Prophylactic salpingectomy for prevention of ovarian cancer at the time of elective laparoscopic cholecystectomy.

BACKGROUND: Most serous ovarian cancers are now understood to originate in the fallopian tubes. Removing the tubes (salpingectomy) likely reduces the risk of developing high-grade serous ovarian cancer. Numerous gynaecological societies now recommend prophylactic (or opportunistic) salpingectomy at the time of gynaecological surgery in appropriate women, and this is widely done. Salpingectomy at the time of non-gynaecological surgery has not been explored and may present an opportunity for primary prevention of ovarian cancer. METHODS: This study investigated whether prophylactic salpingectomy with the intention of reducing the risk of developing ovarian cancer would be accepted and could be accomplished at the time of elective laparoscopic cholecystectomy. Women aged at least 45 years scheduled for elective laparoscopic cholecystectomy were recruited. They were counselled and offered prophylactic bilateral salpingectomy at the time of cholecystectomy. Outcome measures were rate of accomplishment of salpingectomy, time and procedural steps needed for salpingectomy, and complications. RESULTS: A total of 105 patients were included in the study. The rate of acceptance of salpingectomy was approximately 60 per cent. Salpingectomy was performed in 98 of 105 laparoscopic cholecystectomies (93·3 per cent) and not accomplished because of poor visibility or adhesions in seven (6·7 per cent). Median additional operating time was 13 (range 4-45) min. There were no complications attributable to salpingectomy. One patient presented with ovarian cancer 28 months after prophylactic salpingectomy; histological re-evaluation of the tubes showed a previously undetected, focal serous tubal intraepithelial carcinoma. CONCLUSION: Prophylactic salpingectomy can be done during elective laparoscopic cholecystectomy.

ANTECEDENTES: La mayoría de carcinomas serosos de ovario se originan en las trompas de Falopio. La exéresis de las trompas (salpingectomía) probablemente reduce el riesgo de desarrollar un carcinoma seroso ovárico de alto grado. Numerosas sociedades ginecológicas recomiendan efectuar una salpingectomía profiláctica (u oportunista) en el momento de una cirugía ginecológica en determinadas mujeres, y esta conducta está ampliamente difundida. Sin embargo, no se ha analizado la realización de la salpingectomía durante cirugías no ginecológicas como forma de prevención primaria del carcinoma ovárico. MÉTODOS: Determinar si la salpingectomía profiláctica con intención de reducir el riesgo de desarrollar cáncer de ovario sería aceptada y podría llevarse a cabo durante una colecistectomía laparoscópica electiva. Se reclutaron mujeres ≥ 45 años de edad programadas para colecistectomía laparoscópica electiva. A todas ellas se les aconsejó y ofreció la realización de una salpingectomía bilateral profiláctica en el momento de su colecistectomía. Las variables analizadas fueron la tasa de realización de la salpingectomía, la duración y las etapas quirúrgicos para efectuar este procedimiento, y las complicaciones. RESULTADOS: La aceptación de la salpingectomía fue aproximadamente del 60%. La salpingectomía se realizó en 98 de 105 colecistectomías laparoscópicas (93%) y no se pudo realizar en 7 pacientes (7%) por escasa visibilidad o adherencias. La mediana del tiempo quirúrgico adicional fue de 13 (rango 4-45) minutos. No hubo complicaciones atribuibles a la salpingectomía. Una paciente presentó cáncer de ovario 28 meses después de la salpingectomía profiláctica; la reevaluación histológica de las trompas mostró un carcinoma intraepitelial seroso focal tubárico (serous tubal intraepithelial carcinoma, STIC) no detectado previamente. CONCLUSIÓN: La salpingectomía profiláctica se puede realizar durante la colecistectomía laparoscópica electiva.

[Pitfalls and common problems in the differential diagnosis of epithelial ovarian tumors]. / Fallstricke und Probleme bei der Differenzialdiagnose epithelialer Ovarialtumoren.

