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1.  Utility of Alpha-methylacyl-CoA racemase (p504s) Immunohistochemistry In Distinguishing Endometrial Clear Cell Carcinomas from Serous and Endometrioid Carcinomas 
Human pathology  2013;44(12):10.1016/j.humpath.2013.07.033.
The expression of alpha-methylacyl-coenzyme-A-racemase (AMACR) has previously been reported in 75 to 100% of urethral/bladder clear cell carcinomas, tumors that are known to display broad phenotypic overlap with their identically-named müllerian counterparts. Herein, we assess the utility of AMACR in distinguishing endometrial clear cell carcinomas (CCC) from endometrial serous carcinomas (ESC) and endometrial endometrioid carcinomas (EEC). 111 endometrial carcinomas in a tissue microarray, including 49 CCC, 13 ESC and 49 EEC, were assessed for AMACR immunoreactivity, with results scored semi-quantitatively (scores 0, 1+, 2+, 3+ for 0%, 1-5%, 6-50%, >50% immunoreactive cells respectively). 50 (45%) of the 111 carcinomas were AMACR-positive, with the following score distribution: CCC: 0 (n=12), 1+ (n=12), 2+ (n=3), 3+ (n=22); EEC: 0 (n=38), 1+ (n=4), 2+ (n=4), 3+ (n=3); ESC: 0 (n=11), 1+ (n=1), 2+ (n=0), 3+ (n=1). AMACR expression was significantly more frequent in CCC (75%) than in ESC (15%) or EEC (22%), p<0.0001. The sensitivity and specificity of AMACR expression in classifying a carcinoma as CCC were 0.75 (95% CI: 0.61-0.86) and 0.79 (95% CI: 0.66-0.88) respectively, with an odds ratio of 11.62 (95% CI: 5-28, p < 0.001), and an area under the curve of 0.79 (95% CI: 0.68 to 0.88). These findings indicate that AMACR expression is strongly associated with CCC and displays a relatively robust diagnostic test performance. However, its practical utility may be limited by the focal nature of its expression in 32% of the AMACR-positive CCC cases, as well as its expression in 15-22% of the non-CCC histotypes.
doi:10.1016/j.humpath.2013.07.033
PMCID: PMC3865867  PMID: 24119561
Alpha-methylacyl-CoA-racemase; p504s; AMACR; immunohistochemistry; endometrial clear cell carcinoma
2.  Coordinate Patterns of ER, PR and WT1 Expression in the Histopathologic Distinction of Ovarian from Endometrial Serous Adenocarcinomas 
Annals of diagnostic pathology  2013;17(5):430-433.
The purpose of this study is to assess whether composite or coordinate immunoexpression patterns of estrogen receptor (ER), progesterone receptor (PR) and Wilms tumor 1 (WT1) gene can significantly distinguish between endometrial serous carcinoma (ESC) and ovarian serous carcinoma (OSC). Immunohistochemical analyses were performed on whole tissue sections from 22 uterus-confined ESC and on a tissue microarray of 140 high grade, pan-stage ovarian serous carcinomas, using antibodies to ER, PR, and WT-1. ER, PR and WT1 expression were present in 37%, 49% and 81% of OSC respectively, but these markers were also present in 18%, 27% and 36% of ESC. The ER+/PR+/WT1+ coordinate profile was identified in 33.6% of OSC but in none of ESC (p=0.0006), resulting in a calculated sensitivity and specificity of this profile for OSC of 33.6% and 100% respectively. By contrast, the ER−/PR−/WT1− coordinate profile was identified in 41% of ESC but in only 6.4% of OSC (p=0.0001), resulting in a calculated sensitivity and specificity of this profile for ESC of 50% and 94%. In summary, in the differential diagnosis between OSC and ESC, positivity for all 3 markers favors an extrauterine origin whereas negativity for all 3 markers is supportive of an endometrial origin. The use of single markers for this purpose is not recommended, as each lacks optimal discriminatory power. Coordinate profiles, in general, have a high specificity but low sensitivity in this differential diagnosis.
doi:10.1016/j.anndiagpath.2013.04.011
PMCID: PMC4079538  PMID: 23706170
3.  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 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. Seventeen of 50 cases (34%) were p53 positive; the remaining 33 cases had a p53 wild-type (p53-wt) immunophenotype. Of the 11 relapses/recurrences in the entire dataset, 73% were in the p53[+] group (p=0.008). On univariate analyses, the median overall survival for the p53-wt patients (83 mo) was longer than the p53[+] patients (63 mo) (p=0.07), and the median progression-free survival for the p53-wt group (88 mo) was significantly longer than the p53[+] group (56 mo) (p=0.01). On multivariate analyses, p53 expression was not associated with reduced overall or progression-free survival. Additionally, p53 status was not significantly associated with pathologic stage or morphologic patterns. Ten of the 50 cases (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.
doi:10.1038/modpathol.2013.35
PMCID: PMC3886836  PMID: 23524907
4.  TR3 modulates platinum resistance in ovarian cancer 
Cancer research  2013;73(15):4758-4769.
