Katja Gwin

Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth

Intra-abdominal tumors, such as ovarian cancer, have a clear predilection for metastasis to the omentum, an organ primarily composed of adipocytes. Currently, it is unclear why tumor cells preferentially home to and proliferate in the omentum, yet omental metastases typically represent the largest tumor in the abdominal cavities of women with ovarian cancer. We show here that primary human omental adipocytes promote homing, migration and invasion of ovarian cancer cells, and that adipokines including interleukin-8 (IL-8) mediate these activities. Adipocyte–ovarian cancer cell coculture led to the direct transfer of lipids from adipocytes to ovarian cancer cells and promoted in vitro and in vivo tumor growth. Furthermore, coculture induced lipolysis in adipocytes and β-oxidation in cancer cells, suggesting adipocytes act as an energy source for the cancer cells. A protein array identified upregulation of fatty acid–binding protein 4 (FABP4, also known as aP2) in omental metastases as compared to primary ovarian tumors, and FABP4 expression was detected in ovarian cancer cells at the adipocyte-tumor cell interface. FABP4 deficiency substantially impaired metastatic tumor growth in mice, indicating that FABP4 has a key role in ovarian cancer metastasis. These data indicate adipocytes provide fatty acids for rapid tumor growth, identifying lipid metabolism and transport as new targets for the treatment of cancers where adipocytes are a major component of the microenvironment.

Let-7 modulates acquired resistance of ovarian cancer to Taxanes via IMP-1-mediated stabilization of multidrug resistance 1.

Ovarian cancer patients frequently develop resistance to chemotherapy regiments using Taxol and carboplatin. One of the resistance factors that protects cancer cells from Taxol‐based therapy is multidrug resistance 1 (MDR1). micro(mi)RNAs are small noncoding RNAs that negatively regulate protein expression. Members of the let‐7 family of miRNAs are downregulated in many human cancers, and low let‐7 expression has been correlated with resistance to microtubule targeting drugs (Taxanes), although little is known that would explain this activity. We now provide evidence that, although let‐7 is not a universal sensitizer of cancer cells to Taxanes, it affects acquired resistance of cells to this class of drugs by targeting IMP‐1, resulting in destabilization of the mRNA of MDR1. Introducing let‐7g into ADR‐RES cells expressing both IMP‐1 and MDR1 reduced expression of both proteins rendering the cells more sensitive to treatment with either Taxol or vinblastine without affecting the sensitivity of the cells to carboplatin, a non‐MDR1 substrate. This effect could be reversed by reintroducing IMP‐1 into let‐7g high/MDR1 low cells causing MDR1 to again become stabilized. Consistently, many relapsed ovarian cancer patients tested before and after chemotherapy were found to downregulate let‐7 and to co‐upregulate IMP‐1 and MDR1, and the increase in the expression levels of both proteins after chemotherapy negatively correlated with disease‐free time before recurrence. Our data point at IMP‐1 and MDR1 as indicators for response to therapy, and at IMP‐1 as a novel therapeutic target for overcoming multidrug resistance of ovarian cancer.

Frequent expression of napsin a in clear cell carcinoma of the endometrium: Potential diagnostic utility