Epithelial ovarian tumors may cause various diagnostic problems of practical relevance. For the distinction between cystadenomas and borderline tumors/atypically proliferative tumors, a minimum extent of 10% of the atypical epithelial proliferation has been suggested by the WHO. The micropapillary variant of serous borderline tumors is more frequently associated with invasive growth and extraovarian lesions. Extraovarian lesions of borderline tumors are relevant for prognosis and cause a higher stage; their classification is crucial. Traditionally, they were classified into noninvasive and invasive implants based on their morphology. Based on the 2014 WHO classification, invasive lesions should be designated as low-grade serous carcinomas whereas only noninvasive lesions are considered implants. The most frequent invasive growth pattern in low-grade serous carcinomas consists of haphazardly arranged tumor cell nests and small papillae in clefts, whereas mucinous and endometrioid carcinomas mainly show a confluent glandular pattern with maze-like and cribriform structures. For metastatic mucinous tumors a nodular growth pattern is characteristic; ruling them out requires clinical information including imaging and immunohistochemistry. Differential diagnosis between low-grade and high-grade serous carcinoma is based on the degree of nuclear polymorphism and mitotic count. The seromucinous tumor category replaces the endocervical subtype of mucinous tumors and resembles histologically, biologically, and on the molecular level serous and endometrioid tumors. Endometrioid tumors with fibromatous stroma need to be distinguished from tumors with Sertoli cell differentiation and well-differentiated neuroendocrine tumors. For differential diagnosis of epithelial ovarian tumors, in particular carcinomas, a panel of antibodies for immunohistochemistry is very useful under consideration of histomorphology.

[Mesenchymal and mixed uterine tumors : Current overview and practical aspects]. / Mesenchymale und gemischte Uterustumoren : Aktuelle Übersicht und praktische Aspekte.

Benign leiomyomas are the most frequent mesenchymal tumors of the uterus. In contrast, uterine sarcomas are very rare. Leiomyosarcomas are the most frequent sarcomas followed by endometrial stromal sarcomas (ESS). Leiomyosarcomas are characterized by marked nuclear atypia and high mitotic count and may also show tumor cell necrosis and myometrial and vascular invasion. For cases of diagnostic uncertainty, the category of smooth muscle tumor of uncertain malignant potential (STUMP) may be considered but should be rarely used. Besides low-grade ESS and stromal nodules, a category of high-grade ESS was reconsidered by the WHO in 2014. High-grade ESS are characterized by fibromyxoid and round cell histology, myoinvasive growth, and immunoreactivity for cyclin D1 and BCOR and distinct gene fusions involving YWHAE and BCOR, respectively. The very rare undifferentiated uterine sarcomas need to be redefined due to overlap with high-grade ESS. Uterine tumors resembling ovarian sex cord tumors (UTROSCT) rarely behave malignant, but need to be distinguished from endometrial carcinomas. Mixed epithelial and mesenchymal tumors of the uterus are rare with carcinosarcomas occurring more frequently than adenosarcomas. For prognosis of adenosarcomas the recognition of sarcomatous overgrowth is crucial. Carcinosarcomas are histologically heterogeneous although genetically clonal; biologically they are considered as undifferentiated carcinomas. There will be an increasing importance of molecular pathology for the classification of rare and unusual mesenchymal uterine tumors.

[Precursor lesions of endometrial carcinoma]. / Vorläuferläsionen der Endometriumkarzinome.

The 2014 WHO classification distinguishes between endometrial hyperplasia without atypia (EH) and atypical endometrial hyperplasia/endometrioid intraepithelial neoplasia (AEH/EIN). AEH/EIN is characterized by crowded glands with cytologically atypical epithelium separated by little intervening stroma. Cellular atypia is characterized by nuclear enlargement and rounding, pleomorphism, loss of polarity, and presence of nucleoli. The diagnosis of atypia is facilitated by comparison with areas of adjacent normal and non-atypical glands, respectively. AEH/EIN is often associated with squamous but also secretory and mucinous metaplasia. Loss of PTEN and/or PAX2 immunoreactivity occurs in up to two thirds of AEH/EIN. In contrast, invasive low-grade endometrioid carcinoma shows confluent growth with loss of stroma and formation of labyrinth-like or cribriform structures. Differential diagnosis includes different forms of metaplasias, papillary proliferations, and hyperplastic polyps. Epithelial metaplasia may be present in various benign endometrial lesions as well as in endometrioid adenocarcinoma. AEH/EIN may also occur in endometrial polyps. Progestin therapy of AEH/EIN has low level of evidence but frequently leads to complete regression. Serous intraepithelial carcinoma (SEIC) is characterized by high-grade cellular atypia and polymorphism, detachment of cells, a mutant immunoreactive pattern for the P53 and an increased Ki67 labeling index. Although designated as precursor of serous carcinoma of the endometrium, biologically it is considered a non-invasive serous carcinoma since it may already be associated with massive extrauterine spread.