In metastatic ovarian cancer, resistance to platinum chemotherapy is common. Although the orphan nuclear receptor TR3 (nur77/NR4A1) is implicated in mediating chemotherapy-induced apoptosis in cancer cells, its role in ovarian cancer has not been determined. In an ovarian cancer tissue microarray, TR3 protein expression was elevated in stage I tumors, but down-regulated in a significant subset of metastatic tumors. Moreover, TR3 expression was significantly lower in platinum-resistant tumors in patients with metastatic disease, and low TR3 staining was associated with poorer overall and progression-free survival. We have identified a direct role for TR3 in cisplatin-induced apoptosis in ovarian cancer cells. Nucleus-to-cytoplasm translocation of TR3 was observed in cisplatin-sensitive (OVCAR8, OVCAR3, A2780PAR) but not cisplatin-resistant (NCI/ADR-RES, A2780CP20) ovarian cancer cells. Immunofluorescent analyses showed clear overlap between TR3 and mitochondrial Hsp60 in cisplatin-treated cells, which was associated with cytochrome C release. Ovarian cancer cells with stable shRNA- or transient siRNA-mediated TR3 down-regulation displayed substantial reduction in cisplatin effects on apoptotic markers and cell growth in vitro and in vivo. Mechanistic studies demonstrated that the cisplatin-induced cytoplasmic TR3 translocation required for apoptosis induction was regulated by JNK activation and inhibition of Akt. Finally, cisplatin-resistance was partially overcome by ectopic TR3 overexpression, and by treatment with the JNK activator anisomycin and Akt pathway inhibitor, wortmannin. Our results suggest that disruption of TR3 activity, via down-regulation or nuclear sequestration, likely contributes to platinum resistance in ovarian cancer. Moreover, we have described a treatment strategy aimed at overcoming platinum resistance by targeting TR3.
doi:10.1158/0008-5472.CAN-12-4560
PMCID: PMC3944084  PMID: 23720056
Ovarian cancer; TR3; cisplatin; chemoresistance; apoptosis
5.  Salpingo-oophorectomy specimens for endometrial cancer staging: a comparative analysis of representative sampling versus whole tissue processing 
Human pathology  2012;44(4):643-650.
Involvement of the ovary and/or fallopian tube by an endometrial cancer is uncommon but clinically significant, since this is one of the indications for adjuvant chemotherapy. The authors evaluated whether the routine microscopic evaluation of the adnexal organs in this setting should be of the entire specimen, or of representative sections. Slides and reports were reviewed for 105 consecutive patients that underwent a staging salpingo-oophorectomy (205 ovaries, 210 tubes) for endometrial carcinoma/carcinosarcoma. The study period encompassed the periods before and after an institutional policy change from discretionary (predominantly representative) adnexal sampling to obligatory total processing. 94 and 111 ovaries (and 92 and 118 tubes) were entirely and representatively processed respectively. Even when using the most expansive definition of ovarian gross abnormality (definition with the highest sensitivity and lowest specificity for microscopically-confirmed cancer), we still identified 4 (of 148: 2.7%) grossly normal ovaries and 3 (of 187: 1.6%) grossly normal tubes that were found to harbor microscopic cancers. There was no significant increase in the number of grossly occult cancers detected after the policy change, and 5 (71%) of the 7 grossly occult cancers were in the representatively-sampled group. Approximately 3.76 more blocks per patient were required for total over representative processing, and the total cost of these additional sections was estimated to be $25.57 per patient. In conclusion, the 1.6-2.7% of grossly normal adnexa that proved to be cancerous represents, at least theoretically, the risk for misdiagnosis and understaging that is associated with representative sampling, at relatively modest savings. However, the findings in this study do not provide direct evidentiary support for routine complete processing.
doi:10.1016/j.humpath.2012.07.015
PMCID: PMC4079536  PMID: 23084582
6.  Expression of the Oncofetal Protein IGF2BP3 (IMP3) in Endometrial Clear Cell Carcinoma: Assessment of Frequency and Significance 
Human pathology  2013;44(8):1508-1515.
Insulin-like growth factor-II mRNA-binding protein 3 (IGF2BP3 or IMP3) is a biomarker whose expression has been found to be a negative prognostic factor in several neoplasms, including ovarian clear cell carcinoma. In this study, we analyzed the frequency and clinicopathologic significance of IMP3 expression, as assessed by immunohistochemistry and as scored using a modified H-score system, in a cohort of 50 endometrial clear cell carcinomas (CCC). Cases with scores of 0-100, 101-200, and 201-300 were classified as negative/mildly positive (n=17), moderately positive (n=20) and strongly positive (n=13), respectively. A distinctive pattern of increased staining at the myoinvasive front (relative to the main tumor) was evident in 46% of the cases with evaluable foci of myometrial invasion. Moderate/strong IMP3 staining was associated with a tumor architectural pattern that has been reported to be of poor prognostic significance: at least 10% of the tumor composed of solid architecture or individual infiltrating tumor cells (p=0.01). Increasing levels of IMP3 expression showed a trend towards decreasing RFS (median survival 75.6, 81.3 and 48.4 months for the negative/mildly, moderately and strongly positive groups respectively (p=0.09). However, IMP3 expression was not significantly associated with reduced overall survival or RFS in a multivariate analytic model. The finding in a subset of our cases of increased IMP3 expression at the tumoral myoinvasive front is consistent with a role for IMP3 in invasiveness, as is the trend towards reduced RFS in cases expressing IMP3 at high levels. These preliminary findings suggests that IMP3 expression may be involved in the pathogenesis of CCC, and is worthy of further exploration.
doi:10.1016/j.humpath.2012.12.003
PMCID: PMC3888088  PMID: 23465280
7.  Adrenal Gland Metastasis Is an Unusual Manifestation of Endometrial Cancer 
Case Reports in Surgery  2013;2013:428456.
