Precursors in the ovarian stroma: another pathway to explain the origin of ovarian serous neoplasms.

Ovarian serous neoplasms are thought to arise from the fallopian tube or from the ovarian surface epithelium. The possibility of a third pathway-involving the mesenchymal-epithelial transition and mimicking the formation of the Müllerian duct-arose from observations gathered from our routine cases. The purpose of this study is to determine the association of precursors in the ovarian stroma with different types of ovarian serous neoplasms. Three hundred neoplasms, benign (25), borderline (63), and malignant ovarian serous neoplasms (40 low-grade serous carcinomas [LGSCas] and 172 high-grade serous carcinomas [HGSCas]), were reviewed. Clinicopathologic features analyzed included patient's age, tumor size, stage, histologic pattern, and possible precursors in the ovarian parenchyma (endosalpingiosis, inverted macropapillae, polyploid giant cancer cells, and simple cysts). All benign and borderline cases showed continuity with benign serous cysts or endosalpingiosis. In LGSCas, continuity with serous cysts was found in 29 (72%) of 40 cases, and inverted macropapillae were found in 12 (30%) of 40 cases. In untreated HGSCas, there was continuity with simple cysts in 42% of cases. In addition, these HGSCas contained polyploid giant cancer cells in 20% of cases. There were no different features in the ovaries in cases with or without serous tubal intraepithelial carcinoma. Our study shows that in a subset of cases, ovarian serous neoplasms and the Müllerian duct develop in similar fashion, originating from epithelial cells derived from the mesothelium, or occur de novo from structures derived from mesenchymal-epithelial transition.

The role of neoadjuvant chemotherapy in the management of low-grade serous carcinoma of the ovary and peritoneum: Further evidence of relative chemoresistance.

OBJECTIVE: Low-grade serous carcinoma of the ovary/peritoneum (LGSC) is relatively chemoresistant in the adjuvant, neoadjuvant, and recurrent settings. We sought to expand our prior work and evaluate response rates of women with LGSC to neoadjuvant chemotherapy (NACT) compared to women with high-grade serous carcinoma of the ovary/peritoneum (HGSC). METHODS: Thirty-six patients with LGSC who received NACT were matched to patients with HGSC. A single radiologist re-reviewed pre- and post-NACT imaging for response using RECIST 1.1. Pre- and post-NACT CA-125 values were compared using paired t-tests. Kaplan-Meier estimates of progression free survival (PFS) and overall survival (OS) were performed. RESULTS: All patients received neoadjuvant platinum-based regimens. LGSC patients received a median of 5 cycles (range 3-9), HGSC patients received a median of 4 cycles (range 3-9). Interval cytoreductive surgery was performed in 29/36 (81%) of LGSC and 32/36 (89%) HGSC patients. Complete cytoreduction was reported and achieved in 11/29 (38%) of LGSC patients and 24/32 (75%) of HGSC patients (p = 0.002). Median pre- and post-treatment CA-125 levels for LGSC patients were 295.5 U/mL and 144 U/mL (52% decrease) (p < 0.001). The median pre- and post-treatment CA-125 levels for HGSC patients were 767.5 and 35.6 (96% decrease) (p < 0.001). For LGSC patients, 4/36 (11%) had partial response (PR), 30/36 (83%) had stable disease (SD), and 2/36 (6%) had progressive disease (PD). In HGSC patients, 27/36 (75%) had PR, and 9/36 (25%) SD. Median PFS for LGSC patients was 18.5 months and median OS was 47.4 months. CONCLUSIONS: This study provides further evidence of relative chemoresistance of LGSC in patients treated with NACT.

Are polyploid giant cancer cells in high grade serous carcinoma of the ovary blastomere-like cancer stem cells?