The histotyping of high-grade endometrial carcinomas with clear cells may be subject to significant interobserver variability, which suggests that a biomarker that can distinguish endometrial clear cell carcinoma (CCC) from its mimics would be of diagnostic utility. This study assessed the usefulness of napsin A immunohistochemistry in the diagnosis of CCC, on the basis of an analysis of 77 cases diagnosed as such at 9 institutions. After being independently reviewed by a subset of 3 pathologists, cases for which there was diagnostic consensus among all 3 reviewers in agreement with the primary contributor (n=60) were used to establish a “consensus group” that served as a gold standard relative to which napsin A performance was assessed. Duplicate, 1.0-mm-core tissue microarrays were constructed from the 54 cases in the consensus group for which requisite materials were available, as well as from 49 endometrial endometrioid carcinomas (all grades) and 17 endometrial serous carcinomas. Napsin A immunohistochemical analysis was performed on the microarrays and on the 17 cases for which there was no diagnostic consensus, with scoring based on the proportion of immunoreactive cells (0, 1+, 2+, and 3+ indicative of 0, 1% to 25%, 26% to 49%, and ≥50% immunoreactive cells, respectively). The distribution of scores for the 49 CCC cases with evaluable cores was as follows: 0, n=6; 1+, n=6; 2+, n=8; 3+, n=29. Among the evaluable cases, the frequency of ≥1+ napsin A immunoreactivity was significantly higher in CCCs (43/49, 88%) than in endometrial serous carcinomas (1/13, 7.7%; P<0.0001) and endometrial endometrioid carcinomas (0/49, 0%; P<0.0001). The sensitivity, specificity, negative predictive value, and positive predictive value of ≥1+ napsin A expression in predicting the consensus clear cell histotype were 0.88 (95% confidence interval [CI], 0.75-0.95), 0.98 (95% CI, 0.9-1), 0.91 (95% CI, 0.86-0.96), and 0.98 (95% CI, 0.86-1), respectively. Napsin A expression was not associated with survival or clinicopathologic factors. In the group of cases without diagnostic consensus for CCC, 50% showed ≥1+ napsin A expression; all napsin A-negative cases had previously been classified as non-CCC by ≥2 reviewers, whereas only 37.5% of the napsin A-positive cases had been classified as CCC by 2 of the 3 reviewers. In conclusion, napsin A is a sensitive and specific biomarker of the clear cell histotype in endometrial carcinomas and accordingly may have diagnostic utility in their histotyping.

The clinicopathologic significance of p53 and BAF-250a (ARID1A) expression in clear cell carcinoma of the endometrium.

TP53 mutation (and associated p53 protein overexpression) is probably a negative prognostic marker in endometrial cancers, but its relevance in the rarer histologic subtypes, including clear cell carcinomas, has not been delineated. Preclinical studies suggest functional interactions between p53 and the BAF250a protein, the product of a tumor suppressor gene ARID1A (adenine-thymine (AT)-rich interactive domain containing protein 1A) that is frequently mutated in ovarian clear cell carcinoma. In this study, we evaluated the significance of p53 and BAF250a expression, as assessed by immunohistochemistry, in a group of 50 endometrial clear cell carcinomas. Of 50 cases, 17 (34%) were p53+, and the remaining 33 cases had a p53 wild-type (p53-wt) immunophenotype. Of the 11 relapses/recurrences in the entire data set, 73% were in the p53+ group (P=0.008). On univariate analyses, the median overall survival for the p53-wt patients (83 months) was longer than the p53+ patients (63 months) (P=0.07), and the median progression-free survival for the p53-wt group (88 months) was significantly longer than the p53+ group (56 months) (P=0.01). On multivariate analyses, p53 expression was not associated with reduced overall or progression-free survival. In addition, p53 status was not significantly associated with pathologic stage or morphologic patterns. Of the 50 cases, 10 (20%) showed a complete loss of BAF250a expression. There was no significant correlation between p53 and BAF250a expression. The p53+/BAF250a−, p53+/BAF250a+, p53-wt/BAF250a+ and p53-wt/BAF250a− composite immunophenotypes were identified in 8%, 26%, 54% and 12% of cases, respectively, and neither loss of BAF250a expression nor composite p53/BAF250a expression patterns were associated with reduced overall or progression-free survival. In conclusion, a significant subset of CCC express p53, and these cases are apparently not definable by their morphologic features. P53 expression may be a negative prognostic factor in this histotype, and warrants additional studies. Loss of BAF250a expression has no prognostic significance in endometrial clear cell carcinomas.

Is GATA3 expression maintained in regional metastases?: a study of paired primary and metastatic urothelial carcinomas.