This case report describes a woman treated for stage 1 B grade 3 endometrial adenocarcinoma with surgery and adjuvant radiation therapy who presented 6 months later with pain and symptoms of adrenal insufficiency. A large right adrenal mass revealed adenocarcinoma consistent with the endometrial primary.
doi:10.1155/2013/428456
PMCID: PMC3748408  PMID: 23984164
8.  A Case of Extrauterine Endometrial Stromal Sarcoma in the Colon Diagnosed Three Decades after Hysterectomy for Benign Disease 
Extrauterine endometrial stromal sarcoma (ESS) is rare and typified by delayed recurrence of primary ESS. Here, we report an unusual case of colonic ESS in a woman with a remote history of hysterectomy. An 80-year-old woman, with a history of hysterectomy and bilateral salpingo-oophorectomy for abnormal bleeding and endometriosis 37 years prior to presentation, was diagnosed with ESS in the colon. She was treated with laparoscopic low anterior resection, followed by megestrol acetate, and has been in remission for more than 4 years. This case highlights the rarity of extra-uterine ESS in the colon, especially in the absence of a known history of primary uterine ESS. The patient's history of endometriosis may have been a predisposing risk factor. ESS in the colon may be treated successfully with surgical resection and progestin therapy. Indefinite surveillance is recommended to monitor for late recurrences.
doi:10.1155/2013/202458
PMCID: PMC3655501  PMID: 23710389
9.  Imaging the clear cell renal cell carcinoma proteome 
The Journal of urology  2012;189(3):1097-1103.
Introduction
A key barrier to identification of tissue biomarkers of clear cell renal cell carcinoma (ccRCC) is the heterogeneity of protein expression within tissue. However, by providing spectra for every 0.05 mm2 area of tissue, imaging mass spectrometry (IMS) reveals the spatial distribution of peptides. We sought to determine whether this approach could be used to identify and map protein signatures of ccRCC.
Methods
We constructed two tissue microarrays (TMA) with two cores each of matched tumor and normal tissue from nephrectomy specimens of 70 patients with ccRCC. Samples were analyzed by matrix-assisted laser desorption ionization (MALDI) time-of-flight mass spectrometry (MS). Peptide signatures were identified within each TMA that differentiated cancer from normal tissue and then cross-validated. MS/MS sequencing was performed to determine identities of select differentially expressed peptides, and immunohistochemistry was used for validation.
Results
Peptide signatures were identified that demonstrated a classification accuracy within each TMA of 94.7–98.5% for each 0.05mm2 spot (spectrum) and 96.9–100% for each tissue core. Cross-validation across TMA's revealed classification accuracies of 82.6–84.7% for each spot and 88.9–92.4% for each core. We identified vimentin, histone 2A.X, and alpha-enolase as proteins with greater expression in cancer tissue, and validated this by immunohistochemistry.
Conclusions
IMS was able to identify and map specific peptides that accurately distinguished malignant from normal renal tissue, demonstrating its potential as a novel, high-throughput approach to ccRCC biomarker discovery. Given the multiple pathways and known heterogeneity involved in tumors such as ccRCC, multiple peptide signatures that maintain their spatial relationships may outperform traditional protein biomarkers.
