Histological classification of ovarian cancer

The histology of ovarian tumors exhibits a wide variety of histological features. The histological classification of ovarian tumors by the World Health Organization (WHO) is based on histogenetic principles, and this classification categorizes ovarian tumors with regard to their derivation from coelomic surface epithelial cells, germ cells, and mesenchyme (the stroma and the sex cord). Epithelial ovarian tumors, which are the majority of malignant ovarian tumors, are further grouped into histological types as follows: serous, mucinous, endometrioid, clear cell, transitional cell tumors (Brenner tumors), carcinosarcoma, mixed epithelial tumor, undifferentiated carcinoma, and others. Clear cell and endometrioid carcinomas are highly associated with endometriosis. In stage distribution, serous carcinoma is found predominantly is stage III or IV. In contrast, clear cell and endometrioid carcinomas tend to remain confined to the ovary. Clear cell and endometrioid carcinomas may be unique histological types compared with serous carcinomas with respect to stage distribution and association with endometriosis.     

Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis

The pathogenesis of ovarian carcinoma, the most lethal gynecological malignancy, is unknown because of the lack of a tumor progression model. Based on a review of recent clinicopathological and molecular studies, we propose a model for their development. In this model, surface epithelial tumors are divided into two broad categories designated type I and type II tumors that correspond to two main pathways of tumorigenesis. Type I tumors tend to be low-grade neoplasms that arise in a stepwise manner from borderline tumors whereas type II tumors are high-grade neoplasms for which morphologically recognizable precursor lesions have not been identified, so-called de novo development. As serous tumors are the most common surface epithelial tumors, low-grade serous carcinoma is the prototypic type I tumor and high-grade serous carcinoma is the prototypic type II tumor. In addition to low-grade serous carcinomas, type I tumors are composed of mucinous carcinomas, endometrioid carcinomas, malignant Brenner tumors, and clear cell carcinomas. Type I tumors are associated with distinct molecular changes that are rarely found in type II tumors, such as BRAF and KRAS mutations for serous tumors, KRAS mutations for mucinous tumors, and beta-catenin and PTEN mutations and microsatellite instability for endometrioid tumors. Type II tumors include high-grade serous carcinoma, malignant mixed mesodermal tumors (carcinosarcoma), and undifferentiated carcinoma. There are very limited data on the molecular alterations associated with type II tumors except frequent p53 mutations in high-grade serous carcinomas and malignant mixed mesodermal tumors (carcinosarcomas). This model of carcinogenesis reconciles the relationship of borderline tumors to invasive carcinoma and provides a morphological and molecular framework for studies aimed at elucidating the pathogenesis of ovarian cancer.     

Mucosal carcinoma of the fallopian tube coexists with ovarian cancer of serous subtype only: a study of Japanese cases

Previous studies in Western countries have revealed that mucosal carcinoma of the fallopian tube frequently coexists with pelvic (ovarian, tubal, and peritoneal) serous carcinomas, and early tubal carcinoma is now regarded as a possible origin of these tumors. However, the relationship between early tubal carcinoma and non-serous ovarian cancer, such as clear cell adenocarcinoma, has not been studied in detail. In this study, we sought to examine the coexistence of mucosal carcinoma of the fallopian tube in Japanese ovarian cancer cases. We submitted the fallopian tubes in toto for histological examination in 52 ovarian carcinoma cases and three peritoneal serous carcinoma cases. The ovarian tumors included 12 serous adenocarcinomas, 23 clear cell adenocarcinomas, nine endometrioid adenocarcinomas, three mucinous adenocarcinomas, and four mixed epithelial carcinomas. Mucosal carcinoma of the fallopian tube did not coexist with non-serous adenocarcinoma (n = 40). In contrast, mucosal carcinoma of the fallopian tube was observed in six cases of ovarian serous adenocarcinoma and one case of peritoneal serous adenocarcinoma. In these cases, the p53 immunophenotypes were similar in tubal lesions and invasive ovarian or peritoneal carcinomas. Tumors were negative for p53 in four of seven cases, and one of the p53-negative serous adenocarcinomas showed low-grade morphology. We believe that some ovarian and peritoneal serous adenocarcinomas develop from early tubal carcinomas. However, it should be noted that early tubal carcinomas are not always p53-positive immunohistochemically. Finally, it is unlikely that early tubal lesions are involved in the carcinogenesis of clear cell adenocarcinoma and other non-serous adenocarcinomas.     

