Ruthy Shaco-Levy

Malignant struma ovarii: an analysis of 88 cases, including 27 with extraovarian spread.

Struma ovarii that display extraovarian spread or later recurrence is exceedingly rare. Among 88 patients with “malignant” struma ovarii followed for prolonged periods, several features helped to predict the adverse clinical course. Adhesions (graded 2 to 4+), peritoneal fluid (≥1 L) or ovarian serosal rent were worrisome features, occurring in 74% of 27 biologically malignant tumors but only 10% of 61 clinically benign tumors. The size of the strumal component rather than the overall size of the ovarian teratoma also had some predictive value. Tumors with a strumal component ≤6 cm recurred rarely (7%), whereas 33% of the consult and 88% of the literature cases ≥12 cm were clinically malignant. Except for a papillary pattern or poorly differentiated cancer, no microscopic feature reliably predicted the clinical outcome, including those typically associated with malignancy in primary thyroid tumors. Among the consult cases, 7% with histologic follicular adenomas and 29% with papillary carcinomas were clinically malignant. Unequivocal vascular invasion was rare, precluding assessment of its effect. Optically clear nuclei, when extensive, were useful to diagnose papillary carcinoma, but were present nevertheless in smaller numbers in both macrofollicular and microfollicular adenomas. Eight tumors confined initially to the ovary (stage 1) recurred. Papillary carcinomas recurred earlier (average 4 y) than follicular adenomatous neoplasms (average 11 y, range: 1-29 y). Overall, the survival rate for all patients was 89% at 10 years and 84% at 25 years, indicating the need for routine long-term follow-up.

Matrix metalloproteinases 2 and 9, E-cadherin, and β-catenin expression in endometriosis, low-grade endometrial carcinoma and non-neoplastic eutopic endometrium

OBJECTIVES Endometriosis and endometrial endometrioid carcinoma are both capable of invasion and metastasis, but their biological behavior is strikingly different. Matrix metalloproteinases (MMPs) and changes in adhesion molecules have a role in the pathogenesis of various physiological and pathological processes, as well as in the development of endometriosis and endometrioid endometrial carcinoma. We hypothesized that endometriosis, being a benign process, will show different MMPs and adhesion molecules expressions, compared to endometrioid endometrial carcinoma, a disease with potential of malignant behavior. STUDY DESIGN We performed an immunohistochemical study to investigate expression of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), E-cadherin and beta-catenin in endometriosis, low-grade endometrial endometrioid carcinoma, and eutopic proliferative endometrium. Endometriotic tissues (n=15), low-grade endometrial endometrioid carcinomas (n=15), and unremarkable proliferative endometrium from women without endometriosis or carcinoma (n=10) were examined. RESULTS Endometriotic tissues showed statistically significantly stronger staining for MMP-9 and reduced beta-catenin expression when compared with proliferative endometrium. Endometrial endometrioid carcinoma showed decreased E-cadherin expression in comparison with proliferative endometrium. MMP-2 and MMP-9, and E-cadherin expressions were significantly higher and beta-catenin expression was significantly lower in endometriosis as compared to endometrioid carcinoma. CONCLUSIONS We suggest that increased MMPs and altered beta-catenin may play a role in the pathogenesis of endometriosis. Decreased E-cadherin may be important in the development of endometrial endometrioid carcinoma. The changes in MMPs, E-cadherin and beta-catenin differ in endometriosis from those in endometrioid carcinoma, an interesting finding in view of the fact that both these diseases are capable of invasion and metastasis, but have different biological behavior.

