High-grade Endometrial Carcinomas: Morphologic and Immunohistochemical Features, Diagnostic Challenges and Recommendations.

This review of challenging diagnostic issues concerning high-grade endometrial carcinomas is derived from the authors' review of the literature followed by discussions at the Endometrial Cancer Workshop sponsored by the International Society of Gynecological Pathologists in 2016. Recommendations presented are evidence-based, insofar as this is possible, given that the levels of evidence are weak or moderate due to small sample sizes and nonuniform diagnostic criteria used in many studies. High-grade endometrioid carcinomas include FIGO grade 3 endometrioid carcinomas, serous carcinomas, clear cell carcinomas, undifferentiated carcinomas, and carcinosarcomas. FIGO grade 3 endometrioid carcinoma is diagnosed when an endometrioid carcinoma exhibits >50% solid architecture (excluding squamous areas), or when an architecturally FIGO grade 2 endometrioid carcinoma exhibits marked cytologic atypia, provided that a glandular variant of serous carcinoma has been excluded. The most useful immunohistochemical studies to make the distinction between these 2 histotypes are p53, p16, DNA mismatch repair proteins, PTEN, and ARID1A. Endometrial clear cell carcinomas must display prototypical architectural and cytologic features for diagnosis. Immunohistochemical stains, including, Napsin A and p504s can be used as ancillary diagnostic tools; p53 expression is aberrant in a minority of clear cell carcinomas. Of note, clear cells are found in all types of high-grade endometrial carcinomas, leading to a tendency to overdiagnose clear cell carcinoma. Undifferentiated carcinoma (which when associated with a component of low-grade endometrioid carcinoma is termed "dedifferentiated carcinoma") is composed of sheets of monotonous, typically dyscohesive cells, which can have a rhabdoid appearance; they often exhibit limited expression of cytokeratins and epithelial membrane antigen, are usually negative for PAX8 and hormone receptors, lack membranous e-cadherin and commonly demonstrate loss of expression of DNA mismatch repair proteins and SWI-SNF chromatin remodeling proteins. Carcinosarcomas must show unequivocal morphologic evidence of malignant epithelial and mesenchymal differentiation.

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.

Interobserver Reproducibility Among Gynecologic Pathologists in Diagnosing Heterologous Osteosarcomatous Component in Gynecologic Tract Carcinosarcomas.

Distinguishing hyalinized stroma from osteoid production by a heterologous osteosarcomatous component can be challenging in gynecologic tract carcinosarcomas. As heterologous components in a carcinosarcoma may have prognostic and therapeutic implications, it is important that these are recognized. This study examines interobserver reproducibility among gynecologic pathologists in the diagnosis of osteosarcomatous components, and its correlation with expression of the novel antibody SATB2 (marker of osteoblastic differentiation) in these osteosarcomatous foci. Digital H&E images from 20 gynecologic tract carcinosarcomas were reviewed by 22 gynecologic pathologists with a request to determine the presence or absence of an osteosarcomatous component. The 20 preselected cases included areas of classic heterologous osteosarcoma (malignant cells producing osteoid; n=10) and osteosarcoma mimics (malignant cells with admixed nonosteoid matrix; n=10). Interobserver agreement was evaluated and SATB2 scored on all 20 cases and compared with the original diagnoses. Moderate agreement (Fleiss' κ=0.483) was identified for the 22 raters scoring the 20 cases with a median sensitivity of 7/10 and a median specificity of 9/10 for the diagnosis of osteosarcoma. SATB2 showed 100% sensitivity (10/10) and 60% (6/10) specificity in discriminating classic osteosarcoma from osteosarcoma mimics. Utilizing negative SATB2 as a surrogate marker to exclude osteosarcoma, 73% (16/22) of the reviewers would have downgraded at least 1 case to not contain an osteosarcomatous component (range, 1-6 cases, median 1 case). Gynecologic pathologists demonstrate only a moderate level of agreement in the diagnosis of heterologous osteosarcoma based on morphologic grounds. In such instances, a negative SATB2 staining may assist in increasing accuracy in the diagnosis of an osteosarcomatous component.

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.

Update on pathology, staging and molecular pathology of endometrial (uterine corpus) adenocarcinoma.

Endometrial carcinoma is comprised of two major groups: type I that is hormonally driven with a good prognosis and type II that is hormone independent with a poor prognosis. The two most common subtypes are endometrioid adenocarcinoma, the prototypic type I cancer, and uterine serous carcinoma, the prototypic type II cancer, each with their own distinct precursor lesion. The histologic type, as codified by the WHO Tumor Classification system, grade, and stage are used to guide treatment. There is an increasing interest in screening for familial risk factors, specifically Lynch syndrome. A molecular classification of endometrial cancers holds promise for future improvements in care.

A small organ takes center stage: selected topics in fallopian tube pathology.