Polyploid giant cancer cells, either multinucleated or mononucleated, in high grade serous carcinoma of the ovary have been previously recognized. Different theories including degenerative changes or an important step in the development of high grade serous carcinoma have been proposed. Here we investigate possible explanations for the presence of polyploid giant cancer cells in high grade serous carcinoma. We reviewed 33 cases of ovarian high grade serous carcinoma (12 stage I, 7 stage II, and 14 stage III). We counted the number of polyploid giant cancer cells in 20 consecutive 10× fields. In 11 cases where polyploid giant cancer cells were easily found, immunohistochemistry for Ki67, p53, and OCT 3/4 was performed. Patients with polyploid giant cancer cells were older than those without. Polyploid giant cancer cells were more frequent in stage I lesions (75%) than in stages II or III (57% in both) and less frequent in metastases compared with primary ovarian tumors. Mitotic figures were present in regular sized cells but were absent in polyploid giant cancer cells. OCT3/4 was negative in all cases assessed. In 8 cases, more than 70% of the mononuclear cells were positive for Ki-67, similar to the percentage of Ki-67 positive cells in polyploid giant cancer cells. p53 had a perfect correlation in regular sized cancer cells and in polyploid giant cancer cells. Polyploid giant cancer cells are neither degenerative cells nor traditional cancer stem cells but most probably represent an intermediate step between stem cells and mature tumor cells formed by endoreplication.

Histology of the normal ovary in premenopausal patients.

Detailed descriptions of ovarian histology are rare. We reviewed in detail 57 cases of normal ovaries in premenopausal patients, when the ovaries are active and primordial follicles are found. We also proposed updated definitions to more clearly distinguish inclusion cysts, which do not have a known relationship with any disease process, from endosalpingiosis, a lesion closely associated with low grade serous neoplasia of the ovary. The most interesting findings were the significant variation in the histologic features including the variation in the amount and the distribution of primordial follicles, follicular cysts, and endosalpingiosis, within the ovary and between both ovaries in the same patient, the frequent presence of primordial follicles in the medulla, specifically in cases of multiple follicular cysts, and the frequent presence of endosalpingiosis. We believe that to confirm a pathologic process in the ovary, we need to become familiar with the histologic features of the normal ovary and their variations.

Role of Lymphovascular Invasion in Pattern C Invasive Endocervical Adenocarcinoma.

Lymphovascular invasion (LVI) has been reported as an independent predictor of patient outcome in cervical carcinoma. However, not all studies support independent significance, especially in multivariable analyses. A risk stratification system recently introduced for endocervical adenocarcinoma was reported to better predict risk of lymph node (LN) metastasis. A subset of patients with tumors with pattern C features had LN metastasis and died of disease. In this study, we determined whether LVI had any additional significance in this subset of tumors. A total of 127 patients with pattern C tumors and at least 12-month follow-up were included. Tumors were separated into 3 subgroups. Those with no LVI and negative LNs represented 41 cases; most patients (36, 88%) were alive with no evidence of disease at last follow-up, whereas 4 (10%) died of disease, all after tumor recurrence/metastasis. Tumors with LVI, but negative LNs, represented 55 cases; recurrences were seen in 10 (18%) patients, of which 5 (50%) of them died of disease; remaining 5 patients are alive with persistent disease. Tumors with both LVI and positive LNs represented 31 cases; recurrences were seen in 13 (42%) patients; 11 (85%) patients died of disease and 2 are alive with persistent disease. One additional patient who presented with advanced stage also died of disease. Tumor size, horizontal spread, and LN status were significantly associated with outcome in univariate, but not in multivariable analysis; depth of invasion was not a predictor of outcome. Tumors with no LVI and negative LNs behaved significantly less aggressively than tumors with both LVI and positive LNs (P<0.01). LVI status (independent of LN status) was not significantly associated with patient outcome, although approached significance (P=0.06). In conclusion, LVI is a prerequisite for LN metastasis; however, by itself is not sufficient to predict tumor aggressiveness, whereas over 50% of patients with positive LNs died of disease. Stratifying pattern C tumors into subgroups based on LVI and LN status could further determine treatment in patients with pattern C tumors.

Factors Predicting Pelvic Lymph Node Metastasis, Relapse, and Disease Outcome in Pattern C Endocervical Adenocarcinomas.