[Hereditary breast and ovarian cancer]. / Familiäres Mamma- und Ovarialkarzinom.

Hereditary breast and ovarian carcinomas are frequently caused by germline mutations of the BRCA1 and BRCA2 genes (BRCA1/2 syndromes) and are often less associated with other hereditary syndromes such as Li-Fraumeni and Peutz-Jeghers. The BRCA1/2 proteins have a special role in DNA repair. Therefore, loss of function due to mutation causes an accumulation of mutations in other genes and subsequent tumorigenesis at an early age. BRCA1/2 mutations are irregularly distributed over the length of the genes without hot spots, although special mutations are known. Breast and ovarian cancer occur far more frequently in women with BRCA1/2 germline mutations compared with the general population. Breast cancer occurs increasingly from the age of 30, ovarian cancer in BRCA1 syndrome from the age of 40 and BRCA2 from the age of 50. Suspicion of a BRCA syndrome should be prompted in the case of clustering of breast cancer in 1st degree relatives, in particular at a young age, if breast and ovarian cancer have occurred, and if cases of male breast cancer are known. Breast carcinomas with medullary differentiation seem to predominate in BRCA syndromes, but other carcinoma types may also occur. BRCA germline mutations seem to occur frequently in triple-negative breast carcinomas, whereas an association with ductal carcinoma in situ (DCIS) is rare. Ovarian carcinomas in BRCA syndromes are usually high-grade serous, mucinous carcinomas and borderline tumors are unusual. Pathology plays a special role within the multidisciplinary team in the recognition of patients with hereditary cancer syndromes.

[Endometritis : Rare disease with clinical importance?] / Endometritis : Seltene Erkrankung mit klinischer Relevanz?

Endometritis is nowadays rare in developed countries and typically shows a subclinical or mild course; therefore, there are probably more cases of endometritis than diagnosed but they lack clinical relevance. In the fertile period of life it can be the reason for vaginal bleeding and infertility. The most common causes for non-specific endometritis are residual placental tissue after abortion or childbirth, intrauterine interventions, lesions within the uterine cavity, such as endometrial polyps, endometrial hyperplasia and neoplasms, intrauterine devices (IUD) and cervical stenosis. The histological detection of plasma cells in the endometrial stroma is required for the diagnosis of chronic endometritis. These can be detected immunohistochemically using anti-CD138 antibodies, which should be carried out particularly in cases of infertility with only slight inflammatory symptoms and few plasma cells. The use of an IUD containing progestin is frequently associated with an asymptomatic lymphoplasmacytic infiltration. After curettage or endometrial biopsy, an eosinophilic xanthogranulomatous or granulomatous endometritis and also a foreign body granuloma reaction can occur. Specific forms of endometritis, such as caused by tuberculosis, sarcoidosis, mycoplasma and herpes are very rare. Cytomegalovirus endometritis is associated with immunosuppression. Endometritis caused by infections with Chlamydia trachomatis is characterized by an extensive lymphoplasmacytic infiltration. The differential diagnoses of chronic endometritis include the very rare malignant lymphoma, which is usually characterized by a relatively monotonous cell infiltration.

[New features in the 2014 WHO classification of uterine neoplasms]. / Neues in der WHO-Klassifikation 2014 der Tumoren des Corpus uteri.