doi:10.1016/j.juro.2012.09.074
PMCID: PMC3570618  PMID: 23009866
MALDI; imaging mass spectrometry; renal cell carcinoma; biomarkers; proteomics
10.  Morphologic and other clinicopathologic features of endometrial clear cell carcinoma: a comprehensive analysis of 50 rigorously classified cases 
Clear cell carcinoma of the endometrium (CCC) is an uncommon histotype whose analyses have generally been hampered by its rarity and issues of interobserver diagnostic variability. In this study, we analyzed the clinicopathologic features of 50 CCCs that were assembled from multiple institutions and which we considered to be morphologically unambiguous after a rigorous review process for diagnostic accuracy. Forty-four (88%) of the 50 CCC cases showed an admixture of the classic architectural patterns (glandular, papillary, solid and cystic in decreasing order of prevalence). Mitotic indices were variable but were generally low: 60% of cases had a mitotic index of 3 or lower. The predominant cell type lining glands and papillae was invariably hobnail and/or cuboidal. Stratification of nuclei (greater than 3 cells) or columnar cells on glands and papillae were uncommon and never diffusely present. 82% of cases showed an admixture of polygonal cells with clear and eosinophilic cytoplasm; only clear cells were present in 4% and only eosinophilic cells were present in 10%. Hobnail cells were common, being identifiable in 86% of cases, and being diffuse in 60%. Only 2 cases had a predominance of nuclear grade 3 cells. Psammoma, hyaline and targetoid bodies were identified in 32%, 52% and 20% of cases respectively. Clear cell endometrial intraepithelial carcinoma was identified in 41.7% of cases with evaluable background endometrium. The 5-year progression free survival (PFS) for the entire cohort was 61%, and was 88%, 75%, 22% and 28.6% for stages I to IV respectively. On univariate analyses, age >65 years, advanced FIGO stage, and the presence of any lymph node metastases were associated with reduced PFS (p=0.02, 0.002, and 0.002 respectively). On multivariate analyses, the only variable associated with reduced PFS was age >65 years. The 5-year overall survival (OS) for the entire cohort was 78%, and was 94%, 87.5%, 66.7%, and 42.8% for stages I to IV respectively. On univariate analyses, the following factors were associated with reduced OS: age >65 years (p=0.04), advanced FIGO stage (p=0.003), distant metastases (p=0.003), myometrial invasion >30% (p=0.01), a mitotic index >4 (p=0.014), and a specific architectural pattern (at least 10% of the tumor composed of solid masses or individual infiltrating tumor cells, p=0.02). On multivariate analyses, only age >65 years and advanced stage were associated with reduced OS (p=0.023 and 0.022 respectively). In summary, endometrial CCC has a wide morphologic spectrum that is detailed and illustrated herein, but also has core cytoarchitectural features that are of high diagnostic utility. Morphologically unambiguous CCC apparently have patient outcomes that are more favorable than has previously been reported, indicating that ambiguous tumors should be classified separately. The existence of morphologically ambiguous clear-cell rich carcinomas that do not fit the conventional histotypic groupings, is a likely reflection of the biologic complexity of endometrial carcinomas in general; these cases should be reported descriptively, and studied separately from conventional CCC.
PMCID: PMC3555196  PMID: 23359866
Clear cell carcinoma; endometrium; morphologic features
11.  Dedifferentiated Leiomyosarcoma of the Uterus with Heterologous Elements: A Potential Diagnostic Pitfall 
Dedifferentiation is a phenomenon that is well characterized in a variety of tumors and is defined by the occurrence of a high-grade or undifferentiated tumor, typically unrecognizable regarding its line of differentiation, from a low-grade/borderline neoplasm. This phenomenon has previously been described in 2 uterine leiomyosarcomas, but both were devoid of heterologous elements. The authors describe herein a case of a dedifferentiated leiomyosarcoma of the uterus with osteoid heterologous elements, believed to be the first such reported case. The original tumor was a high-grade leiomyosarcoma with large low-grade and leiomyoma-like areas and whose constituent cells displayed intense nuclear immunoreactivity for both estrogen receptor (ER) and progesterone receptor (PR) in approximately 30% of cells. The tumor recurred six months after its resection as an undifferentiated sarcoma that was negative for smooth muscle markers, but which remained positive for ER and PR. Osteoid production was only identified in the recurrent tumor and was significant in extent therein. This case highlights the immunophenotypic changes that may occur in dedifferentiated leiomyosarcomas, and this possibility should be a consideration when an apparently undifferentiated sarcoma is identified in a patient with a history of uterine leiomyosarcoma. In our case, the expression of ER and PR provided significant supportive evidence of the uterine origin of the recurrent tumor.
doi:10.1155/2012/534634
PMCID: PMC3483660  PMID: 23119198
14.  Ovarian serous carcinoma: recent concepts on its origin and carcinogenesis 
Recent morphologic and molecular genetic studies have led to a paradigm shift in our conceptualization of the carcinogenesis and histogenesis of pelvic (non-uterine) serous carcinomas. It appears that both low-grade and high-grade pelvic serous carcinomas that have traditionally been classified as ovarian in origin, actually originate, at least in a significant subset, from the distal fallopian tube. Clonal expansions of the tubal secretory cell probably give rise to serous carcinomas, and the degree of ciliated conversion is a function of the degree to which the genetic hits deregulate normal differentiation. In this article, the authors review the evidentiary basis for aforementioned paradigm shift, as well as its potential clinical implications.
doi:10.1186/1756-8722-5-8
PMCID: PMC3328281  PMID: 22405464
Ovarian cancer; Fallopian tube; Carcinogenesis; Serous carcinoma; p53 signatures
15.  Does the Loss of ARID1A (BAF-250a) Expression in Endometrial Clear Cell Carcinomas Have Any Clinicopathologic Significance? A Pilot Assessment 
Journal of Cancer  2012;3:129-136.