A pattern-based classification system has recently been proposed for invasive endocervical adenocarcinoma (EAC), which is predictive of the risk for lymph node metastases (LNM). The main utility of the system lies in separating cases with very low risk for LNM (pattern A) from those with higher risk (pattern B and C). Different growth patterns (GPs) are found in pattern C cases. The aim of the study was to evaluate the effect of GP on the behavior of pattern C EAC. By reevaluating 189 pattern C EACs, we documented 6 architectural GPs: diffuse destructive (DD), confluent (CON), extensive linear destructive (ELD), band-like lymphocytic infiltrate (BLL), solid (SOL), and micropapillary (MP). When an EAC had an appreciable second component (≤50%) the designation of a mixed EAC was used. We found 32 (17%) tumors to be DD, 23 (12%) CON, 27 (14%) ELD, 9 (5%) SOL, 7 (4%) BLL, and 7 (4%) micropapillary. A total of 84 (44%) EACs were mixed (DD+CON). All micropapillary EACs had LNM versus none of the patients with EAC with an ELD GP (P=0.002). Recurrent disease was seen in 44% of EACs with a DD GP, whereas 0% of EACs with BLL GP developed recurrent disease. Mixed (DD+CON) tumors had a significantly worse 6-year overall survival. This study demonstrated that not all pattern C EACs have an aggressive behavior. These patients should be treated with radical hysterectomy and sentinel lymph node biopsy.

Pattern classification of endocervical adenocarcinoma: reproducibility and review of criteria.

Previously, our international team proposed a three-tiered pattern classification (Pattern Classification) system for endocervical adenocarcinoma of the usual type that correlates with nodal disease and recurrence. Pattern Classification-A tumors have well-demarcated glands lacking destructive stromal invasion or lymphovascular invasion, Pattern Classification-B tumors show localized, limited destructive invasion arising from A-type glands, and Pattern Classification-C tumors have diffuse destructive stromal invasion, significant (filling a 4 × field) confluence, or solid architecture. Twenty-four cases of Pattern Classification-A, 22 Pattern Classification-B, and 38 Pattern Classification-C from the tumor set used in the original description were chosen using the reference diagnosis originally established. One H&E slide per case was reviewed by seven gynecologic pathologists, four from the original study. Kappa statistics were prepared, and cases with discrepancies reviewed. We found a majority agreement with reference diagnosis in 81% of cases, with complete or near-complete (six of seven) agreement in 50%. Overall concordance was 74%. Overall kappa (agreement among pathologists) was 0.488 (moderate agreement). Pattern Classification-B has lowest kappa, and agreement was not improved by combining B+C. Six of seven reviewers had substantial agreement by weighted kappas (>0.6), with one reviewer accounting for the majority of cases under or overcalled by two tiers. Confluence filling a 4 × field, labyrinthine glands, or solid architecture accounted for undercalling other reference diagnosis-C cases. Missing a few individually infiltrative cells was the most common cause of undercalling reference diagnosis-B. Small foci of inflamed, loose or desmoplastic stroma lacking infiltrative tumor cells in reference diagnosis-A appeared to account for those cases up-graded to Pattern Classification-B. In summary, an overall concordance of 74% indicates that the criteria can be reproducibly applied by gynecologic pathologists. Further refinement of criteria should allow use of this powerful classification system to delineate which cervical adenocarcinomas can be safely treated conservatively.

New pattern-based personalized risk stratification system for endocervical adenocarcinoma with important clinical implications and surgical outcome.

We present a recently introduced three tier pattern-based histopathologic system to stratify endocervical adenocarcinoma (EAC) that better correlates with lymph node (LN) metastases than FIGO staging alone, and has the advantage of safely predicting node-negative disease in a large proportion of EAC patients. The system consists of stratifying EAC into one of three patterns: pattern A tumors characterized by well-demarcated glands frequently forming clusters or groups with relative lobular architecture and lacking destructive stromal invasion or lymphovascular invasion (LVI), pattern B tumors demonstrating localized destructive invasion (small clusters or individual tumor cells within desmoplastic stroma often arising from pattern A glands), and pattern C tumors with diffusely infiltrative glands and associated desmoplastic response. Three hundred and fifty-two cases were included; mean follow-up 52.8 months. Seventy-three patients (21%) had pattern A tumors; all were stage I and there were no LN metastases or recurrences. Pattern B was seen in 90 tumors (26%); all were stage I and LVI was seen in 24 cases (26.6%). Nodal disease was found in only 4 (4.4%) pattern B tumors (one IA2, two IB1, one IB not further specified (NOS)), each of which showed LVI. Pattern C was found in 189 cases (54%), 117 had LVI (61.9%) and 17% were stage II or greater. Forty-five (23.8%) patients showed LN metastases (one IA1, 14 IB1, 5 IB2, 5 IB NOS, 11 II, 5 III and 4 IV) and recurrences were recorded in 41 (21.7%) patients. This new risk stratification system identifies a subset of stage I patients with essentially no risk of nodal disease, suggesting that patients with pattern A tumors can be spared lymphadenectomy. Patients with pattern B tumors rarely present with LN metastases, and sentinel LN examination could potentially identify these patients. Surgical treatment with nodal resection is justified in patients with pattern C tumors.

