Divergent differentiation in gynecologic carcinomas encompasses a broad range of lineages, including mesenchymal, germ cell, high-grade neuroendocrine, neuroectodermal, and cutaneous adnexal ...differentiation. Here we present a case of ovarian endometrioid adenocarcinoma with divergent malignant melanocytic differentiation (MMeD). The background ovarian endometrioid adenocarcinoma showed focally aberrant β-catenin expression and histologic patterns associated with β-catenin activation, including spindled elements and corded and hyalinized foci. The areas with MMeD had both spindled and epithelioid morphology, diffusely aberrant β-catenin expression, expression of melanocytic markers (an HMB45/Mart-1 cocktail, MITF, and S100), and no staining for myogenic markers (SMA and desmin) or epithelial markers (cytokeratins and E-cadherin). INI1, BRG1, PMS2, and MSH6 were retained, and p53 showed a wild-type expression pattern. No areas with definitive carcinosarcomatous differentiation were identified despite extensive sampling. While a single case of gynecologic carcinosarcoma with a serous epithelial component and a small focus on malignant melanoma has been reported in the English literature, the current case represents what is, to the best of our knowledge, the first case of MMeD arising in the context of a β-catenin activated endometrioid adenocarcinoma. Pathogenetic and differential diagnostic considerations are discussed.
While human papillomavirus (HPV)-associated adenocarcinoma of the anus resembling endocervical adenocarcinoma has recently been described, anal adenocarcinoma in situ/AIS has not. Moreover, to the ...best of our knowledge, truly biphasic anal adenosquamous carcinoma in situ (ADSQ-IS) is essentially non-existent in the literature. Here, we report four cases of anal ADSQ-IS including one with associated invasive adenosquamous carcinoma. Histologically, all cases of ADSQ-IS showed a basal/peripheral population of stratified, p40-positive dysplastic squamous cells adjacent to luminal, columnar, p40-negative dysplastic glandular cells, bearing a striking resemblance to the normal anal transitional epithelium. Both lesional components were diffusely and strongly positive for p16 and positive for high-risk HPV by RNA in situ hybridization. These cases expand the morphological spectrum of high-risk HPV-associated pre-invasive lesions and underscore the plasticity of HPV-associated neoplasia.
Borderline Brenner tumors (BBT) have a range of morphology that shows considerable overlap with that of malignant Brenner tumors (MBT). In particular, two histological patterns of BBT can be ...particularly challenging: 1) BBT with intraepithelial carcinoma (BBT-IEC) and 2) BBT with a small nested pattern (BBT-SNP). BBT-IEC is characterized by a tumor with the low-power non-infiltrative silhouette of a conventional BBT, but with increased cytological atypia and mitotic activity similar to that of MBT. Conversely, BBT-SNP is characterized by a complex proliferation of small tumor nests that closely resemble the infiltrative growth pattern of MBT, but without the obligate cytologic atypia and mitotic activity of MBT.
We suggest that the combination of p16, p53 and Ki-67 may be helpful in distinguishing these 2 patterns of BBT from both conventional BBT and from MBT. While both conventional BBT and BBT-IEC show a null pattern of p16 expression, our case of BBT-IEC showed aberrant p53 overexpression, albeit with a maturation pattern similar to that described for TP53 mutant mucinous ovarian carcinoma and differentiated vulvar intraepithelial neoplasia (dVIN). Similarly, while BBT-SNP shows an infiltrative-like growth pattern similar to that of MBT, our case also showed a wild-type pattern of p53 expression and a Ki-67 proliferative index similar to areas with conventional BBT histology. In conclusion, in our small case series, we show that the use of immunohistochemistry for p53 and Ki-67 may help to distinguish challenging patterns of BBT from MBT. Further studies are needed to validate this finding in a larger case cohort.