The 2014 World Health Organization (WHO) classification of uterine tumors revealed simplification of the classification by fusion of several entities and the introduction of novel entities. Among the multitude of alterations, the following are named: a simplified classification for precursor lesions of endometrial carcinoma now distinguishes between hyperplasia without atypia and atypical hyperplasia, the latter also known as endometrioid intraepithelial neoplasia (EIN). For endometrial carcinoma a differentiation is made between type 1 (endometrioid carcinoma with variants and mucinous carcinoma) and type 2 (serous and clear cell carcinoma). Besides a papillary architecture serous carcinomas may show solid and glandular features and TP53 immunohistochemistry with an "all or null pattern" assists in the diagnosis of serous carcinoma with ambiguous features. Neuroendocrine neoplasms are categorized in a similar way to the gastrointestinal tract into well differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas (small cell and large cell types). Leiomyosarcomas of the uterus are typically high grade and characterized by marked nuclear atypia and lively mitotic activity. Low grade stromal neoplasms frequently show gene fusions, such as JAZF1/SUZ12. High grade endometrial stromal sarcoma is newly defined by cyclin D1 overexpression and the presence of the fusion gene YWHAE/FAM22 and must be distinguished from undifferentiated uterine sarcoma. Carcinosarcomas (malignant mixed Mullerian tumors MMMT) show biological and molecular similarities to high-grade carcinomas.

[Pitfalls in the histopathological diagnostics of endometrial carcinoma and its precursors : Clinically relevant differential diagnoses, avoidance of false positive diagnoses]. / Fallstricke bei der histopathologischen Diagnostik des Endometriumkarzinoms und seiner Vorstufen : Klinisch wichtige Differenzialdiagnosen, Vermeidung falsch-positiver Diagnosen.

Making an incorrect histopathological diagnosis of an endometrial lesion may lead to unwanted loss of fertility and therapy-associated morbidity; therefore, endometrial carcinomas need to be correctly typed and differentiated from hyperplastic precursors, benign lesions and artifacts. Typical diagnostic pitfalls are described in this article. Misdiagnosing endometrial lesions can be avoided by paying thorough attention to gross as well as microscopic features and by taking crucial differential diagnoses into consideration. These are, in particular, well-differentiated endometrioid adenocarcinoma of the endometrium versus atypical endometrial hyperplasia, myoinvasive endometrioid adenocarcinoma versus atypical polypoid adenomyoma and endometrioid carcinoma versus serous carcinoma of the endometrium with a predominantly glandular pattern. It is also important to consider the possibility of a false positive diagnosis of atypical endometrial hyperplasia or carcinoma in cases of biopsy-induced artifacts.

[Metastatic mechanisms of uterine malignancies and therapeutic consequences]. / Metastasierung von Malignomen des Uterus und therapeutische Konsequenzen.

Malignancies of the uterus metastasize by direct invasion of neighboring structures, lymphatically or hematogenously. Endometrial and cervical cancers lymphatically spread to the pelvic and para-aortic lymph nodes. For endometrial cancer the depth of myometrial invasion, lymphosvascular space involvement (LVSI) and a microcystic, elongated and fragmented (MELF) glandular invasion pattern are predictors for lymph node metastases. Metastases to the pelvic lymph nodes occur in approximately 10 % of endometrial cancer patients and in 30 % of these cases the para-aortic lymph nodes are also involved. Sentinel lymph node biopsy is possible for clinical stage I endometrial cancer and early stages of cervical cancer but is not yet routine. The presence of LVSI is considered to be the strongest predictor of distant metastases, particularly if assessed by immunohistochemistry with antibodies against factor VIII-related antigen or CD31. Endometrioid and clear cell carcinomas can hematogenously metastasize to the lungs, bones, liver and brain and can rarely be manifested as a solitary metastasis. In contrast, serous carcinomas can show extensive peritoneal spread. To date molecular biomarkers cannot predict the occurrence of distant metastasis. Overexpression of P53, p16 and L1CAM have been identified as negative prognostic factors and are associated with the prognostically unfavorable serous tumor type. The metastatic spread of squamous cell cervical cancer is strongly associated with tumor volume. Microinvasive carcinomas have a very low rate of parametrial and lymph node involvement and do not require radical hysterectomy. In contrast, lymph node metastases occur in up to 50 % of bulky stages IB and II cervical cancers. Distant metastases can occur in the lungs, liver, bones and brain. Molecular biomarkers have not been shown to predict metastatic spread. In well-differentiated adenocarcinoma of the cervix the pattern of invasion is strongly predictive for the presence of lymph node metastases, irrespective of tumor size and depth of invasion.