Ovarian carcinoma: current diagnostic principles

Ovarian cancer is the most common cause of death from a gynecologic cancer. The most common types of ovarian cancer are carcinomas of surface epithelial-stromal origin. Ovarian carcinomas are a heterogeneous group of neoplasms. Based on proposed different pathways of tumorigenesis, these tumors are divided into two broad subgroups (type I and II) with different biologic behaviour, prognosis and response to therapy. Type I tumors include low-grade serous adenocarcinoma, low-grade endometrioid adenocarcinoma, mucinous adenocarcinoma, malignant Brenner tumor and some clear cell carcinomas. These tumors are low-grade neoplasms evolving from a defined precursor lesion. Type II tumors are high-grade neoplasms including undifferentiated carcinoma, high-grade serous adenocarcinoma, high-grade endometrioid adenocarcinoma, malignant mixed Müllerian tumor and probably some clear cell carcinomas. At present, the histological type of ovarian carcinoma has only limited impact on the management of these tumors. However, with progress towards the type-specific treatment of ovarian carcinoma, accurate histopathological diagnosis of ovarian carcinoma becomes increasingly important. In this review we summarize recent advances in the histopathological diagnosis of ovarian carcinoma. Moreover, we mention genetic changes in different types of ovarian carcinoma.     

Increasing expression of serine protease matriptase in ovarian tumors: tissue microarray analysis of immunostaining score with clinicopathological parameters.

Matriptase is a type II transmembrane serine protease expressed by cells of surface epithelial origin, including epithelial ovarian tumor cells. Matriptase cleaves and activates proteins implicated in the progression of cancer and represents a potential prognostic and therapeutic target. The aim of this study was to examine the expression of matriptase in ovarian tumors and to assign clinicopathological correlations. Immunohistochemical analysis of matriptase was performed in tissue microarrays of 164 ovarian neoplasms including 84 serous adenocarcinomas, 23 mucinous adenocarcinomas, 10 endometrioid adenocarcinomas, six yolk sac tumors, 12 clear cell carcinomas, six dysgerminomas, eight granulosa cell tumors, four transitional cell carcinomas, five fibromas, and six Brenner tumors. All ovarian tumors except the fibromas and Brenner tumors showed significant expression of matriptase. The matriptase scores were significantly higher in the tumors than in their nontumor counterparts (304+/-26 for serous adenocarcinoma; 361+/-28 for mucinous adenocarcinoma; 254+/-17 for endometrioid adenocarcinoma; 205+/-19 for yolk sac tumor; 162+/-16 for clear cell carcinoma; 109+/-11 for dysgerminoma; 105+/-9 for granulosa cell tumor; and 226+/-18 for transitional cell carcinoma). Matriptase scores in serous adenocarcinoma were correlated with TNM stage and FIGO stage. Our findings demonstrate for the first time that matriptase is overexpressed in many malignant ovarian tumors. It may be a novel biomarker for diagnosis and treatment of malignant ovarian tumors.     