Paget disease of the vulva: a study of 56 cases

OBJECTIVE To resolve controversial issues regarding vulvar Paget disease through analysis of a substantial number of cases. STUDY DESIGN The medical records and pathology slides of 56 patients with a diagnosis of vulvar Paget disease were reviewed. Possible correlation between clinical and pathological data was examined. RESULTS Most patients were Caucasian and their mean age at diagnosis was 69 years. The average length of follow-up was 5.6 years. The most common symptom was pruritus, almost always accompanied by erythematous-white plaques. Substantial delay between appearance of symptoms and diagnosis was observed in many patients, and was significantly associated with larger lesions. Recurrence rate after surgical management was 32%, with disease involving the perineum being the only statistically significant risk factor. Patients with positive surgical margins had an increased recurrence rate, but this was not statistically significant. Intra-operative frozen section analysis of the margins as well as radical surgery as initial treatment did not reduce recurrence rate. In general, stromal invasion was not associated with worse prognosis, but the single patient who died of disease had the deepest stromal invasion. Radiation therapy given to five patients who either had multiple positive surgical margins or experienced disease recurrence and refused additional surgery resulted in complete response with no further recurrences. On the last day of follow-up 24 patients (43%) had no evidence of disease, 24 patients (43%) were dead of other causes, 5 patients (9%) were alive with disease, 2 patients (3%) were lost to follow-up, and 1 (2%) died due to vulvar Paget disease with invasive adenocarcinoma. CONCLUSIONS Vulvar Paget disease only rarely results in a patients death, but long term follow-up is required, as recurrences are common and can be noted many years after the initial treatment.

Paget Disease of the Vulva: A Histologic Study of 56 Cases Correlating Pathologic Features and Disease Course

The Duke experience with 56 vulvar Paget disease patients was analyzed emphasizing pathologic features and controversial issues. Nearly all patients were Caucasian, and their mean age was 69 years. The average length of follow-up was 5.6 years. For each case, the following histologic features were evaluated and their association with disease course was examined: pseudo-invasion, adnexal involvement, signet-ring cells, cytologic atypia, glands formation, epidermal acantholysis, parakeratosis, hyperkeratosis, and chronic inflammation. The recurrence rate after surgical management was 32%, with epidermal acantholysis being the only statistically significant risk factor. Stromal invasion occurred in 10 patients (18%), and was not a statistically significant adverse prognostic indicator, although the single patient who died of the disease had the deepest stromal invasion. Recurrence was more common after resections with positive surgical margins, but this correlation was not statistically significant. Intraoperative frozen section analysis of the margins did not reduce recurrence rate, nor was it useful in attaining permanent free margins. The Paget cells were consistently reactive with cytokeratin-7 and carcinoembryonic antigen and unreactive with S-100 protein, HMB-45, and Mart-1. In addition, the tumor cells were usually positive for mucin stains. This profile helps distinguish vulvar Paget disease from its mimics, Pagetoid squamous cell carcinoma and malignant melanoma.

Pancreatic Acinar Cell Carcinomas With Prominent Ductal Differentiation: Mixed Acinar Ductal Carcinoma and Mixed Acinar Endocrine Ductal Carcinoma

BackgroundPancreatic acinar cell carcinomas (ACCs) are clinically and pathologically distinct from pancreatic ductal adenocarcinomas (PDAs). Whereas endocrine differentiation has been well shown in ACCs, significant ductal components are rare. This paper reviews the clinicopathologic features of a series of ACCs with prominent ductal differentiation. DesignCases of pancreatic ACCs with significant ductal differentiation were identified in the surgical pathology databases of 2 academic centers. Patient clinical information, gross and histologic features, and histochemical and immunohistochemical (IHC) results were recorded. Cases were tested for KRAS2 mutations. ResultsEleven cases were identified (10 men and 1 woman; age range 52 to 79 y). Four patients presented with jaundice. At last follow-up, 7 patients died of disease and 2 others had recurrences. Tumors measured between 2 and 5.5 cm and were ill-defined, nodular, and multilobulated. Ten were located in the head of the pancreas. All but 2 exhibited extrapancreatic invasion. All cases showed significant evidence of both acinar and ductal differentiation, estimated to be at least 25% of the neoplastic cells, and 3 cases in addition had endocrine differentiation in more than 25% of cells. Five cases were predominately acinar with intracellular and sometimes extracellular mucin (“mucinous acinar cell carcinoma” pattern). Six cases seemed more mixed with areas recapitulating typical PDAs whereas the other portions of the tumors seemed akin to typical acinar cell carcinomas (“combined acinar and ductal” pattern). IHC positive staining results were as: trypsin (92%), chymotrypsin (92%), monoclonal carcinoembryonic antigen (100%), CK19 (100%), B72.3 (73%), CA19.9 (73%), CD56 (18%), synaptophysin (36%), and chromogranin (36%). One case showed p53 over-expression aznd none showed DPC4/Smad4 loss. Two cases had KRAS2 mutations. ConclusionDespite the early embryologic divergence of acinar and ductal cell lineages, rare pancreatic tumors have both acinar and ductal differentiation, usually predominantly the former. The clinical course is highly aggressive.