The Origin of Epithelial Neoplasms of the Ovary: An Alternative View.

Several theories have been proposed to explain the origin of epithelial neoplasms of the ovary. However, most of them did not receive serious consideration until recently when it has been proposed that most ovarian neoplasms arise from the fallopian tube. In this review, we mention the different theories, we discuss in detail the fallopian tube theory, and the reasons why this theory is probably inaccurate. We are also proposing a new theory, the fere ex nihilo, based on the observation of numerous cases, old and new concept, and experimental works with animals. We believe that, most probably, ovarian epithelial neoplasms are related to hormones and the identification of these hormones will allow us not only to diagnose and treat these lethal neoplasms, but also to prevent them.

Vascular invasion in uterine sarcomas and its significance. A multi-institutional study.

Although metastases and high-mortality are frequent in high-grade endometrial sarcomas (HGSs), these findings are less commonly seen in low-grade endometrial stromal sarcomas (LGESSs), even in cases with lymphovascular invasion (LVI). We hypothesized that the "bulging plugs" of tumor characteristic of LVI in LGESS are fundamentally different from LVI seen in HGS. We reviewed 70 uterine sarcomas: 42 HGSs (high-grade endometrial stromal sarcomas, undifferentiated uterine sarcoma, and leiomyosarcoma) and 28 LGESSs. All cases had LVI documented on the histologic slides. Immunostains for CD31, ERG, and D2-40 were performed. LGESS harbored cohesive intravascular tumor foci with direct communication from the main tumor and attached to the vessel wall. The intravascular foci included tumor cells and small arteriole-type vessels and were surrounded by a thin fibrous band. Vascular markers confirmed the LVI and highlighted positively stained endothelial cells separating intravascular tumor foci from the blood itself. In contrast, intravascular tumor foci in HGS were composed of discohesive cells clusters, lacking the features described in LGESS. Only 8 (30.8%) patients with LGESS had recurrence/metastases (6 with lung metastasis); only 1 patient died of disease. Thirty (77%) patients with HGS had recurrence/metastases, 27 (69%) patients had lung metastases, and 22 (56.4%) patients died of disease. We propose that in most LGESSs, LVI represents vascular intrusion; manipulation or trauma is potentially responsible for tumor cell detachment into the circulation increasing the chances of recurrence/metastases. Classic LVI features were identified in HGS. This important distinction may allow for better management of patients and avoid unnecessary treatment in LGESS, reducing morbidity.

Risk factor analysis of recurrence in low-grade endometrial adenocarcinoma.

Prognosis of endometrial adenocarcinoma is favorable; however, the risk of recurrence ranges from 7% to 13%. Recurrence has been related to age, tumor type, International Federation of Gynecology and Obstetrics grade, depth of invasion, and lymphovascular invasion (LVI); however, morphologic features that would predict the site of recurrence have not been established. In this multi-institutional study, we reviewed 589 patients with International Federation of Gynecology and Obstetrics grades 1 or 2 endometrial adenocarcinoma, endometrioid type. Cox proportional hazard analysis was used to identify univariate and multivariate risk factors for recurrence and survival. Univariate analysis revealed features of tumors that recurred only in the vagina: low nuclear grade; superficial myoinvasion; minimal to no LVI; and minimal myoinvasion with microcystic, elongated, and fragmented (MELF) pattern; low nuclear grade and superficial myoinvasion persisted on multivariate analysis. Features of tumors that recurred at other sites included large size, deep myoinvasion, tumor necrosis, 1 or more LVI foci, LVI foci distant/deeper than invasive tumor front, MELF myoinvasion pattern, lower uterine segment and cervical stromal involvement, pelvic and/or paraaortic lymph node metastases at presentation, and higher grade of tumor in the metastatic foci, whereas increased percentage of solid component and lower percentage of mucinous features were marginally associated. Tumors with recurrences only in vagina had different features than tumors that recurred at other sites. The presence of tumor necrosis, MELF foci at the invasive tumor front, and the percentage of solid component and mucinous features could be helpful in grading endometrioid adenocarcinomas, if a 2-tier rather than a 3-tier grading system is accepted in the future.

