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.     

Ovarian carcinoma pathology and genetics: recent advances

In this review we summarize recent advances in the histopathological diagnostic criteria and molecular pathology of the main subtypes of ovarian surface epithelial carcinoma. These advances have greatly improved our understanding of the biology of ovarian carcinoma and are also relevant to patient management. With progress toward subtype-specific treatment of ovarian carcinoma, accurate, reproducible histopathological diagnosis of these subtypes by practicing pathologists is increasingly important.     

Squamous cell carcinoma of the uterine cervix--a review with emphasis on prognostic factors and unusual variants

Although the incidence of squamous cell carcinoma of the cervix has declined in recent years, it remains the most common type of cervical cancer in our society. In this review, the salient pathologic features of squamous cell carcinoma are discussed. Early invasive, International Federation of Gynecology and Obstetrics (FIGO) stage la carcinoma has been a source of controversy in diagnosis and therapy for many years. Specific requirements must be met in order to make this diagnosis. Most importantly, the cervical conization specimen must be handled properly, so that the features of tumor dimensions, vascular involvement, and completeness of excision can be correctly evaluated. Important diagnostic and prognostic pathologic findings of early invasive carcinoma are discussed. The risk of lymph node metastasis in lesions with depths of invasion up to 3 mm is less than 1%. This risk increases significantly with deeper levels of invasion. In the area of frankly invasive squamous cell carcinoma of the cervix, certain pathologic features have been shown to be clinically relevant. These include the extent of local disease, cell type, and the presence of vascular or lymphatic invasion. Regarding cell type, it is critical to distinguish between poorly differentiated small cell squamous carcinoma and small cell undifferentiated carcinoma, as the prognosis for these tumors may differ. Finally, several rare but pathologically distinct variants of squamous cell carcinoma of the cervix are reviewed, with emphasis on differential histologic features. As they often have different natural histories than typical squamous cell carcinoma, correct diagnosis of these lesions is vital.     

端粒酶的研究进展,存在问题及其在病理学中的应用

从Ｋｉｍ等于 1994年报道了用ＴＲＡＰ法能检测到数十个肿瘤细胞的端粒酶活性以来 ,端粒酶的研究已经取得了长足的进展。重要的进展可概括为其蛋白质成分的分离、纯化及其基因克隆 ;端粒酶的功能研究 ;表达细胞群的研究和潜在的应用价值 4个方面。一、端粒酶蛋白质成分分离端粒酶是一个以自身ＲＮＡ为模板逆转录出一段ＤＮＡ以补充染色体ＤＮＡ在复制中由于末端ＲＮＡ引物被水解后 ,其缺口不能被ＤＮＡ聚合酶修复而丢失的端粒末端ＤＮＡ的核蛋白。不同种属的端粒酶的ＲＮＡ在 1995年和 1996年先后由Ｇｒｅｉｄｅｒ等[1 ] 克隆到。但端粒酶蛋…     

Clinicopathologic and molecular aspects of high-grade neuroendocrine carcinoma of the uterine cervix: emphasis on novel chemotherapeutic strategies

High-grade neuroendocrine carcinomas (HGNEC) of the cervix are rare and carry an extremely poor prognosis. Fortunately, there have been recent advances in our molecular understanding of these carcinomas and some advances offer novel therapeutic options. The vast majority of HGNEC of the cervix are associated with human papillomavirus (HPV) and would be prevented by currently available vaccines. TP53 mutations are variably identified and likely drive a second pathway, one unrelated to high-risk HPV. Most carcinomas express VEGF and some patients have seen durable response to therapy with the addition of a VEGF inhibitor. PIK3CA mutations are among the most common mutations identified and mTOR inhibitors may be considered in these cases. KRAS mutations can be identified; an impressive response to MEK inhibitors has been seen in one case. PD-L1 positivity is frequently seen and complete responses to PD-1/PD-L1 inhibitors have been reported. These molecular advances offer numerous approaches to targeted personalized therapy.     