[Categorization of uterine cervix tumors : What's new in the 2014 WHO classification]. / Kategorisierung der Tumoren der Cervix uteri : Neues in der WHO-Klassifikation 2014.

In the 2014 WHO classification, squamous cell precursor lesions are classified as low-grade and high-grade intraepithelial lesions. LSIL corresponds to CIN1, HSIL includes CIN2 and CIN3. Only adenocarcinoma in situ (AIS) is accepted as precursor of adenocarcinoma and includes the stratified mucin-producing intraepithelial lesion (SMILE). Although relatively rare, adenocarcinoma and squamous cell carcinoma can be mixed with a poorly differentiated neuroendocrine carcinoma. Most cervical adenocarcinomas are low grade and of endocervical type. Mucinous carcinomas show marked intra- and extracellular mucin production. Almost all squamous cell carcinomas, the vast majority of adenocarcinomas, and many rare carcinoma types are HPV related. For low grade endocervical adenocarcinomas, the pattern-based classification according to Silva should be reported. Neuroendocrine tumors are rare and are classified into low-grade and high-grade, whereby the term carcinoid is still used.

ESR1, PGR, ERBB2, and MKi67 mRNA expression in postmenopausal women with hormone receptor-positive early breast cancer: results from ABCSG Trial 6.

BACKGROUND: The purpose of this study was to assess the concordance of real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) detection of ESR1, PGR, ERBB2, and MKi67 messenger RNA (mRNA) in breast cancer tissues with central immunohistochemistry (IHC) in women treated within the prospective, randomized Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 6. PATIENTS AND METHODS: We evaluated ESR1, PGR, ERBB2, and MKi67 mRNA expression by Xpert® Breast Cancer STRAT4 (enables cartridge-based RT-qPCR detection of mRNA in formalin-fixed paraffin-embedded tissues) and estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki67 protein expression by IHC [in situ hybridization (ISH) for HER2 IHC 2+] in 1115 surgical formalin-fixed paraffin-embedded specimens from patients of ABCSG Trial 6. Overall percent agreement (concordance), positive percent agreement (sensitivity), and negative percent agreement (specificity) between STRAT4 and IHC were determined for each marker. The primary objective of the study was concordance between STRAT4 mRNA measurements of ESR1, PGR, ERBB2, and MKi67 with central reference laboratory IHC (and ISH for HER2 IHC 2+ cases). Time to distant recurrence was analyzed by Cox models. RESULTS: All performance targets for ER, PR, and Ki67 were met. For HER2, the negative percent agreement target but not the positive percent agreement target was met. Concordance between STRAT4 and IHC was 98.9% for ER, 89.9% for PR, 98.2% for HER2, and 84.8% for Ki67 (excluding intermediate IHC 10%-20% staining). In univariable and multivariable Cox regression analyses, all four biomarkers tested by either STRAT4 RT-qPCR or by central IHC (ISH) had a comparable time to distant recurrence indicating similar prognostic value. CONCLUSIONS: With the exception of HER2, we demonstrate high concordance between centrally assessed IHC and mRNA measurements of ER, PR, and Ki67 as well as a high correlation of the two methods with clinical outcome. Thus, mRNA-based assessment by STRAT4 is a promising new tool for diagnostic and therapeutic decisions in breast cancer.

A binary architectural grading system for uterine endometrial endometrioid carcinoma has superior reproducibility compared with FIGO grading and identifies subsets of advance-stage tumors with favorable and unfavorable prognosis.