SWI/SNF chromatin-modification complexes use the energy of ATP hydrolysis to remodel nucleosomes and to affect transcription and several cellular processes. Accordingly, their loss of function has been associated with malignant transformation. ARID1A (the expression of whose product, BAF250a, a key complex component, is lost when mutated) has recently been identified as a tumor suppressor gene that is mutated in 46-57% of ovarian clear cell carcinoma (CCC). The purposes of this study are to assess the frequency of loss of BAF250a expression in endometrial CCC and whether this loss has any discernable clinicopathologic implications. 34 endometrial carcinomas with a CCC component (including 22 pure CCC, 8 mixed carcinomas with a 10% CCC component, and 4 carcinosarcomas with a CCC epithelial component), were evaluated by immunohistochemistry using a monoclonal antibody directed against the human BAF250a protein. 5 (22.7%) of the 22 pure CCC were entirely BAF250a negative, whereas the remainder showed diffuse immunoreactivity. None of 4 carcinosarcomas and only 1 (12.5%) of the 8 mixed carcinomas were BAF250a negative. There was no discernable relationship between BAF250a immunoreactivity status and tumor architectural patterns (solid, papillary or tubulocystic areas) or cell type (flat, hobnail or polygonal). Of the 22 patients with pure CCC, 14, 2, 3, and 3 were International Federation of Gynecology and Obstetrics stages 1, II, III and IV respectively. Interestingly, all 5 BAF250a negative cases were late stage [stages III or IV] as compared with 1 of 17 BAF250a positive cases (p=0.0002). Thus, 83% (5/6) of all late stage cases were BAF250a [-], as compared with 0 (0%) of the 16 early stage (I or II) cases (p=.0002). BAF250a negative and positive cases did not show any statistically significant difference regarding patient age and frequency of lymphovascular invasion or myometrial invasion. As may be anticipated from the concentration of late stage cases in the BAF250a negative group, patient outcomes were worsened in that group on univariate analysis. In conclusion, we found in this pilot assessment that 22.7% of endometrial CCC displays complete loss of BAF250a expression. There was a disproportionate concentration of BAF250a negative cases in the late stage group, with the attendant possibility of an associated worsened prognosis for those CCC patients whose tumors are BAF250a negative. These preliminary findings suggest the need for larger analyses to evaluate the prognostic significance, if any, of the loss of BAF250a expression in this rare histotype of endometrial cancer.
doi:10.7150/jca.4140
PMCID: PMC3297840  PMID: 22408686
BAF250a; ARID1A; endometrial cancer
16.  An orthotopic model of platinum-sensitive high grade serous fallopian tube carcinoma 
Fallopian tube carcinoma (FTCA) is a very rare cancer type, but may be a useful platform for investigating high grade serous tumors of the pelvis that originate from a serous tubal intraepithelial carcinoma (STIC) precursor. Metastatic tumors from a patient diagnosed with Stage IIIC high grade serous FTCA (P0) were transplanted via intraperitoneal (IP) injection into a small cohort of mice (passage, P1). Patient information was obtained from the medical record. Tumors were grown, harvested and re-implanted or archived through P3. The P3 cohort was treated with saline (n=8) or cisplatin, 5 mg/kg (n=8), weekly for 4 weeks. After sacrifice, tumors from each passage and treatment group were passaged further, frozen or paraffin embedded. The patient underwent optimal cytoreductive surgery for Stage IIIC high grade serous FTCA in the presence of a STIC. The FTCA, areas of STIC and normal appearing FT stained positive for p53, PAX8, pH2AX and mib-1. The patient remained in remission 9 months after platinum-based chemotherapy. IP tumor propagation was readily achieved up to P3 in the mice. Similar to the patient, orthotopic tumors were identified along peritoneal and mesenteric surfaces. Tumor histopathological and molecular features were confirmed and maintained through P3. The P3 cisplatin-treated mice had fewer tumor implants, higher levels of pH2AX and lower levels of mib-1 expression compared to controls. This orthotopic model of platinum sensitive high grade serous FTCA is a viable platform to study the biology and treatment of FTCA and other STIC-related pelvic serous carcinomas.
PMCID: PMC3267484  PMID: 22295145
Fallopian tube carcinoma; pelvic serous carcinoma; STIC; orthotopic model
18.  High and intermediate grade ductal carcinoma in-situ of the breast: a comparison of pathologic features in core biopsies and excisions and an evaluation of core biopsy features that may predict a close or positive margin in the excision 
Diagnostic Pathology  2009;4:26.