•The small nested pattern and intraepithelial carcinoma pattern of borderline Brenner tumors can be difficult to recognize.•The small nested pattern mimics the infiltrative pattern of malignant Brenner tumor.•The intraepithelial carcinoma pattern mimics conventional borderline Brenner tumor.•P53, p16 and Ki-67 may be useful to distinguish the above 2 patterns from their respective mimickers.
Clinically, increased breast tumor stiffness is associated with metastasis and poorer outcomes. Yet, in vitro studies of tumor cells in 3D scaffolds have found decreased invasion in stiffer ...environments. To resolve this apparent contradiction, MDA-MB-231 breast tumor spheroids were embedded in ‘low’ (2 kPa) and ‘high’ (12 kPa) stiffness 3D hydrogels comprised of methacrylated gelatin/collagen I, a material that allows for physiologically-relevant changes in stiffness while matrix density is held constant. Cells in high stiffness materials exhibited delayed invasion, but more abundant actin-enriched protrusions, compared to those in low stiffness. We find that cells in high stiffness had increased expression of Mena, an invadopodia protein associated with metastasis in breast cancer, as a result of EGFR and PLCγ1 activation. As invadopodia promote invasion through matrix remodeling, we examined matrix organization and determined that spheroids in high stiffness displayed a large fibronectin halo. Interestingly, this halo did not result from increased fibronectin production, but rather from Mena/α5 integrin dependent organization. In high stiffness environments, FN1 knockout inhibited invasion while addition of exogenous cellular fibronectin lessened the invasion delay. Analysis of fibronectin isoforms demonstrated that EDA-fibronectin promoted invasion and that clinical invasive breast cancer specimens displayed elevated EDA-fibronectin. Combined, our data support a mechanism by which breast cancer cells respond to stiffness and render the environment conducive to invasion. More broadly, these findings provide important insight on the roles of matrix stiffness, composition, and organization in promoting tumor invasion.
•Initial inhibition to invasion in stiff environments is overcome through Mena and integrin α5 organization of fibronectin•Demonstrate that MENA and MENA-INV are upregulated in response to stiffness and EGFR/PLCγ1 signaling•Identify EDA-fibronectin as responsible for the onset of invasion in high stiffness environments•Confirm that EDA-fibronectin is increased in primary tumors from patients with invasive breast cancer
Peritoneal metastasis of high-grade serous ovarian cancer (HGSOC) occurs when tumor cells suspended in ascites adhere to mesothelial cells. Despite the strong relationship between metastatic burden ...and prognosis in HGSOC, there are currently no therapies specifically targeting the metastatic process. We utilized a coculture model and multivariate analysis to examine how interactions between tumor cells, mesothelial cells, and alternatively-activated macrophages (AAM) influence the adhesion of tumor cells to mesothelial cells. We found that AAM-secreted MIP-1β activates CCR5/PI3K signaling in mesothelial cells, resulting in expression of P-selectin on the mesothelial cell surface. Tumor cells attached to this
P-selectin through CD24, resulting in increased tumor cell adhesion in static conditions and rolling underflow. C57/BL6 mice treated with MIP-1β exhibited increased P-selectin expression on mesothelial cells lining peritoneal tissues, which enhanced CaOV3 adhesion
and ID8 adhesion
Analysis of samples from patients with HGSOC confirmed increased MIP-1β and P-selectin, suggesting that this novel multicellular mechanism could be targeted to slow or stop metastasis in HGSOC by repurposing anti-CCR5 and P-selectin therapies developed for other indications.
This study reports novel insights on the peritoneal dissemination occurring during progression of ovarian cancer and has potential for therapeutic intervention.