Non-endometrioid carcinomas of the uterine corpus: a review of their pathology with emphasis on recent advances and problematic aspects

This review considers the clinical and pathologic features of the various histologic subtypes of endometrial carcinoma excluding those of pure endometrioid type, as the latter tumors were the subject of a previous contribution in the Journal (Vol. 9, No. 2). Non-endometrioid carcinomas, which account for about 10% of endometrial carcinomas, may pose a great array of problems in differential diagnosis, including their distinction not only from benign lesions but also endometrioid carcinoma and various tumors that may secondarily involve the uterine corpus. The most common subtypes are serous, mucinous, and undifferentiated. Rarer tumors are clear cell, squamous, transitional cell carcinomas, and a variety of poorly differentiated carcinomas with unusual forms of differentiation, such as hepatoid carcinoma, carcinomas with trophoblastic elements, and giant cell carcinoma. Mixed carcinomas, which are common, are also discussed, including those with a component of endometrioid carcinoma. The final section deals with endometrial involvement by metastatic tumors, lesions that, albeit rare, are sometimes neglected in the differential diagnosis of endometrial carcinomas. Important aspects emphasized are: (1) The potential for serous carcinoma to be mimicked by various forms of papillary endometrioid carcinoma. (2) The rarity of clear cell carcinoma and the greater frequency of clear cells in endometrioid carcinoma. (3) The frequency of mucinous epithelium in tumors of mixed cell type. (4) The frequency with which neoplastic mucinous epithelium originates from the endometrium. (5) The striking degree of differentiation of some squamous cell carcinomas. (6) The occasional predominance of non-endometrioid carcinomas (especially serous or undifferentiated carcinoma) within malignant mullerian mixed tumors. (7) The spectrum of reactive epithelial changes and other non-neoplastic abnormalities that may mimic serous or clear cell carcinoma.     

Endometrial carcinomas: a review emphasizing overlapping and distinctive morphological and immunohistochemical features

This review focuses on the most common diagnostic pitfalls and helpful morphologic and immunohistochemical markers in the differential diagnosis between the different subtypes of endometrial carcinomas, including: (1) endometrioid versus serous glandular carcinoma, (2) papillary endometrioid (not otherwise specified, villoglandular and nonvillous variants) versus serous carcinoma, (3) endometrioid carcinoma with spindle cells, hyalinization, and heterologous components versus malignant mixed müllerian tumor, (4) high-grade endometrioid versus serous carcinoma, (5) high-grade endometrioid carcinoma versus dedifferentiated or undifferentiated carcinoma, (6) endometrioid carcinoma with clear cells versus clear cell carcinoma, (7) clear cell versus serous carcinoma, (8) undifferentiated versus neuroendocrine carcinoma, (9) carcinoma of mixed cell types versus carcinoma with ambiguous features or variant morphology, (10) Lynch syndrome-related endometrial carcinomas, (11) high-grade or undifferentiated carcinoma versus nonepithelial uterine tumors. As carcinomas in the endometrium are not always primary, this review also discusses the differential diagnosis between endometrial carcinomas and other gynecological malignancies such as endocervical (glandular) and ovarian/peritoneal serous carcinoma, as well as with extra-gynecologic metastases (mainly breast and colon).     

In ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low-grade serous tumours

Genes of the RAF family, which mediate cellular responses to growth signals, encode kinases that are regulated by RAS and participate in the RAS/RAF/MEK/ERK/MAP-kinase pathway. Activating mutations in BRAF have recently been identified in melanomas, colorectal cancers, and thyroid and ovarian tumours. In the present study, an extensive characterization of BRAF and KRAS mutations has been performed in 264 epithelial and non-epithelial ovarian neoplasms. The epithelial tumours ranged from adenomas and borderline neoplasms to invasive carcinomas including serous, mucinous, clear cell, and endometrioid lesions. It is shown that BRAF mutations in ovarian tumours occur exclusively in low-grade serous neoplasms (33 of 91, 36%); these included serous borderline tumours (typical and micropapillary variants), an invasive micropapillary carcinoma and a psammocarcinoma. KRAS mutations were identified in 26 of 91 (29.5%) low-grade serous tumours, 7 of 49 (12%) high-grade serous carcinomas, 2 of 6 mucinous adenomas, 22 of 28 mucinous borderline tumours, and 10 of 18 mucinous carcinomas. Of note, two serous borderline tumours were found to harbour both BRAF and KRAS mutations. The finding that at least 60% of serous borderline tumours harbour mutations in two members of the ERK-MAP-kinase pathway (BRAF 36%, KRAS 30%) compared with 12% of high-grade serous carcinomas (BRAF 0%, KRAS 12%) indicates that the majority of serous borderline tumours do not progress to serous carcinomas. Furthermore, no BRAF mutations were detected in the other 173 ovarian tumours in this study.     