STUMP un"stumped": anti-tumor response to anaplastic lymphoma kinase (ALK) inhibitor based targeted therapy in uterine inflammatory myofibroblastic tumor with myxoid features harboring DCTN1-ALK fusion.

BACKGROUND: Recurrent, metastatic mesenchymal myxoid tumors of the gynecologic tract present a management challenge as there is minimal evidence to guide systemic therapy. Such tumors also present a diagnostic dilemma, as myxoid features are observed in leiomyosarcomas, inflammatory myofibroblastic tumors (IMT), and mesenchymal myxoid tumors. Comprehensive genomic profiling was performed in the course of clinical care on a case of a recurrent, metastatic myxoid uterine malignancy (initially diagnosed as smooth muscle tumor of uncertain malignant potential (STUMP)), to guide identify targeted therapeutic options. To our knowledge, this case represents the first report of clinical response to targeted therapy in a tumor harboring a DCTN1-ALK fusion protein. METHODS: Hybridization capture of 315 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer was applied to >50 ng of DNA extracted from this sample and sequenced to high, uniform coverage. Therapy was given in the context of a phase I clinical trial ClinicalTrials.gov Identifier: ( NCT01548144 ). RESULTS: Immunostains showed diffuse positivity for ALK1 expression and comprehensive genomic profiling identified an in frame DCTN1-ALK gene fusion. The diagnosis of STUMP was revised to that of an IMT with myxoid features. The patient was enrolled in a clinical trial and treated with an anaplastic lymphoma kinase (ALK) inhibitor (crizotinib/Xalkori®) and a multikinase VEGF inhibitor (pazopanib/Votrient®). The patient experienced an ongoing partial response (6+ months) by response evaluation criteria in solid tumors (RECIST) 1.1 criteria. CONCLUSIONS: For myxoid tumors of the gynecologic tract, comprehensive genomic profiling can identify clinical relevant genomic alterations that both direct treatment targeted therapy and help discriminate between similar diagnostic entities.

Invasive endocervical adenocarcinoma: a new pattern-based classification system with important clinical significance.

A new 3-tier pattern-based system to classify endocervical adenocarcinoma was recently presented. In short, pattern A tumors were characterized by well-demarcated glands frequently forming clusters or groups with relative lobular architecture. Pattern B tumors demonstrated localized destructive invasion defined as desmoplastic stroma surrounding glands with irregular and/or ill-defined borders or incomplete glands and associated tumor cells (individual or small clusters) within the stroma. Tumors with pattern C showed diffusely infiltrative glands with associated extensive desmoplastic response. In total, 352 cases (all FIGO stages) from 12 institutions were identified. Mean patient age was 45 years (range, 20 to 83 y). Forty-nine (13.9%) cases demonstrated lymph nodes (LNs) with metastatic endocervical carcinoma. Using this new system, 73 patients (20.7%) were identified with pattern A tumors (all stage I); none had LN metastases and/or recurrences. Ninety patients (25.6%) were identified with pattern B tumors (all stage I); only 4 (4.4%) had LN metastases; 1 had vaginal recurrence. The 189 (53.7%) remaining patients had pattern C tumors; 45 (23.8%) of them had LN metastases. This new classification system demonstrated 20.7% of patients (pattern A) with negative LNs, and patients with pattern A tumors can be spared of lymphadenectomy. Patients with pattern B tumors rarely presented with metastatic LNs, and sentinel LN examination could potentially identify these patients. Aggressive treatment is justified in patients with pattern C tumors.

Risk factors for recurrence and prognosis of low-grade endometrial adenocarcinoma; vaginal versus other sites.