In this paper we consider a number of non-neoplastic and neoplastic lesions of the fallopian tube. Emphasis has been placed on diagnostically difficult entities, some of which result in misdiagnosis and consequent alteration of treatment, including "pseudocarcinomas" that represent a florid epithelial response to acute and/or chronic salpingitis. Endometriosis-related lesions may cause infertility, or undergo malignant transformation to a Mullerian carcinoma, most frequently endometrioid and clear cell types. Pregnancy-related tubal lesions include the easily misdiagnosed metaplastic papillary tumor as well as several manifestations of ectopic pregnancy. Covered briefly are familial conditions such as the Peutz-Jeghers syndrome and its association with tubal mucinous metaplasia, clear cell papillary cystadenoma associated with von Hippel-Lindau syndrome, and the Li Fraumeni syndrome's germline p53 mutation and its association with distal tubal p53 signatures. Miscellaneous tumors discussed include the common adenomatoid tumor and the uncommon female adnexal tumor of probable Wolffian origin. Important issues including the updated staging of fallopian tube carcinomas, and the histopathologic variants of endometrioid carcinomas and their sometimes unusual patterns that engender the potential for confusion with other tumors are briefly noted. The final section covers the relatively recent and novel concept of the fallopian tube as the predominant site of origin of ovarian and peritoneal carcinomas. Discussed are the histologic, immunohistochemical, and molecular biologic evidence that support the tubal fimbria as the site of serous tubal intraepithelial carcinoma, possibly the immediate precursor to high-grade ovarian and peritoneal serous carcinoma.

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.

Desmoplastic stromal response as defined by positive α-smooth muscle actin staining is predictive of invasion in adenocarcinoma of the uterine cervix.

The objective of this research was to examine the immunohistochemical profiles of adenocarcinoma in situ (AIS) and early invasive adenocarcinoma (AC) to identify biomarkers that enhance the accurate diagnosis of early invasive glandular lesions of the cervix. The University of California, Irvine, and Long Beach Memorial tumor registries were used to identify 20 women with AIS or early AC treated between 1990 and 2008. An immunohistochemical study was performed, and the primary endpoint measured was the correlation between biomarker expression and invasive disease as diagnosed on hematoxylin and eosin examination. The biomarkers studied included α-smooth muscle actin (α-SMA), estrogen receptor, carcinoembryonic antigen, Ki67, p16, cyclooxygenase-2, and cluster of differentiation 1a. Stains were described on the basis of (1) positive or negative staining; (2) intensity; (3) percentage of positive cells; and (4) pattern of staining. Statistical analysis was performed using SYSTAT v. 11.0. Fisher exact test, Mann-Whitney nonparametric test, κ statistic, and intraclass correlation coefficient were used to evaluate results and interpreter agreement. A statistically significant increase in the staining of the periglandular stroma for α-SMA was seen in AC as compared with AIS. The intensity was 2.2 versus 1.2 (P=0.04) and the percent of positive-staining cells was 44% versus 18% (P=0.05) in AC and AIS, respectively. The presence of a desmoplastic stromal response as identified by the increased periglandular staining for α-SMA is useful in identifying invasive glandular lesions of the endocervix. Further studies are necessary to establish biologically relevant cut-off values for α-SMA staining.

DNA mismatch repair deficiency in endometrial carcinoma.

Microsatellite instability (MSI) is the hallmark of a molecular pathway to carcinogenesis due to sporadic or inherited abnormalities of DNA mismatch repair genes. Inherited mutations are seen in hereditary nonpolyposis colorectal cancer syndrome. Endometrial carcinoma shows as high an incidence of MSI as does colorectal carcinoma. This review provides a framework for the gynecologic pathologist to understand the complexities of MSI in endometrial carcinoma, by discussing the basic mechanisms of mismatch repair and carcinogenesis, testing, the morphologic features of MSI endometrial cancer and the contradictory data regarding prognosis.

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.

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.

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.

Surgical cytoreduction and hormone therapy of an advanced endometrial stromal sarcoma of the ovary.

BACKGROUND: Primary endometrial stromal sarcomas of the ovary are rare gynecologic malignancies. We report a disseminated case of this tumor arising from ovarian endometriosis. CASE: A 45-year-old woman presented with an abdominal pelvic mass and an elevated CA 125. Exploration showed extensive tumor spread from the ovaries to the upper abdomen. Surgery included a total hysterectomy, bilateral salpingo-oophorectomy, splenectomy, partial gastrectomy, partial pancreatectomy, transverse colectomy, appendectomy, and omentectomy. Final pathology showed a low-grade endometrial stromal sarcoma of the ovary arising from foci of endometriosis. Megestrol acetate was initiated, and she is currently without evidence of disease. CONCLUSION: This is an advanced case of a primary low-grade endometrial stromal sarcoma of the ovary arising from endometriosis managed by total resection and progestational therapy.