Intracytoplasmic lumina and mucinous inclusions in ovarian carcinomas

Intracytoplasmic mucinous inclusions and lumina have been previously described in non-glandular neoplasms such as urothelial carcinoma. We describe their presence in 93% of non-mucinous ovarian carcinomas. They were found in abundance in all 25 cases (100%) of clear cell carcinoma, in 48 of 50 cases (96%) of serous carcinoma and 20 of 25 cases (80%) of endometrioid carcinoma. The degree of the differentiation of the tumour did not influence the number of inclusions or lumina observed. These results suggest that the presence of intracytoplasmic lumina and mucinous inclusions is more widespread than hitherto appreciated. Their presence in an otherwise poorly differentiated metastatic carcinoma might, at the very least, prompt one to consider the ovary as a possible primary site. In addition, an abundance of intracytoplasmic mucinous inclusions and lumina with microcyst formation, in an otherwise poorly differentiated malignant primary ovarian epithelial tumour, might suggest the possibility of a clear cell carcinoma.     

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.     

Muzinöse Ovarialtumoren

Mucinous ovarian neoplasms represent the second largest group of epithelial ovarian tumors after serous neoplasms, of which benign cystadenomas constitute more than 80?%. Mucinous cystadenomas and carcinomas cannot be distinguished by the clinical features or the mean age of onset of the disease. They typically occur unilaterally, are confined to the adnexae (FIGO stage I) and clinically present with non-specific abdominal symptoms or are diagnosed by chance. The mean age of disease onset is around 50 years old. The prognosis is excellent. Implants, peritoneal metastases and bilateral occurrence of ovarian mucinous neoplasms should lead to the suspicion of metastasis particularly from a gastrointestinal tumor. Neither microinvasion defined as a maximum extent of invasion of 5 mm, nor intraepithelial carcinoma characterized by high grade atypia without invasion, affect the prognosis of mucinous borderline tumors. Mucinous carcinomas typically show confluent glandular, expansile growth that leads to a labyrinth-like pattern. A destructive infiltrative or nodular growth pattern, however, should lead to the consideration of metastasis. Mural nodules that may reveal a spindle cell sarcomatous or anaplastic carcinomatous pattern occur infrequently in mucinous and do not affect the prognosis. Pax8 positivity is indicative of a primary ovarian neoplasm. In this case, however, mucinous tumors associated with teratomas may show the colonic immunoreaction pattern (CK7?/CK20+/CDX2+). The rare mucinous tumors with endocervical differentiation are now designated as seromucinous tumors and consist of two or more distinct cell types, are frequently associated with endometriosis and seem to show a molecular genetic relationship to endometrioid neoplasms.     

Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm

Recent morphologic, immunohistochemical, and molecular genetic studies have led to the development of a new paradigm for the pathogenesis and origin of epithelial ovarian cancer based on a dualistic model of carcinogenesis that divides epithelial ovarian cancer into 2 broad categories designated types I and II. Type I tumors comprise low-grade serous, low-grade endometrioid, clear cell and mucinous carcinomas, and Brenner tumors. They are generally indolent, present in stage I (tumor confined to the ovary), and are characterized by specific mutations, including KRAS, BRAF, ERBB2, CTNNB1, PTEN, PIK3CA, ARID1A, and PPP2R1A, which target specific cell signaling pathways. Type I tumors rarely harbor TP53 mutations and are relatively stable genetically. Type II tumors comprise high-grade serous, high-grade endometrioid, malignant mixed mesodermal tumors (carcinosarcomas), and undifferentiated carcinomas. They are aggressive, present in advanced stage, and have a very high frequency of TP53 mutations but rarely harbor the mutations detected in type I tumors. In addition, type II tumors have molecular alterations that perturb expression of BRCA either by mutation of the gene or by promoter methylation. A hallmark of these tumors is that they are genetically highly unstable. Recent studies strongly suggest that fallopian tube epithelium (benign or malignant) that implants on the ovary is the source of low-grade and high-grade serous carcinoma rather than the ovarian surface epithelium as previously believed. Similarly, it is widely accepted that endometriosis is the precursor of endometrioid and clear cell carcinomas and, as endometriosis, is thought to develop from retrograde menstruation; these tumors can also be regarded as involving the ovary secondarily. The origin of mucinous and transitional cell (Brenner) tumors is still not well established, although recent data suggest a possible origin from transitional epithelial nests located in paraovarian locations at the tuboperitoneal junction. Thus, it now appears that type I and type II ovarian tumors develop independently along different molecular pathways and that both types develop outside the ovary and involve it secondarily. If this concept is confirmed, it leads to the conclusion that the only true primary ovarian neoplasms are gonadal stromal and germ cell tumors analogous to testicular tumors. This new paradigm of ovarian carcinogenesis has important clinical implications. By shifting the early events of ovarian carcinogenesis to the fallopian tube and endometrium instead of the ovary, prevention approaches, for example, salpingectomy with ovarian conservation, may play an important role in reducing the burden of ovarian cancer while preserving hormonal function and fertility.     

Ovarian carcinomas: five distinct diseases with different origins,genetic alterations,and clinicopathological features

Malignant epithelial tumors (carcinomas) are the most common ovarian cancers and also the most lethal gynecological malignancies. Based on histopathology and molecular genetic alterations, ovarian carcinomas are divided into five main types (high-grade serous (70%), endometrioid (10%), clear cell (10%), mucinous (3%), and low-grade serous carcinomas (<5%)) that account for over 95% of cases. These types are essentially distinct diseases, as indicated by differences in epidemiological and genetic risk factors, precursor lesions, patterns of spread, and molecular events during oncogenesis, response to chemotherapy, and prognosis. For a successful specific treatment, reproducible histopathological diagnosis of the tumor cell type is critical. The five tumor types are morphologically diverse and resemble carcinomas of the uterus. Actually, recent investigations have demonstrated that a significant number of cancers, traditionally thought to be primary ovarian tumors (particularly serous, endometrioid, and clear cell carcinomas), originate in the fallopian tube and the endometrium and involve the ovary secondarily. This review summarizes recent advances in the molecular pathology which have greatly improved our understanding of the biology of ovarian carcinoma and are also relevant to patient management.     

Morphological subtypes of ovarian carcinoma: a review with emphasis on new developments and pathogenesis

Ovarian carcinomas comprise a heterogeneous group of neoplasms, the four most common subtypes being serous, endometrioid, clear cell and mucinous. In recent years, our understanding of the underlying pathogenesis and initiating molecular events in the different tumour subtypes has greatly increased, and although ovarian carcinoma is often considered clinically as one disease, there is now a much greater realisation that the various subtypes have a different natural behaviour and prognosis. At present, adjuvant therapy is mainly dependent upon tumour stage and grade rather than type; however, this is likely to change in the future with the development of new chemotherapeutic agents and targeted therapies and clinical trials are necessary to evaluate the efficacy of different agents in clear cell, mucinous and low grade serous carcinomas, neoplasms which are considered relatively resistant to traditional chemotherapeutic regimes. In this review, the major subtypes of ovarian carcinoma are discussed. It is now firmly established that there are two distinct types of ovarian serous carcinoma, low grade and high grade, the former being much less common and arising in many cases from a serous borderline tumour. Low grade and high grade serous carcinoma represent two distinct tumour types with a different underlying pathogenesis rather than low grade and high grade variants of the same neoplasm. Both are usually advanced stage (stage III or IV) at diagnosis. B-raf and k-ras mutations are important molecular events in low grade serous carcinomas while high grade serous carcinomas are almost always associated with TP53 mutation. There is now emerging and compelling evidence that many high grade serous carcinomas (by far the most common subtype of ovarian carcinoma) actually arise from the epithelium of the distal fallopian tube. Future studies regarding the initiating molecular events in the development of this aggressive neoplasm should concentrate on this site. Primary ovarian mucinous carcinomas are uncommon, almost always unilateral and stage I, and largely of so-called intestinal or enteric type. Most arise in a stepwise manner from a pre-existing mucinous cystadenoma and mucinous borderline tumour. Endometrioid and clear cell carcinomas typically present as low stage neoplasms and in many, or most, cases arise from endometriosis; the former are usually well differentiated and there is now evidence that the majority of neoplasms reported in the past as high grade endometrioid carcinoma are of serous type. WT1 is useful in this regard since it is a relatively specific marker of a serous phenotype. It is recommended that different subtypes of ovarian carcinoma are graded using different systems rather than employing a universal grading system.     