GATA3 has been recognized as a promising marker for primary urothelial carcinoma (UC), consistently showing higher expression levels than urothelial markers thrombomodulin and uroplakin III. However, expression of GATA3 in comparison with UC-associated markers CK7 and p63 has not been systematically studied. Moreover, no studies have been conducted to establish GATA3 sensitivity in regional metastases. In this study, high-density tissue microarrays were constructed from 69 matched paired primary and metastatic bladder tumors including pure urothelial UCs with papillary (n=48) or flat phenotype (n=9), mixed tumors with micropapillary, glandular, small cell, squamous, giant cell, and plasmacytoid features (n=9), and 3 adenocarcinomas. GATA3 was expressed in 62/69 (90%) primary UC and 64/69 (93%) metastases, with significantly higher staining intensity in nodal metastases (P=0.03). In primary tumors, GATA3 was positive in 44/48 (92%) papillary UCs, 9/9 (100%) flat UCs, 8/9 (89%) mixed UCs, and 1/3 (33%) adenocarcinomas, whereas in metastases these numbers were 45/48 (94%), 9/9 (100%), 8/9 (89%), and 2/3 (67%), respectively. The majority of positive cases showed strong diffuse nuclear reactivity: 75% of primary UCs and 79% of metastases. GATA3 sensitivity in primary and metastatic UCs was comparable to that of CK7 and superior to that of p63 (P<0.05). GATA3 specificity was computed in comparison with its morphologic mimics expressing CK7 and p63, including 208 primary and 24 metastatic tumors from the lung, cervix, and head and neck regions. Strong GATA3 expression was present in 2/51 (4%) cervical carcinomas, whereas weak GATA3 expression was present in 7/51 (14%) cervical, 6/74 (8%) head and neck cancers, and 2/83 (3%) lung carcinomas. Remaining 191 primary and 24 metastatic tumors were GATA3 negative. Therefore, specificity of GATA3 calculated on the basis of morphologic and immunophenotypic UC mimics from lung, cervix, head and neck was 92%. Our findings demonstrate high sensitivity and specificity of the GATA3 diagnostic marker, with not only maintained but increased expression in regional metastases.

Complementary Value of the Ki-67 Proliferation Index to the Oncotype DX Recurrence Score

Oncotype DX is a 21-gene assay that quantifies the recurrence risk in estrogen receptor—positive breast cancer, which is expressed as the recurrence score (RS). Studies have shown that patients with a high-risk RS will most likely benefit from adjuvant chemotherapy, but there is no proven advantage for patients with a low-risk RS who still face an average recurrence risk of 7%. In this study, the relationship between the RS and the cell cycle—related antigen Ki-67 was assessed in 32 breast carcinomas and evaluated for a potential association. Comparison of the RS with tumor type, grade, and the Ki-67 proliferation index (PI) revealed an overall concordance. However, some tumors with a low RS revealed a surprisingly high Ki-67 PI. These cases may correspond to the 7% of low-risk RS carcinomas that recur. Therefore, the authors propose a combined evaluation of the RS and Ki-67 PI to identify tumors with high recurrence potential from the low-risk and intermediate-risk RS groups.

Circumscribed palmar hypokeratosis: two cases and a review of the literature.

A 60‐year‐old female and a 59‐year‐old male each presented with a solitary circumscribed patch of depressed skin of the right thenar palm and right sole, respectively. Both lesions were present for approximately 30 years without a history of trauma or other inciting incident. Histologically, the lesions showed a well‐demarcated abrupt decrease in the thickness of the stratum corneum with a central area of thinned stratum corneum and hypogranulosis. Inflammation was absent. Ultrastructurally, keratin filaments were evident in the stratum corneum, and a diminished granular cell layer was apparent. There was a decrease in maturation of the keratinocytes, however, no defects in corneodesmosomes or other ultrastructural components were identified. No evidence of human papilloma virus was detected by in situ hybridization studies. Based on these 2 cases and the 25 cases reported in the literature to date, this entity seems to represent a chronic localized non‐inflammatory defect in keratinization on acral sites.

Comparative analysis of Napsin A, alpha-methylacyl-coenzyme A racemase (AMACR, P504S), and hepatocyte nuclear factor 1 beta as diagnostic markers of ovarian clear cell carcinoma: an immunohistochemical study of 279 ovarian tumours