Low and high-grade ductal carcinoma in-situ (DCIS) are known to be highly disparate by a multitude of parameters, including progression potential, immunophenotype, gene expression profile and DNA ploidy. In this study, we analyzed a group of intermediate and high-grade DCIS cases to determine how well the core biopsy predicts the maximal pathology in the associated excisions, and to determine if there are any core biopsy morphologic features that may predict a close (≤ 0.2 cm) or positive margin in the subsequent excision. Forty-nine consecutive paired specimens [core biopsies with a maximal diagnosis of DCIS, and their corresponding excisions, which included 20 and 29 specimens from mastectomies and breast conserving surgeries respectively] were evaluated in detail. In 5 (10%) of 49 cases, no residual carcinoma was found in the excision. In another 4 cases, the changes were diagnostic only of atypical ductal hyperplasia. There were 4 and 3 respective cases of invasive and microinvasive carcinoma out of the 49 excision specimens, for an overall invasion frequency of 14%. In 28 cases where a sentinel lymph node evaluation was performed, only 1 was found to be positive. Among the 40 cases with at least residual DCIS in the excision, there were 5 cases in which comedo-pattern DCIS was present in the excision but not in the core biopsy, attributed to the lower maximal nuclear grade in the biopsy proliferation in 4 cases and the absence of central necrosis in the 5th. For the other main histologic patterns, in 8 (20%) of 40 cases, there were more patterns identified in the core biopsy than in the corresponding excision. For the other 32 cases, 100%, 66%, 50%, 33% and 25% of the number of histologic patterns in the excisions were captured in 35%, 5%, 17.5%, 15% and 7.5% of the preceding core biopsies respectively. Therefore, the core biopsy reflected at least half of the non-comedo histologic patterns in 77.5% of cases. In 6(15%) of the 40 cases, the maximum nuclear grade of the excision (grade 3) was higher than that seen in the core biopsy (grade 2). Overall, however, the maximum nuclear grade in the excision was significantly predicted by maximum nuclear grade in the core biopsy (p = 0.028), with a Phi of 0.347, indicating a moderately strong association. At a size threshold of 2.7 cm, there was no significant association between lesional size and core biopsy features. Furthermore, the clear margin width of the cases with lesional size ≤ 2.7 cm (mean 0.69 cm) was not significantly different (p = 0.4) from the cases with lesional size > 2.7 cm (mean 0.56 cm). Finally, among a variety of core biopsy features that were evaluated, including maximum nuclear grade, necrosis, cancerization of lobules, number of tissue cores with DCIS, number of DCIS ducts per tissue core, total DCIS ducts, or comedo-pattern, only necrosis was significantly associated with a positive or close (≤ 0.2 cm) margin on multivariate analysis (Phi of 0.350). It is concluded that a significant change [to invasive disease (14%) or to no residual disease (10%)] is seen in approximately 24% of excisions that follow a core biopsy diagnosis of intermediate or high-grade DCIS. Core biopsy features are of limited value in predicting a close or positive margin in these lesions.
doi:10.1186/1746-1596-4-26
PMCID: PMC2740842  PMID: 19691836
19.  Insights into Endometrial Serous Carcinogenesis and Progression 
Endometrial serous carcinomas (ESC) constitute only approximately 10% of endometrial cancers, but have a substantially higher case-fatality rate than their more common endometrioid counterparts. The precise composite of factors driving endometrial serous carcinogenesis and progression remain largely unknown, but we attempt to review the current state of knowledge in this report. ESC probably do not evolve through a single pathway, and their underlying molecular events probably occur early in their evolution. TP53 gene mutations occur in 22.7 to 96% of cases, and p53 protein overexpression is seen in approximately 76%. By gene expression profiling, p16 is upregulated in ESC significantly above both normal endometrial cells and endometrioid carcinomas, and 92–100% of cases display diffuse expression of the p16 protein by immunohistochemistry (IHC). Together, these findings suggest dysregulation of both the p16INKA/Cyclin D-CDK/pRb-E2F and the ARF-MDM2-p53 cell cycle pathways in ESC. By IHC, HER2/neu is overexpressed (2+ or 3+) in approximately 32.1% of ESC, and approximately 54.5% of cases scored as 2+ or 3+ by IHC display c-erbB2 gene amplification as assessed by fluorescent in situ hybridization. Genetic instability, typically manifested as loss of heterozygosity in multiple chromosomes, is a common feature of ESC, and one study found loss of heterozygosity at 1p32-33 in 63% of cases. A subset of ESC display protein expression patterns that are characteristic of high grade endometrial carcinomas, including loss of the metastasis suppressor CD82 (KAI-1) and epithelial-to-mesenchymal transformation, the latter manifested as E-cadherin downregulation, P-cadherin upregulation, and expression of epithelial-to-mesenchymal transformation-related molecules such as zinc-finger E-box-binding homeobox 1 (ZEB1) and focal adhesion kinase. Preliminary data suggests differential patterns of expression in ESC of some isoforms of claudins, proteases, the tumor invasiveness and progression-associated oncofetal protein insulin-like growth factor II mRNA-binding protein 3 (IMP3), as well as a variety of other molecules. At the morphologic level, evidence that indicates that endometrial glandular dysplasia (EmGD) is the most likely morphologically recognizable precursor lesion to ESC is presented. We advocate use of the term endometrial intraepithelial carcinoma (EIC, or its other appellations) only as a morphologic descriptor and never as a diagnostic/pathologic statement of biologic potential. Given its potential for extrauterine extension, we consider the lesions described as EIC, when present in isolation, as examples of localized ESC, and patients should be managed as such. Morphologically normal, p53 immunoreactive endometrial cells (the so-called “p53 signatures”), show a statistically significant association with ESC, display p53 mutations in a significant subset, and form the start of a progression model, outlined herein, from p53 signatures to EmGD to localized ESC to the more conventionally invasive neoplasm. The identification of a morphologically-recognizable precursor holds the promise of early detection of ESC, with the attendant reduction in its overall associated mortality rate. Deciphering the molecular basis for endometrial serous carcinogenesis should uncover potential targets for diagnosis, therapy, and/or disease surveillance.
PMCID: PMC2655156  PMID: 19294001
Endometrial serous carcinoma; endometrial glandular dysplasia; endometrial intraepithelial carcinoma; p53; cadherins; claudins; CDKs; MDM2 and HER2/neu (erb-B2)
20.  Does the radiofrequency impedance-controlled endometrial ablation have any morphologic effects on uterine leiomyomata?: Report of 3 cases 
Diagnostic Pathology  2008;3:28.