The International Federation of Gynecology and Obstetrics (FIGO) grading of uterine endometrial endometrioid carcinoma requires evaluation of histologic features that can be difficult to assess, including recognition of small amounts of solid growth, distinction of squamous from nonsquamous solid growth, and assessment of degree of nuclear atypia. The authors describe a novel, binary architectural grading system that uses low-magnification assessment of amount of solid growth, pattern of invasion, and presence of necrosis to divide endometrioid carcinomas into low- and high-grade tumors. The authors analyzed its performance for predicting prognosis and with respect to intra- and interobserver reproducibility. A total of 141 endometrioid carcinomas from hysterectomy specimens were graded according to the FIGO system, nuclear grading, and the binary architectural system. A tumor was classified as high grade if at least two of the following three criteria were present: (1) more than 50% solid growth (without distinction of squamous from nonsquamous epithelium); (2) a diffusely infiltrative, rather than expansive, growth pattern; and (3) tumor cell necrosis. For tumors that were confined to the endometrium, only percent solid growth and necrosis were evaluated, and those with both solid growth of more than 50% and necrosis were considered high grade. All tumors were graded independently by three pathologists on two separate occasions. Both inter- and intraobserver agreement using the binary grading system (kappa = 0.65 and 0.79) were superior compared with FIGO (kappa = 0.55 and 0.67) and nuclear grading (kappa = 0.22 and 0.41). The binary grading system stratified patients into three distinct prognostic groups. Patients with stage I low-grade tumors with invasion confined to the inner half of the myometrium (stages IA and IB) had a 100% 5-year survival rate. Patients with low-grade tumors that invaded beyond the outer half of the myometrium (stage IC and stages II-IV) and those with high-grade tumors with invasion confined to the myometrium (stages IB and IC) had a 5-year survival rate of 67% to 76%. In striking contrast to patients with advance-stage low-grade tumors, patients with advance-stage high-grade tumors had a 26% 5-year survival rate. This binary grading system has advantages over FIGO and nuclear grading that permit greater interobserver and intraobserver reproducibility and should be tested in other studies of endometrial endometrioid carcinomas to validate its reproducibility and use for segregating patients into different prognostic groups.

Altered expression of hMLH1 and hMSH2 protein in endometrial carcinomas with microsatellite instability.

Microsatellite instability (MI) has been observed in approximately 20% of presumably sporadic cases of uterine endometrioid carcinoma (UEC). A previous mutational analysis of the 4 known DNA mismatch repair genes (hMSH2, hMLHI, hPMS1, and hPMS2) on a small number of Ml-positive tumors detected mutations in only 2 of 8 cases, both in hMSH2. To further explore the underlying cause of MI in UEC, we analyzed the protein expression of hMSH2 and hMLHI in UEC of known MI status. Formalin-fixed, paraffin-embedded archival tissue from 21 UECs was analyzed by immunoperoxidase staining with monodonal antibodies against hMLH1 and hMSH2 protein. Tumors were evaluated for presence of nuclear staining by 3 investigators. Lack of nuclear hMLHI staining was found in 7 of 13 carcinomas with MI, but in none of 8 carcinomas without MI (Fischer's exact, 0.018). Lack of nuclear hMSH2 staining was found in 3 of the MI-positive cases, but none of the MI-negative cases (not statistically significant). Taken together, lack of nuclear staining of either hMLH1 or hMSH2 was found in 9 of 13 cases with MI and in none of 8 cases without MI (Fischer's exact, 0.005). We conclude that MI in sporadic UEC appears to be associated with lack of expression of either hMLH1 or hMSH2, suggesting that inactivation of these genes may be responsible for MI in most MI-positive sporadic UECs.

Clear cell carcinoma of the endometrium is characterized by a distinctive profile of p53, Ki-67, estrogen, and progesterone receptor expression.