Summary Napsin A and &agr;-methylacyl-coenzyme A racemase (AMACR, P504S) have recently been described as being frequently expressed in clear cell carcinomas (CCC) of the gynecological tract. The present study was conducted to assess the test performance of these newer markers relative to the more traditional marker, hepatocyte nuclear factor 1&bgr; (HNF1&bgr;), in a large and histotypically diverse dataset. A total of 279 ovarian tumours in tissue microarrays were immunohistochemically assessed for the expression of Napsin A, AMACR and HNF1&bgr;. HNF1&bgr;, Napsin A and AMACR were expressed in 92%, 82% and 63% of 65 CCC, 7%, 1% and 1% of 101 serous carcinomas, 37%, 5.3% and 0% of 19 endometrioid carcinomas, 60%, 0% and 0% of 45 mucinous tumours, 100%, 0% and 0% of seven yolk sac tumours, and 0%, 16.7% and 16.7% of six steroid cell tumours NOS, respectively. All other tumours, including 18 adult-type granulosa cell tumours, eight dysgerminomas and nine other miscellaneous tumour types were negative for all three markers. Using a benchmark of ≥1% of tumour cells for positivity and CCC as the diagnostic end-point, the sensitivity, specificity, negative predictive value and positive predictive value of Napsin A expression were 0.82, 0.99, 0.94, and 0.98, respectively (odds ratio 439, p < 0.0001). Respective parameters were 0.92, 0.79, 0.97, and 0.58 (odds ratio 44, p < 0.0001) for HNF1&bgr; and 0.63, 0.99, 0.89, and 0.5 (odds ratio 112, p < 0.0001) for AMACR. The combination of any two positive markers, irrespective of the staining pattern of the third, significantly predicted the CCC histotype in every analytic scenario. In summary, HNF1&bgr; is highly sensitive but is suboptimally specific in isolation, whereas AMACR is highly specific but is suboptimally sensitive. Napsin A is specific but of intermediate sensitivity. Napsin A, AMACR and HNF1&bgr; are all viable markers of CCC that can be deployed as components of larger panels when CCC is a diagnostic consideration.

Pathologic diagnosis, origin, and natural history of pseudomyxoma peritonei.

Mucinous ascites and pools of mucin within the peritoneal cavity associated with neoplastic, mucinous epithelium are the characteristic features of pseudomyxoma peritonei (PMP). Clinically, PMP presents with abdominal distension and gelatinous ascites. In female patients, pelvic masses can be seen. Radiologic findings on computed tomography include scalloping of the hepatic and splenic margins and dense ascites. Surgically, PMP is encountered as grossly visible mucin in the peritoneal cavity. The presence of mucin outside of the appendix, in the right lower quadrant, and beyond is an important diagnostic finding. The appendix may be distended or ruptured. In women, there is often bilateral surface involvement of the ovaries, raising the differential diagnosis of primary ovarian neoplasms; however, these are extremely rare causes of PMP. Because of the association between appendiceal lesions and metastatic mucinous neoplasms of the ovary, appendectomy in the setting of any mucinous peritoneal or ovarian process may be prudent, even if the appendix is grossly normal. The gastrointestinal tract, especially the hepatopancreato biliary system, also needs to be assessed by the surgeon. Pathologically, PMP arises almost exclusively from low- or high-grade mucinous neoplasms of the appendix. These neoplasms must be distinguished both from rare benign causes of mucinous ascites and from nonappendiceal primary tumors. PMP has a protracted clinical course with progressive fibrous adhesions and obstructive disease; aggressive surgical and cytoreductive therapy with hyperthermic intraperitoneal chemotherapy has been reported to improve clinical outcomes.

Breast Carcinoma With Chondroid Differentiation: A Clinicopathologic Study of 21 Triple Negative (ER-, PR-, Her2/neu-) Cases

A total of 21 metaplastic breast carcinomas (MCs) with chondroid differentiation were evaluated to better establish the clinicopathological features of this variant. The tumors exhibited mainly invasive carcinoma admixed with areas of cartilaginous matrix production. An associated ductal intraepithelial neoplasia component grade 2 or 3 was observed in 43% of cases. Immunohistochemical analysis revealed a triple negative (ER−, PR−, and Her2/neu−) immunoprofile and no expression of the androgen receptor. EGFR-positivity was found in 88% of evaluated cases, consistent with the proposed basaloid phenotype for all MC. Compared with previous studies that reviewed MC with osseus and cartilaginous elements, the incidence of axillary lymph node metastasis was significantly higher in our study and 60% of positive nodes exhibited chondroid differentiation. Available follow-up data (n = 10) revealed aggressive behavior of this MC variant with frequent metastasis, including visceral involvement and local chest wall recurrence despite chemotherapy and radiation. Three patients subsequently died of metastatic disease.