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In general, endometrioid-defining features such as squamoid morular metaplasia are not thought to be associated with mesonephric adenocarcinoma (MA) and mesonephric-like adenocarcinoma (MLA). Here, ...we report a case of
FGFR2
-mutated ovarian MLA with squamoid morular metaplasia accompanied by aberrant nuclear and cytoplasmic β-catenin expression and
CTNNB1
mutation. Histologically, the tumor showed classical MLA histology, including well-formed glands with intraluminal eosinophilic secretions and cells with papillary thyroid carcinoma-like nuclei. Squamoid morular metaplasia was intimately associated with the tumor. Glandular epithelial elements, including those immediately associated with the squamoid morules, were negative for ER, but positive for both GATA3 and PAX8; aberrant β-catenin expression was limited to the squamoid morules. This case illustrates the ability of mesonephric neoplasia to exhibit histological features previously thought to be restricted to an endometrioid phenotype.
High-grade serous ovarian cancer (HGSOC) metastasizes when tumor spheroids detach from the primary tumor and re-attach throughout the peritoneal cavity. Once the cancer cells have implanted in these ...new sites, the development of metastatic lesions is dependent on the disaggregation of cancer cells from the spheroids and subsequent expansion across the collagenous extracellular matrix (ECM). As HGSOC progresses an increase in alternatively activated macrophages (AAMs) in the surrounding ascites fluid has been observed and AAMs have been shown to enhance tumor invasion and growth in a wide range of cancers. We hypothesized that soluble factors from AAMs in the peritoneal microenvironment promote the disaggregation of ovarian cancer spheroids across the underlying ECM. We determined that co-culture with AAMs significantly increased HGSOC spheroid spreading across a collagen matrix. Multivariate modeling identified AAM-derived factors that correlated with enhanced spread of HGSOC spheroids and experimental validation showed that each individual cell line responded to a distinct AAM-derived factor (FLT3L, leptin, or HB-EGF). Despite this ligand-level heterogeneity, we determined that the AAM-derived factors utilized a common signaling pathway to induce spheroid spreading: JAK2/STAT3 activation followed by MMP-9 mediated spreading. Furthermore, immunostaining demonstrated that FLT3, LEPR, EGFR, and pSTAT3 were upregulated in metastases in HGSOC patients, with substantial patient-to-patient heterogeneity. These results suggest that inhibiting individual soluble factors will not inhibit AAM-induced effects across a broad group of patients; instead, the downstream JAK2/STAT3/MMP-9 pathway should be examined as potential therapeutic targets to slow metastasis in ovarian cancer.
•Macrophages promote ovarian cancer spheroid spreading through FLT3L, leptin, HB-EGF.•These disparate ligands activate JAK2/STAT3 in cells that express cognate receptor.•JAK2/STAT3 activation increased MMP-9 secretion to induce spreading.•The identified pathways were dysregulated in ovarian cancer patients.
Triple negative breast cancer represents a heterogeneous group of breast carcinomas, both at the histologic and genetic level. Although recent molecular studies have comprehensively characterized the ...genetic landscape of these tumors, few have integrated a detailed histologic examination into the analysis. In this study, we defined the genetic alterations in 39 triple negative breast cancers using a high-depth targeted massively parallel sequencing assay and correlated the findings with a detailed morphologic analysis. We obtained representative frozen tissue of primary triple negative breast cancers from patients treated at our institution between 2002 and 2010. We characterized tumors according to their histologic subtype and morphologic features. DNA was extracted from paired frozen primary tumor and normal tissue samples and was subjected to a targeted massively parallel sequencing platform comprising 229 cancer-associated genes common across all experiments. The average number of non-synonymous mutations was 3 (range 0-10) per case. The most frequent somatic alterations were mutations in TP53 (74%) and PIK3CA (10%) and MYC amplifications (26%). Triple negative breast cancers with apocrine differentiation less frequently harbored TP53 mutations (25%) and MYC gains (0%), and displayed a high mutation frequency in PIK3CA and other PI3K signaling pathway-related genes (75%). Using a targeted massively parallel sequencing platform, we identified the key somatic genetic alterations previously reported in triple negative breast cancers. Furthermore, our findings show that triple negative breast cancers with apocrine differentiation constitute a distinct subset, characterized by a high frequency of PI3K pathway alterations similar to luminal subtypes of breast cancer.
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