Carcinoma of the uterine cervix: a review of its pathology and commentary on the problem in Malaysians

Since its recognition about 150 years ago, there has been much progress in the understanding of the pathogenesis, prevention, early detection and management of carcinoma of the uterine cervix. Important historical landmarks include the (1) recognition of pre-invasive and pre-clinical lesions, and the devise of various systems for reporting these lesions, (2) improvements in diagnostic techniques particularly colposcopy, (3) advent of therapeutic procedures (electrocoagulation, cryotherapy, laser therapy and loop electrosurgical excision), and (4) recognition of the aetiological relationship between the human papillomavirus and cervical neoplasia. The susceptibility of the cervical transformation zone to malignant change is now well recognised. The WHO classification system remains the one most commonly utilised for histological reporting of cervical cancers. In the recent 1994 update, cervical carcinoma is divided into 3 main categories: squamous cell carcinoma, adenocarcinoma and other epithelial tumours. Squamous cell carcinoma (60-80%) predominates among invasive cervical carcinoma. Recognised variants include verrucous, warty (condylomatous), papillary squamous (transitional) and lymphoepithelioma-like carcinoma. Adenocarcinoma (5-15% of invasive carcinomas) shows an increasing trend in young females. Like its squamous counterpart, preinvasive and microinvasive versions are known. Variants such as mucinous, endometrioid, clear cell, mesonephric, serous, villoglandular and minimal deviation carcinoma are now defined. Adenosquamous carcinoma (5-25%), adenoid-cystic, adenoid-basal, neuroendocrine and undifferentiated carcinomas constitute other epithelial tumours of the cervix. The management of invasive cervical carcinoma remains heavily dependent on its stage. The FIGO staging system remains the most widely used. The 1995 update provides more definite criteria in subdividing stage IA tumours by delimiting stromal invasion of stage IA1 lesions to a maximum depth of 3 mm and a horizontal axis of 7 mm. In Malaysia, an appreciation of the cervical carcinoma problem has to take into consideration the population at risk, its multi-ethnicity, its socio-economic and geographical diversities and the constraints of the health care system. Females form 48.9% of the Malaysian population. 52.9% of them are in the sexually active age group of 15-50 years, indicating a significant population at risk for cervical carcinoma. Cervical carcinoma was the third most common cause of death due to solid tumours among Malaysian females in 1995 following carcinoma of the breast and respiratory tract. East Malaysia is predominantly rural with many communities having limited modern facilities. Such areas imply a lower educational and socio-economic status, raising the worry of a population at higher risk for developing cervical carcinoma. The population: doctor for Malaysia of 2153:1 compares poorly with nearby Singapore. Besides a shortage of doctors, there is also an uneven distribution of doctors, resulting in a ratio in East Malaysia of > 4000:1. Although Malaysia does not have a national cervical cancer-screening programme, many action plans and cancer awareness campaigns have been launched throughout the years, which appear to have made an impact as evidenced by the decreasing mortality rates from cervical carcinoma. Another interesting feature of cervical carcinoma in Malaysia relates to its multiethnic population. In Malaysian Chinese and Malay females, the prevalence of cervical carcinoma ranks second to breast cancer whereas the pattern is reversed in Malaysian Indian females. Studies into its aetiology and pathogenesis are being undertaken and may shed more light on this matter.     

Ovarian spindle cell lesions: a review with emphasis on recent developments and differential diagnosis

Ovarian lesions composed of spindle cells comprise a heterogeneous group; most are neoplastic but several non-neoplastic conditions are also composed of spindle cells. This review discusses the main differential diagnoses of an ovarian spindle cell lesion, especially concentrating on the recent literature. The majority of ovarian spindle cell lesions fall into the broad category of fibromatous neoplasms whereas others in the sex cord-stromal group may also be composed of spindle cells, including thecomas, granulosa, and Sertoli-Leydig cell tumors and rarer neoplasms, such as sclerosing stromal tumor and signet-ring stromal tumor. In the recent past there have been several major contributions on various aspects of ovarian spindle cell lesions, including cellular and mitotically active cellular fibromatous lesions, smooth muscle neoplasms, and metastatic gastrointestinal stromal tumors. Other mesenchymal or epithelial tumors and mixed epithelial and mesenchymal neoplasms may also enter into the differential diagnosis of an ovarian spindle cell lesion. Several non-neoplastic lesions may be composed of spindle cells, including massive edema, ovarian fibromatosis, stromal hyperplasia, and stromal hyperthecosis. Morphology remains the mainstay in diagnosis but immunohistochemistry may be invaluable in certain circumstances, one example being the identification of a metastatic gastrointestinal stromal tumor within the ovary.     