Loss of DNA mismatch repair protein hMSH6 in ovarian cancer is histotype-specific

Microsatellite instability (MSI) due to defects in DNA mismatch repair genes may be involved in the development of a subset of human ovarian carcinomas. The role of one such gene, hMSH6, in ovarian cancer is not well documented. We investigated the expression of hMSH6 protein in different histotypes of ovarian carcinoma and the associations between loss of hMSH6 protein and tumor grade, disease stage, familial history of cancer and patient survival. We stained an ovarian carcinoma tissue microarray consisting of formalin-fixed, paraffin-embedded tissue samples from 322 patients with an anti-hMSH6 antibody and scored the results semiquantitatively as negative or positive. Twelve cases were excluded owing to loss of cores during staining. Absence of hMSH6 protein was noted in 20 of 230 serous carcinomas (8.7%), in 7 of 16 clear cell carcinomas (43.7%), in 4 of 34 endometrioid carcinomas (11.7%), in 1 of 14 malignant mixed Müllerian tumors, 2 of 6 mucinous carcinomas, 0 of 2 transitional cell carcinomas and in 0 of 8 undifferentiated carcinomas. Loss of hMSH6 protein was not associated with survival, patient age, tumor grade, or disease stage but was associated with clear cell, mucinous and endometrioid carcinoma histology (P<0.007). These findings indicate that loss of hMSH6 expression in ovarian carcinoma is more common in certain histologic subtypes, particularly in clear cell, endometrioid, and mucinous carcinoma, suggesting that loss of hMSH6 function may participate in the pathogenesis of these subtypes of cancer. Loss of hMSH6 expression did not predict survival and was not associated with disease stage, tumor grade, patient age or family history of cancer.     

Loss of cables, a novel gene on chromosome 18q, in ovarian cancer.

Cables, a cyclin-dependent kinase (cdk) interacting protein, has recently been identified and mapped to human chromosome 18q11. Cables appears to be primarily involved in cell cycle regulation and cell proliferation. Overexpression of Cables in Hela and other cell lines inhibits cell proliferation and tumor formation. We hypothesize that loss of Cables expression is associated with ovarian cancer. To test our hypothesis, we examined Cables expression in the four most common subtypes of ovarian carcinomas: serous, endometrioid, mucinous, and clear cell. In addition, mucinous and serous borderline tumors were also included. Loss of Cables expression was observed at high frequency in ovarian serous (11 of 14 cases, 79%) and endometrioid (5 of 10 cases, 50%) carcinomas. In contrast, strong Cables staining was detected in all clear cell carcinomas (10 cases) and mucinous tumors (5 carcinomas and 5 borderline tumors). The majority of serous borderline tumors (11 of 14 cases, 79%) showed positive Cables staining, with the rest showing focal loss of Cables expression. Furthermore, RT-PCR revealed the lack of Cables mRNA in a human ovarian cancer xenograft. No correlation was noted between loss of Cables and histologic grade, tumor stage, and survival. In conclusion, our results indicate that loss of Cables is common in ovarian serous and endometrioid carcinomas and imply that Cables may be involved in the pathogenesis of these two types of ovarian carcinomas.     