This study was designed to analyze certain clinicopathological features and the profile of p53, Ki-67, estrogen (ER), and progesterone (PR) receptor expression of clear cell carcinoma of the endometrium and to determine whether the pathogenesis of clear cell carcinoma can be accommodated by a dualistic model of endometrial carcinogenesis. In this model, endometrioid carcinoma develops from endometrial hyperplasia under unopposed estrogenic stimulation, and serous carcinoma develops in atrophic endometrium from a putative precursor lesion designated endometrial intraepithelial carcinoma (EIC). Twenty-one clear cell carcinomas of the endometrium were analyzed and compared with 77 endometrioid carcinomas of all grades and 30 serous carcinomas. Clear cell carcinomas showed a distinctive immunoprofile characterized by immunonegativity for ER and PR, low immunoreactivity for p53, and a high Ki-67 proliferation index. ER, PR, and Ki-67 expression were similar to serous carcinoma, but p53 expression was significantly lower in clear cell carcinoma (P < .05). ER and PR expression were significantly lower, and the Ki-67 proliferation index was significantly higher in clear cell carcinoma compared with endometrioid carcinomas (P < .05). p53 expression tended to be higher in clear cell carcinoma compared with endometrioid carcinoma, but the difference was not statistically significant. In contrast to endometrioid carcinoma, clear cell carcinoma was rarely associated with endometrial hyperplasia and serous carcinoma was not. Subdividing clear cell carcinoma morphologically into one that resembled serous carcinoma (clear cell carcinoma with serous features) and another that did not (typical clear cell carcinoma) showed that clear cell carcinoma with serous features had a higher Ki-67 proliferation index than typical clear cell carcinoma, although expression of ER, PR, and p53 were similar. Clear cell carcinoma with serous features was associated with EIC in 50% and was not associated with endometrial hyperplasia. In contrast, typical clear cell carcinoma was associated with endometrial hyperplasia in 40% and was not associated with EIC. In summary, this study provides evidence that clear cell carcinoma of the endometrium, like serous carcinoma, is estrogen independent and shows a high Ki-67 proliferation index. In contrast to serous carcinoma, strong p53 expression occurred less frequently in clear cell carcinoma and predominantly in clear cell carcinoma with serous features. The findings suggest that the molecular events that underlie the development of clear cell carcinoma differ from those of endometrioid and serous carcinoma.

Comparison of estrogen and progesterone receptor, Ki-67, and p53 immunoreactivity in uterine endometrioid carcinoma and endometrioid carcinoma with squamous, mucinous, secretory, and ciliated cell differentiation.

An analysis of 77 uterine endometrioid carcinomas was performed to compare pure endometrioid carcinomas and endometrioid carcinomas with various types of cellular differentiation for the expression of estrogen (ER) and progesterone (PR) receptors, p53, and Ki-67 and to correlate these findings with clinicopathologic features. Forty-three pure endometrioid carcinomas and 34 endometrioid carcinomas displaying additional types of cellular differentiation in at least 10% of the tumor (16 squamous, 11 mucinous, four ciliated cell, and three secretory) were analyzed. In 8 of the 16 tumors with squamous differentiation, the squamous component was histologically benign (low grade), and in eight tumors it was histologically malignant (high grade). In tumors showing various types of cellular differentiation except those with a high-grade squamous component, comparison of the endometrioid glandular component with the squamous, mucinous, secretory, and ciliated cell components showed that ER/PR, Ki-67, and p53 expression were generally higher in the glandular component compared with the various differentiated components. These findings parallel the changes that occur in the endometrium in the secretory phase of the menstrual cycle and, therefore, suggest that the differentiated components have undergone terminal differentiation. In contrast, in endometrioid carcinomas with a high-grade squamous component, Ki-67 and p53 expression were the same in the glandular and squamous components suggesting that squamous epithelium in these tumors represented another pathway of cellular differentiation but not one that was terminally differentiated. Endometrioid carcinomas with a high-grade squamous component had significantly higher grade (P = .002), stage (P < .001), cellular proliferation index (P = .0005), and worse outcome (P = .0009) compared with tumors with the other types of cellular differentiation, including those with a low-grade squamous component and pure low-grade endometrioid carcinomas. In addition, carcinomas with a high-grade squamous component occurred in older women and were more frequently associated with atrophic endometrium and less replacement hormone therapy, but the differences were not statistically significant. In conclusion, endometrioid carcinomas with various types of cellular differentiation can be broadly divided into two groups. Tumors with mucinous, secretory, and ciliated cell differentiation and those with a low-grade squamous component are similar to pure low-grade endometrioid carcinomas in that most have high ER and PR expression, low cellular proliferation indices, low p53 immunoreactivity, and good prognosis. In contrast, endometrioid carcinomas with a high-grade squamous component lack expression of ER and PR, have high cellular proliferation indices, often express p53, and have a prognosis similar to poorly differentiated endometrioid carcinomas.