Natural history of biologically malignant struma ovarii: analysis of 27 cases with extraovarian spread.

The natural history of 27 cases of biologically malignant struma ovarii from a series of 88 cases of histologically malignant or histologically proliferative struma ovarii is described. The extraovarian spread was evident at presentation in 17 patients. The malignant nature of the other 10 tumors became apparent only after they recurred. The tumors measured 5 to 24.5 cm and were more than 50% thyroid tissue in all but 2 cases. The microscopic diagnosis of the thyroid tissue was follicular adenoma in 17 cases (63%), papillary carcinoma in 7 (26%), unremarkable in 2 (7%), and follicular carcinoma in 1 case (4%). Generally, the clinical course was protracted, with long-term survival documented in most patients. Clinical features predictive of biologic malignancy were the presence of adhesions, peritoneal fluid (≥1 L), or a serosal rent in the struma ovarii (including cystectomy). In addition, pathologic factors predictive of a poorer prognosis were large size (≥10 cm), strumal component more than 80%, and extensive papillary carcinoma, especially with solid areas, necrosis, and ≥5 mitoses per 10 high-power fields. Follow-up for all patients was 1.5 to 33 years (mean=13.5 yr). On last follow-up 3 patients (11%) had no evidence of disease, 9 (33%) were alive with disease, 5 (19%) died of other causes, and 10 patients (37%) died of the disease. Death from disease occurred 1.5 to 32 years after diagnosis (mean=14 yr). Recurrence was seen as early as 2 months and as late as 29 years after initial surgery (mean=7 yr). Long-term follow-up is indicated in patients with any of the above-mentioned adverse indicators.

Sister Mary Joseph’s nodule originating from endometrial carcinoma incidentally detected during surgery for an umbilical hernia: a case report

IntroductionUmbilical metastasis (Sister Mary Joseph’s nodule) is rare. It is encountered in 1–3% of patients with intra-abdominal and/or pelvic malignancy, with gastric carcinoma being the commonest origin in men and ovarian carcinoma—in women. Only 27 cases of Sister Mary Joseph’s nodule originating from endometrial carcinoma have previously been documented in the literature.Case reportIn a 51-year-old woman, a Sister Mary Joseph’s nodule coexisting with a large fibroid uterus was incidentally detected during surgery for suspected strangulated umbilical hernia. Subsequent laparotomy confirmed endometrial carcinoma metastasizing to the umbilical region.ConclusionThis is the 28th case reported in the literature of Sister Mary Joseph’s nodule originating from endometrial carcinoma and the first case of Sister Mary Joseph’s nodule originating from endometrial carcinoma incidentally detected during surgery for umbilical hernia. Surgeons should be aware of the possibility of Sister Mary Joseph’s nodule coexisting with an umbilical hernia.

Increased matrix metalloproteinases-1,-9 in the uterosacral ligaments and vaginal tissue from women with pelvic organ prolapse