A variety of novel endometrial ablation technologies are now in routine use. A subset of uteri that had previously undergone these treatments will ultimately be evaluated by the pathologist. However, the full spectrum of histologic changes that may result from these treatments has received only sporadic attention. The NovaSure™ [Hologic Corporation, Marlborough, MA, USA] endometrial ablation system is one of several available second-generation technologies and its particular endometrial ablative power is based on the delivery of radiofrequency energy. The present analysis was designed to decipher any histologic changes (if any) associated with the NovaSure™ endometrial ablation system relative to benign smooth muscle tumors of the uterine corpus. Over a one-year period, 3 uteri that had previously undergone the NovaSure™ endometrial ablation and which also had leiomyomatous mass lesions were evaluated. The leiomyomatous mass lesions were extensively sampled and were evaluated for cellular shapes (epithelioid change, cellular rounding, extraordinary cytoplasmic eosinophilia, clear cell change, cytoplasmic vacuolation), nuclear changes (nucleomegaly, nucleolomegaly, multinucleation, hyperchromasia, symplastic changes), necrosis (coagulative and/or infarct), mitotic activity, apoptotic bodies or pyknotic cells, myxoid change, hyalinization. The three uteri were resected 61, 47 and 74 (mean 60.7) days post-ablation. After a detailed evaluation of multiple submucosal, intramural and subserosal leiomyomata from these 3 uteri, no noteworthy histologic changes were identified in the tumors. Since the presence or absence of tumor necrosis is one histologic criterion by which malignant potential is assigned to uterine smooth muscle neoplasms, defining any extrinsic processes that may establish, or contribute to this finding is clinically relevant. The findings reported herein suggests that if a leiomyoma that was obtained from a patient that had recently undergone the NovaSure™ endometrial ablation displays any degenerative changes such as necrosis, the changes are probably not attributable to the ablation.
doi:10.1186/1746-1596-3-28
PMCID: PMC2491603  PMID: 18593468
21.  Pleomorphic Lymphoepithelioma-like Carcinoma of the Urinary Bladder 
Lymphoepithelioma-like carcinoma (LELC) of the urinary bladder is often mixed with conventional transitional cell carcinoma and/or other histotypes. The pathologist’s determination of the morphologic purity of a given LELC at the biopsy stage is a clinically relevant endeavour, because there is some anecdotal evidence suggesting that pure or predominant LELC may be comparatively chemosensitive and have a favorable prognostic profile, which may potentially offer the possibility of effective therapy without bladder resection. The precise degree of cellular pleomorphism that is allowed in a pure LELC is unclear. We describe herein an otherwise conventional and pure LELC that showed, in a localized area that constituted approximately 25% of the overall tumor volume, a two to six fold variation in nuclear size, including multinucleated tumor cells. These pleomorphic areas were set in the same lymphoplasmacytic infiltrate as their conventional counterparts, and similarly displayed cellular syncytia. We performed a detailed immunophenotypic comparison between the conventional areas and the pleomorphic areas. No significant differences were found between the 2 areas in overall lymphoplasmacytic or histiocytic density, lymphocytic CD4/CD8 ratio, and lymphoplasmacytic kappa/lambda ratio. Similarly, both displayed similar qualitative and quantitative staining indices for p53, Ki67, cytokeratin AE1/AE3 and p16INKa. Scattered cells were cytoplasmically beta-catenin positive exclusively in the pleomorphic areas; however these cells were not notably larger than the cells in the conventional areas. Both components were immunohistochemically negative for HMB-45, CD1a, the estrogen receptor, Epstein-Barr virus, CD117, D2-40, CD56, cytokeratin 20 and chromogranin. Clinicopathologic analysis of a series of cases is required to establish if there is any significance to nuclear pleomorphism in LELC. However, the phenotypic similarity between the 2 areas in this case, the intimate admixture of the pleomorphic cells with the lymphoplasmacytic infiltrate, and their syncytial pattern of growth, all suggest that pure LELC may display marked nuclear pleomorphism, and that this finding may not, in of itself, be a valid basis for removing a case from the “pure” group.
PMCID: PMC2583638  PMID: 19079656
Bladder; lymphoepithelioma; lymphoepithelioma-like
22.  Mucocele-like tumor and columnar cell hyperplasia of the breast occurring in a morphologic continuum 
Introduction
Mucocele-like tumor was originally described in 1986 as a benign breast proliferation consisting of multiple dilated cysts lined by cytologically bland, flat to cuboidal cells. Subsequent reports described the coexistence of, including the morphologic inter-transitions between, mucocele-like tumor and a variety of other breast proliferations, including intraductal carcinoma, invasive carcinoma, atypical ductal hyperplasia, and hyperplasia of the usual type. The spectrum of breast alterations characterized by variably enlarged terminal-ductal lobular units lined by variably hyperplastic and variably atypical columnar cells has been the subject of significant discussion in the recent literature. In one scheme, these lesions may be classified into four groups, that is, columnar cell change with and without atypia and columnar cell hyperplasia with and without atypia. Morphologic and molecular observations suggest an association, perhaps in a nonobligate precursor role, between some columnar cell lesions and a variety of other neoplastic lesions.