Endometrial adenocarcinoma is the most common gynecologic cancer in the United States. The prognosis is generally favorable, however, a significant number of patients do develop local or distant recurrence. The most common site of recurrence is vaginal. Our aim was to better characterize patients with vaginal recurrence of low-grade endometrioid adenocarcinoma with respect to associated tumor parameters and clinical outcome. We compiled 255 cases of low-grade (FIGO Grade I or II) endometrioid adenocarcinoma on hysterectomy specimens with lymph node dissection. A total of 113 cases with positive lymph nodes or recurrent disease were included in our study group. Seventy-three cases (13 Grade 1, 60 Grade 2) developed extravaginal recurrence and 40 cases (7 Grade 1, 33 Grade 2) developed vaginal recurrence. We evaluated numerous tumor parameters including: percentage myoinvasion, presence of microcystic, elongated, and fragmented pattern of myoinvasion, lymphovascular space invasion, and cervical involvement. Clinical follow-up showed that 30% (34/113) of all patients with recurrent disease died as a result of their disease during our follow-up period, including 31 (42.5%) with extravaginal recurrence and 3 (7.5%) with primary vaginal recurrence (P=0.001). The 3 patients with vaginal recurrence developed subsequent extravaginal recurrence before death. Vaginal recurrence patients show increased cervical involvement by tumor, but lack other risk factors associated with recurrent disease at other sites. There were no deaths among patients with isolated vaginal recurrence, suggesting that vaginal recurrence is not a marker of aggressive tumor biology.

Invasive endocervical adenocarcinoma: proposal for a new pattern-based classification system with significant clinical implications: a multi-institutional study.

The management of endocervical adenocarcinoma is largely based on tumor size and depth of invasion (DOI); however, DOI is difficult to measure accurately. The surgical treatment includes resection of regional lymph nodes, even though most lymph nodes are negative and lymphadenectomies can cause significant morbidity. We have investigated alternative parameters to better identify patients at risk of node metastases. Cases of invasive endocervical adenocarcinoma from 12 institutions were reviewed, and clinical/pathologic features assessed: patients' age, tumor size, DOI, differentiation, lymph-vascular invasion, lymph node metastases, recurrences, and stage. Cases were classified according to a new pattern-based system into Pattern A (well-demarcated glands), B (early destructive stromal invasion arising from well-demarcated glands), and C (diffuse destructive invasion). In total, 352 cases (FIGO Stages I-IV) were identified. Patients' age ranged from 20 to 83 years (mean 45), DOI ranged from 0.2 to 27 mm (mean 6.73), and lymph-vascular invasion was present in 141 cases. Forty-nine (13.9%) demonstrated lymph node metastases. Using this new system, 73 patients (20.7%) with Pattern A tumors (all Stage I) were identified. None had lymph node metastases and/or recurrences. Ninety patients (25.6%) had Pattern B tumors, of which 4 (4.4%) had positive nodes; whereas 189 (53.7%) had Pattern C tumors, of which 45 (23.8%) had metastatic nodes. The proposed classification system can spare 20.7% of patients (Pattern A) of unnecessary lymphadenectomy. Patients with Pattern B rarely present with positive nodes. An aggressive approach is justified in patients with Pattern C. This classification system is simple, easy to apply, and clinically significant.

Ovarian serous cystadenofibromas associated with a low-grade serous carcinoma of the peritoneum.

Ovarian serous cystadenofibromas are benign neoplasms that sometimes have focal areas of borderline serous tumor and rarely have been associated with epithelial proliferations in the peritoneum, resembling implants. We are reporting 2 cases of ovarian serous cystadenofibromas with serous peritoneal lesions of higher grade than the ovarian tumor: 1 case had a serous carcinoma and another 1 a serous borderline tumor.

Low-grade smooth muscle tumors of the primary and the secondary mullerian system: a proposed concept of multicentricity.

Some patients with bland smooth muscle tumors in the uterus have synchronous or asynchronous smooth muscle tumors in the peritoneum and/or the retroperitoneum. It is usually assumed that the uterine tumor is the primary lesion, and the extrauterine neoplasm represents its metastasis. Thus, they are designated as low-grade leiomyosarcomas because they lack the diagnostic features of a conventional spindle cell leiomyosarcoma. Nineteen such cases were retrieved from the files of the Department of Pathology at The University of Texas M.D. Anderson Cancer Center, covering a period of 18 yr. Institutional Review Board approval was obtained before the initiation of this study. In addition, 31 cases of conventional uterine leiomyosarcomas of a high grade were reviewed for comparison. Clinicopathologic features such as patients' age, tumor location, histologic features, stage, treatment, and follow-up were recorded. Immunohistochemical stains for estrogen receptor (ER), progesterone receptor (PR), p53, Ki-67, and WT-1 were performed in the initially detected tumor and the subsequent neoplasm of all cases with available material in the low-grade group and selected cases in the high-grade group. Compared with high-grade leiomyosarcomas, the low-grade group cases were found at an early age (45 vs. 52.8 yr), had a longer median time of "recurrence" (42 mo for the low-grade group vs. 12 mo for high-grade leiomyosarcomas), longer median survival (165 mo for the low-grade group vs. 41 mo for the high-grade group), and a much better overall survival (84% vs. 13%). Three (16%) patients died of disease in the low-grade group versus 27 (87%) patients in the high-grade leiomyosarcoma group. We also found a difference in the location of the extrauterine tumors. Most cases of low-grade tumors were found in the pelvis, abdomen, or retroperitoneum, whereas most high-grade leiomyosarcomas involved the lung. In the low-grade tumors, there were some differences in the immunophenotype between the uterine and the extrauterine neoplasms, but in the high-grade tumors, there were no differences in the immunohistochemistry between the primary tumor and the metastasis. In addition to these differences between the 2 groups in the age of the patients, sites of recurrences, and the immunophenotype of the uterine and extrauterine tumor, neither the uterine nor the extrauterine low-grade lesions had histologic features of malignancy. On the basis of these differences, the possibility that the extrauterine lesions in the low-grade group represent independent primaries involving the secondary mullerian system is proposed.