Immunohistochemistry as a diagnostic aid in the evaluation of ovarian tumors

Aspects of immunohistochemistry (IHC), which are useful in the diagnosis of ovarian tumors (mostly neoplasms but also a few tumor-like lesions), are discussed. The topic is first approached by considering the different growth patterns and cell types that may be encountered. Then a few other specific situations in which IHC may assist are reviewed. Selected findings largely, or only, of academic interest are also mentioned. One of the most common situations in which IHC may aid is in the evaluation of tumors with follicles or other patterns which bring a sex cord-stromal tumor into the differential. The distinction between a sex cord tumor and an endometrioid carcinoma with sex-cord-like patterns may be greatly aided by the triad of epithelial membrane antigen (EMA), inhibin, and calretinin, the latter two being typically positive and EMA negative in sex cord tumors, the converse being typical of endometrioid carcinoma. It should be emphasized that granulosa cell tumors may be inhibin negative and, albeit less specific, calretinin is more reliable in evaluating this particular issue. Lack of staining for inhibin and calretinin may also be supportive in leading to consideration of diverse other neoplasms that may form follicles, including metastatic tumors as varied as carcinoid and melanoma. The well-known staining of the latter neoplasm for S-100 protein and HMB-45 may be very helpful in evaluating melanomas with follicular or other unusual patterns, a challenging aspect of ovarian tumor interpretation. The most common monodermal teratoma, struma ovarii, usually has an overt follicular pattern and is easily recognized, but recognition of unusual appearances ranging from oxyphilic to clear cell to various patterns of malignant struma may be greatly aided by a thyroglobulin or TTF 1 stain. IHC for neuroendocrine markers may assist in the diagnosis of primary and metastatic carcinoid tumor. The broad differential diagnosis of glandular neoplasms with an endometrioid-pseudoendometrioid morphology, or mucinous cell type, has been the subject of much exploration in recent years, particularly the distinction between primary and metastatic neoplasms. The well-known CK7 positive, CK20 negative phenotype of primary endometrioid carcinoma, and the converse profile in most metastatic large intestinal adenocarcinomas with a pseudoendometrioid morphology, has been much publicized but albeit an appropriate supportive adjunct in many cases, exceptions from the typical staining pattern may be encountered. It is even less helpful in the case of primary versus metastatic mucinous neoplasia. Evaluation of the expression of mucin gene products has shown mixed, essentially unreliable, results. Experience with other new markers, such as CDX-2, villin, beta catenin, and P504S (racemase), is limited but is in aggregate promising with regard to providing some aid in this area. The rare differential of metastatic cervical adenocarcinoma versus primary ovarian mucinous or endometrioid carcinoma may be aided by strong p16 staining of the former. Staining for alpha-fetoprotein may aid in confirming the diagnosis of endometrioid-like (and hepatoid) variants of yolk sac tumor. Ependymoma of the ovary may also have an endometrioid-like glandular pattern, but positive stains for glial fibrillary acidic protein contrast with the negative results in others neoplasms with a similar pattern. Immunostains may be very helpful in the evaluation of oxyphilic tumors and tumor-like lesions and in some unusual forms of clear cell neoplasia, such as clear cell struma, both subjects being reviewed herein. Immunostains may highlight both the presence and extent of epithelial cells in a variety of circumstances, including microinvasive foci in cases of serous borderline tumors and mucinous carcinomas, and in determining the extent of carcinoma cells and reactive cells within mural nodules of mucinous neoplasms. As in tumor pathology in general, various markers may be crucial in the diagnosis of small round cell tumors of the ovary, and familiar markers of epithelial, lymphoid, leukemic, and melanocytic neoplasms may assist in the analysis of high grade tumors with a poorly differentiated carcinoma, lymphoma-granulocytic sarcoma, malignant melanoma differential. The evaluation of ovarian cystic lesions may be aided by thyroglobulin or TTF 1 (cystic struma), glial fibrillary acid protein (ependymal cysts), and inhibin-calretinin (follicle cysts and unilocular granulosa cell tumors). Stains for trophoblast markers may occasionally aid in the evaluation of germ cell tumors, although routine stains should usually suffice; they may be of academic interest in confirming trophoblastic differentiation in some high grade surface epithelial carcinomas.     