Case presentation
We describe the case of a 43-year-old woman whose breast tumor contained areas diagnostic of mucocele-like tumor and columnar cell hyperplasia, with morphologic transitions in between.
Conclusion
Our case represents the second broadly similar case that has been reported, and suggests a potential relationship between these two enigmatic lesions.
doi:10.1186/1752-1947-2-138
PMCID: PMC2386799  PMID: 18447919
23.  Diagnostic Utility of P63 and CD10 in Distinguishing Cutaneous Spindle Cell/Sarcomatoid Squamous Cell Carcinomas and Atypical Fibroxanthomas 
The pathologic distinction of atypical fibroxanthomas (AFXs) from cutaneous spindle cell/sarcomatoid squamous cell carcinomas (SCSCCs) may occasionally pose a significant diagnostic challenge, given the substantial clinicopathologic overlap between these lesions. Recent studies indicate that p63 and CD10 are expressed in significant proportions of SCSCC and AFX, respectively. The purpose of this study is to investigate the utility of CD10 and p63 in distinguishing cutaneous SCSCCs and AFXs. The immunohistochemical expression of p63, CD10, cytokeratin AE-1/3, cytokeratin 5/6 and a cytokeratin cocktail (Kermix) was evaluated in an archived group of 23 AFXs and 10 SCSCCs. CD10 was positive in 18/23 AFXs (78%), with most demonstrating strong and/or diffuse staining. Three of 23 AFXs (13%), all negative for cytokeratins, showed focal and weak nuclear staining for p63. Two of 23 AFXs (9%) demonstrated very focal or weak staining for only one cytokeratin; in both cases, p63 and CD10 were negative. One AFX was negative with all immunostains. CD10 was positive in 6/10 SCSCCs (60%), with half demonstrating strong and/or diffuse staining. P63 was positive in 9/10 SCSCCs (90%), with most demonstrating strong and diffuse staining. One SCSCC was negative for p63, but positive with two cytokeratin immunostains. In conclusion, the expression of any of the cytokeratins evaluated herein significantly distinguished AFX from SCSCC. CD10 used in isolation, however, was not useful in making this distinction (positive in 18/23 AFXs versus 6/10 SCSCCs, p=0.4). The addition of CD10 to a panel that includes p63 did not provide any additional information to that obtained from the latter alone. Overall, the most effective combination to distinguish AFX from SCSCC was p63 and cytokeratin AE-1/3. Positivity for both p63 and cytokeratin AE-1/3 was seen in 9/10 SCSCCs (90%) and was not observed in any of the 23 AFXs (p<0.0001). The usefulness of CD10 in this differential diagnosis is limited.
PMCID: PMC2480581  PMID: 18787630
Atypical fibroxanthoma; p63; CD10; skin; sarcomatoid/spindle cell squamous cell carcinoma
24.  Uterine PEComa: appraisal of a controversial and increasingly reported mesenchymal neoplasm 
In recent years, a group of tumors that have been designated "perivascular epithelioid cell tumors" (PEComa) have been reported with increasing frequency from a wide variety of anatomic locations. The uterus and retroperitoneum appear to be the most frequent sites of origin for these lesions. PEComas belong to an identically named family of tumors comprised of conventional angiomyolipomas, clear cell sugar tumors, lymphangiomyomatosis and clear cell myomelanocytic tumor of the falciform ligament/ligament teres, and are also known as PEComa-NOS. This article is a primer for clinicians on the most salient clinicopathologic features of uterine PEComas, as most of the debate and discussion have taken place in the pathologic literature. The author appraises in detail the current state of knowledge on PEComas of the uterus based on a review of published data on the 44 previously reported cases, and comments on areas of controversy. The latter are centered predominantly on the significant morphologic and immunophenotypic overlap that exists between uterine PEComa and some smooth muscle tumors of the uterus. The clinicopathologic features of cases reported as epithelioid smooth muscle tumors and cases reported as uterine PEComas are compared and contrasted, and a practical approach to their reporting is proposed.
doi:10.1186/1477-7800-5-7
PMCID: PMC2278149  PMID: 18325099
25.  Endometrial Glandular Dysplasia (EmGD): morphologically and biologically distinctive putative precursor lesions of Type II endometrial cancers 
In this article, the authors briefly review the historical evolution of the various putative precursor lesions for Type II endometrial cancers, with an emphasis on the newly defined "Endometrial Glandular Dysplasia (EmGD)". The evidentiary basis for delineating serous EmGD as the most probable precursor lesions to endometrial serous carcinoma is reviewed in detail. An argument is advanced for the discontinuation of the term serous "endometrial intraepithelial carcinoma (EIC)" as a descriptor for a supposedly intraepithelial, precancerous lesion. Preliminary evidence is also presented that suggests that there is a morphologically recognizable "clear cell EmGD" that probably represents a precancerous lesion to endometrial clear cell carcinomas.
doi:10.1186/1746-1596-3-6
PMCID: PMC2266702  PMID: 18261213

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