivity might be of diagnostic utility in these tumors. Given the frequency of androgen receptor, estrogen receptor-ß and COX2 co-expression in desmoid tumors, further assessment of the efficacy of combination pharmacotherapy using hormonal agonists/antagonists together with COX2 inhibitors should be considered.

Signal transduction pathway analysis in fibromatosis: receptor and nonreceptor tyrosine kinases.

Despite reports of receptor tyrosine kinase activation in desmoid-type fibromatosis, therapeutic benefits of kinase inhibitor therapy are unpredictable. Variability in signal transduction or cellular kinases heretofore unevaluated in desmoid tumors may be responsible for these inconsistent responses. In either case, a better understanding of growth regulatory signaling pathways is necessary to assess the theoretical potential of inhibitor therapy. Immunohistochemical analysis of tyrosine kinases and activated isoforms of downstream signal transduction proteins was performed on a tissue microarray containing 27 cases of desmoid-type fibromatosis and 14 samples of scar; 6 whole sections of normal fibrous tissue were studied for comparison. Platelet-derived growth factor receptor, ß type, and focal adhesion kinase 1 were expressed in all desmoid tumors and healing scars but only 80% and 50% of nonproliferative fibrous tissue samples, respectively. Hepatocyte growth factor receptor was detected in 89% of desmoids and all scars tested, but not in any of the fibrous tissue samples. Epidermal growth factor receptor was detected in only 12% of desmoids and not in scar or fibrous tissue. Mast/stem cell growth factor receptor, receptor tyrosine-protein kinase erbB-2, and phosphorylated insulin-like growth factor 1 receptor/insulin receptor were negative in all study cases. Variable levels of phosphorylated downstream signal transduction molecules RAC-α/ß/γ serine/threonine-protein kinase, mitogen-activated protein kinase, and signal transducer and activator of transcription-3 were observed in desmoids (58%, 62%, and 67%), scar tissues (100%, 86%, and 86%), and fibrous tissue (33%, 17%, and 17%). These results indicate that tyrosine kinase signaling is active in both fibromatosis and healing scar, but not in most nonproliferating fibrous tissues. Although platelet-derived growth factor receptor, ß type, is expressed ubiquitously in desmoids, the kinases driving cell proliferation in desmoids remain unresolved.

Markers of epithelial-mesenchymal transition and epithelial differentiation in sarcomatoid carcinoma: utility in the differential diagnosis with sarcoma.

The distinction between sarcomatoid carcinoma (SC) and bona fide sarcoma can be difficult using conventional immunohistochemical markers. Epithelial-mesenchymal transition (EMT) has been proposed as a histogenetic mechanism for the development of SC. Expression of selected markers of EMT (Twist and Slug) was compared with other markers of epithelial differentiation in SC and spindle cell sarcoma to determine the utility of these antigens in this differential diagnosis. Twenty-seven cases of SC (excluding those of gynecologic origin) were stained by immunohistochemistry for cytokeratins (AE1/AE3, 5D3, CK5/6, and 34betaE12), p63, claudin-1, claudin-7, epithelial cadherin, placental cadherin, epithelial cell adhesion molecule/epithelial-specific antigen, 14-3-3sigma, Twist, and Slug. A comparison group of 21 spindle or pleomorphic spindle cell sarcomas was also studied. Immunohistochemical stains were scored in a semiquantitative manner and subsequent exploratory analyses were performed using logistic regression and chi2 tests. Only cytokeratin AE1/AE3 specifically labeled SC in a statistically significant manner. Other epithelial-specific markers tested did not distinguish SC from sarcoma primarily owing to low sensitivity. However, when positive, immunostains such as CK5/6, membranous epithelial cadherin, and nuclear p63 may aid in the distinction of SC from sarcoma. EMT markers were expressed in most cases of both SC and sarcoma, and were not useful in making a differential diagnosis between these neoplasms.

Steroid hormone receptor and COX-2 expression in chordoma.

Reports of sex steroid receptor expression in chordoma suggest that these tumors may be responsive to hormone manipulation therapy. Immunohistochemical stains for estrogen receptor (ER)-alpha, ER-beta, progesterone receptor (PR), androgen receptor (AR), and cyclooxygenase 2 (COX-2), were performed on a tissue microarray containing 21 samples of chordoma. Most chordomas expressed COX-2, ER-beta, and AR, whereas ER-alpha and PR stains were negative in all cases. ER-beta expression did not correlate with AR expression (P = .4142; McNemar test). There were no statistically significant correlations between the expression of any of these markers and anatomic location of tumor, patient sex, patient age, or disease-free survival. Chordomas commonly express COX-2, AR, and ER-beta. These findings may have therapeutic implications concerning the use of agents that inhibit or modulate these signaling molecules.