Peritoneal washing cytologic analysis of ovarian serous tumors of low malignant potential to detect peritoneal implants and predict clinical outcome.

BACKGROUND: Patients with ovarian serous tumors of low malignant potential (OSLMP) who have peritoneal implants, especially invasive implants, are at an increased risk of developing tumor recurrence. To the best of the authors' knowledge, the ability of peritoneal washing (PW) cytology to detect the presence and type of peritoneal implants has not been adequately investigated, and its prognostic significance is unknown. METHODS: Records and PW specimens of 101 patients diagnosed with and treated for OSLMP between 1996 and 2010 at The University of Texas MD Anderson Cancer Center were retrospectively reviewed. Patients' staging biopsy findings were compared with the results of the authors' review of the PWs. Follow-up data were also analyzed. RESULTS: Of the 96 patients for whom staging biopsy results were available, 26 (27%) had peritoneal implants (17 noninvasive and 9 invasive), 19 (20%) had endosalpingiosis, and 51 (53%) had negative findings. The PW specimens of 18 of the 26 patients (69%) with peritoneal implants were positive for serous neoplasm, and a correlation was found between cytologic and histologic findings (P < .0001). The sensitivity, specificity, positive predictive value, and negative predictive value were 69%, 84%, 62%, and 88%, respectively. Four of 101 patients had disease recurrence; 3 of these patients had invasive implants and 1 patient had noninvasive implants. None of the patients who had negative staging biopsy findings or endosalpingiosis but did have PW specimens that were positive for serous neoplasm developed disease recurrence. CONCLUSIONS: PW cytology detects the presence of peritoneal implants with moderate accuracy. However, long-term studies are needed to determine whether positive PW cytologic findings are an independent predictor of tumor recurrence.

The 2 stromal compartments of the normal cervix with distinct immunophenotypic and histomorphologic features.

Cervical plasticity is partially attributed to subepithelial stromal cells. Knowing this population of cells in its variable physiologic states, with its immunophenotypic variations, will lead to better understanding of neoplastic processes related to these stromal cells. We reviewed slides of cervices from premenopausal, postmenopausal, and postpartum patients and used mesenchymal immunohistochemical stains. Results demonstrate 2 distinct subepithelial compartments, within the ectocervix and the endocervix/transformation zone. The endocervix/transformation zone has twice the number of stromal cells as the ectocervix, regardless of age. Ectocervical stromal cells are desmin+/smooth muscle actin (SMA)-, and endocervical stromal cells are desmin+/SMA-. In postpartum/premenopausal patients, the cervix has less desmin+ ectocervical and SMA- endocervical cells. In postmenopausal/prolapse patients, the cervix has no desmin+ ectocervical cells. Desmin+/SMA, calponin, caldesmon, myogenin, myoD1, CD34- cells could represent unusual myofibroblasts that should not be confused with a neoplastic process, especially if a mass is not present.

Clonality in gynecologic neoplasms: is it time to reevaluate clonality studies in gynecologic neoplasms? Is it possible to confirm multicentricity with clonality studies?

This article reviews issues with clonality applied to gynecologic neoplasms. It is our opinion that the current interpretation of clonality studies in gynecologic neoplasms needs to be reevaluated because multicentricity, probably a common mechanism of tumor development in gynecology, cannot be confirmed with clonality.