OBJECTIVES To investigate the possible association of increased matrix metalloproteinases (MMPs)-1,-9 with pelvic organ prolapse (POP) and to evaluate whether inflammatory processes contribute to its development. STUDY DESIGN Forty women who underwent hysterectomy, 20 with POP grade 2 and above, and 20 without POP, participated in the study. Biopsies from the uterosacral ligaments and vaginal mucosa were obtained from each woman. Each biopsy was sectioned and stained for MMP-1 and MMP-9 by immunohistochemical methods and with hematoxylin and eosin (H&E). MMP-1,-9 expressions were evaluated on the immunostained slides. H&E stained sections were examined for possible inflammatory changes. RESULTS A higher stromal (extra-cellular) expression of MMPs-1,-9 was found in POP cases compared with controls in vaginal biopsies (MMP-1: p=0.004; MMP-9: p=0.042) as well as in uterosacral ligament biopsies (MMP-1: p=0.011; MMP-9: p=0.015). Increased intracellular expression of both MMPs was also demonstrated in fibroblasts in biopsies of women with POP (p<0.001 for all). Most of these differences persisted after controlling for age. The degree of inflammatory changes reflected by the number of lymphocytes, plasma cells and capillary-sized blood vessels per 10 high power fields, was similar in specimens obtained from women with and without POP. CONCLUSIONS The expression of MMPs-1,-9 appears to be increased in tissues from women with POP. This supports an association, although not a causal relation, between increased MMPs-1,-9 and POP. Inflammation does not seem to play an important role in the pathogenesis of POP.

MMP-2, TIMP-1, E-cadherin, and β-catenin expression in endometrial serous carcinoma compared with low-grade endometrial endometrioid carcinoma and proliferative endometrium

Objective. To investigate the expression of MMP‐2, TIMP‐1, E‐cadherin and β‐catenin in endometrial serous carcinoma (ESC), low‐grade endometrial endometrioid carcinoma (EEC), and proliferative endometrium. Methods. We performed an immunohistochemical study on 14 cases of ESC, 15 cases of low‐grade EEC, and 10 cases of proliferative endometrium. Results. Compared with low‐grade EEC, ESC showed significantly increased MMP‐2 and TIMP‐1 expression, as well as decreased membranous β‐catenin staining. E‐cadherin expression was significantly lower in ESC and EEC as compared with proliferative endometrium. Conclusions. We suggest that MMP‐2 and TIMP‐1 expression and loss of β‐catenin have a role in the pathogenesis and progression of ESC. Decreased E‐cadherin may have an important role in the development of both ESC and EEC. Furthermore, the dissimilarities in MMP‐2, TIMP‐1, E‐cadherin and β‐catenin expressions in ESC compared with EEC may be responsible, along with other factors, for their different biological behavior.

Native human autoantibodies targeting GIPC1 identify differential expression in malignant tumors of the breast and ovary

BackgroundWe have been studying the native humoral immune response to cancer and have isolated a library of fully human autoantibodies to a variety of malignancies. We previously described the isolation and characterization of two fully human monoclonal antibodies, 27.F7 and 27.B1, from breast cancer patients that target the protein known as GIPC1, an accessory PDZ-domain binding protein involved in regulation of G-protein signaling. Human monoclonal antibodies, 27.F7 and 27.B1, to GIPC1 demonstrate specific binding to malignant breast cancer tissue with no reactivity with normal breast tissue.MethodsThe current study employs cELISA, flow cytometry, Western blot analysis as well as immunocytochemistry, and immunohistochemistry. Data is analyzed statistically with the Fisher one-tail and two-tail tests for two independent samples.ResultsBy screening several other cancer cell lines with 27.F7 and 27.B1 we found consistently strong staining of other human cancer cell lines including SKOV-3 (an ovarian cancer cell line). To further clarify the association of GIPC1 with breast and ovarian cancer we carefully studied 27.F7 and 27.B1 using immunocytochemical and immunohistochemical techniques. An immunohistochemical study of normal ovarian tissue, benign, borderline and malignant ovarian serous tumors, and different types of breast cancer revealed high expression of GIPC1 protein in neoplastic cells. Interestingly, antibodies 27.F7 and 27.B1 demonstrate differential staining of borderline ovarian tumors. Examination of different types of breast cancer demonstrates that the level of GIPC1 expression depends on tumor invasiveness and displays a higher expression than in benign tumors.ConclusionThe present pilot study demonstrates that the GIPC1 protein is overexpressed in ovarian and breast cancer, which may provide an important diagnostic and prognostic marker and will constitute the basis for further study of the role that this protein plays in malignant diseases. In addition, this study suggests that human monoclonal antibodies 27.F7 and 27.B1 should be further evaluated as potential diagnostic tools.