K-ras activation occurs frequently in mucinous adenocarcinomas and rarely in other common epithelial tumors of the human ovary.

To explore the role of mutational activation of members of the ras family of cellular protooncogenes in the development of human ovarian neoplasms, a series of 37 ovarian tumors from Japanese patients was studied. These included 30 common epithelial tumors (1 mucinous tumor of borderline malignancy, 7 mucinous adenocarcinomas, and 22 nonmucinous carcinomas: 10 serous, 3 clear cell, 8 endometrioid, and 1 undifferentiated), 5 tumors of germ cell origin, and 2 sex cord/stromal cell tumors. Polymerase chain reaction was performed from selected areas of deparaffinized sections of formalin-fixed paraffin-embedded tissue, and the presence of activating point mutations in codons 12, 13, and 61 of the H-, N-, and K-ras genes was probed by dot-blot hybridization analysis with mutation specific oligonucleotides. Mutations in K-ras were also looked for by direct genomic sequencing. The overall frequency of ras gene mutations was 10/37 (27%). Mutations were detected only in K-ras, and were found in most of the mucinous tumors, including the one such tumor of borderline malignancy (6/8; 75%). In one mucinous adenocarcinoma, two mutations were detected in paraffin-embedded material that had not previously been found in high molecular weight DNA isolated from frozen tissue from the same case. K-ras mutations occurred significantly more frequently in mucinous tumors (6/8, 75%) than in serous carcinomas (2/10, 20%; P = 0.031) or in all nonmucinous types of epithelial ovarian tumors combined (3/22, 14%; P = 0.0031).     

Characterization of the specificity by immunohistology of a monoclonal antibody to a novel epithelial antigen of ovarian carcinomas

An immunohistological study, using the avidin-biotin-peroxidase complex method, was carried out to define the reactivity profile of a murine monoclonal antibody, MOv2, which recognizes a novel glycoprotidic antigen associated with ovarian epithelial tumors. Among the primary ovarian tumors tested, MOv2 immunostained 93% of mucinous and 75% of serous cystadenomas, 100% of mucinous, 81% of serous and 73% of endometrioid carcinomas. Undifferentiated and clear cell tumors revealed more limited reactivity with the antibody, whereas ovarian sex cord-stromal and germinal tumors were immunonegative. Positive reactions were also documented in omental metastases from primary ovarian carcinomas. No immunoreactivity was detected in normal ovarian epithelium, whereas the cells lining Walthard's nests adjacent to the fallopian tubes and a variety of normal epithelia were consistently immunolabeled. These included the lining epithelia of the gastrointestinal tract, bronchi and endocervix, and the epithelium of salivary, biliary and pancreatic ducts and sweat glands. To a lesser extent, positive reactions were detected in other surface epithelia, such as squamous and transitional epithelia. Among tumors other than ovarian, MOv2 consistently reacted with adenocarcinomas and squamous cell carcinomas from different sites, most notably breast, lung and gastrointestinal tract, and with transitional cell carcinomas. In contrast, no staining was demonstrated in non-epithelial malignancies. The antigen defined by MOv2 may be operationally useful as a marker of epithelial lineage in tumor histopathology. Its pattern of immunohistochemical distribution indicates that an antigenic phenotype shared by normal surface epithelia and non-ovarian carcinomas is strongly associated with common epithelial neoplasms of the ovaries.