Heterologous and rare homologous sarcomas of the uterine corpus: a clinicopathologic review

Pure sarcomas of the uterine corpus are uncommon, constituting less than 3% of all malignancies at this site, and most of them are leiomyosarcomas and endometrial stromal sarcomas. Rare histotypes of homologous sarcomas and heterologous sarcomas are occasionally encountered, and the absence of significant accumulated experience with these histotypes at this location may potentially raise diagnostic and patient management difficulties. In this article, the clinicopathologic attributes of all earlier reported sarcomas of the uterine corpus other than leiomyosarcomas and endometrial stromal sarcomas are summarized. Included are embryonal rhabdomyosarcoma, pleomorphic rhabdomyosarcoma, angiosarcoma, alveolar soft part sarcoma, malignant perivascular epithelioid cell tumors (PEComas), osteosarcoma, chondrosarcoma, liposarcomatous tumors, malignant extrarenal rhabdoid tumors, Ewing sarcoma/primitive neuroectodermal tumor, and other rare histotypes. Embryonal rhabdomyosarcoma (20%), Ewing sarcoma/primitive neuroectodermal tumor (17%), angiosarcoma (14%), and pleomorphic rhabdomyosarcoma (13%) appeared to be more common than the others, although there was no single overwhelmingly prevalent histotype in the group. A subset, including embryonal rhabdomyosarcoma, alveolar soft part sarcoma, and PEComas, peak in the premenopausal years, but most of the others were observed in postmenopausal women. Favorable outcomes have been reported for the patients diagnosed with alveolar soft part sarcoma, and the prognosis for their counterparts with PEComa remains a matter of debate. Multimodal therapeutic approaches to contemporary patients with embryonal rhabdomyosarcomas have resulted in significantly improved outcomes. Unfortunately, most of the other sarcomas have been associated with rapid tumor progression and unfavorable patient outcomes. The differential diagnosis for these sarcomas is often extensive and varies by histotype, but their accurate diagnosis fundamentally requires the careful exclusion of biphasic malignancies.     

Coccidia: a review of recent advances on immunity and vaccine development

The genus Eimeria contains a number of obligate intracellular protozoan parasites with a complicated life-cycle involving both asexual and sexual stages of development. Coccidiosis is caused by Eimeria infecting primarily the intestine of the susceptible host, thereby seriously impairing the growth and feed utilization of poultry and other livestock. The desire to develop a vaccine against Eimeria has promoted active research to elucidate the mechanisms of protective immunity and identification of candidate vaccine antigens. Protozoa are unique in their modes of transmission and nature of disease manifestations, the significance of which should be considered in the development of a control strategy. An intricate and complex interplay of different cell populations and cytokines is involved not only in the pathogenesis of coccidiosis, but also in the development of protective immunity. Thus, comprehensive understanding of the events leading to protection following Eimeria infection will be crucial for the development of an effective vaccine.     

The pathology of gestational trophoblastic disease: recent advances

When inundated with numerous specimens of products of conception as the consequence of miscarriage, it is all too easy for histopathologists to forget that the biology of trophoblast and the events of early placental implantation continue to fascinate because of the inherently invasive properties of the non-villous (extravillous) trophoblast. However, unlike the invasion of a malignant tumour, the invasion of trophoblast is controlled. The failure of adequate conversion of maternal uteroplacental arteries is a major pathogenetic phenomenon of important disorders of pregnancy including pre-eclampsia. However, it is in the field of gestational trophoblastic disease that diagnostic acumen is most called for. There are several problematic areas that give rise to diagnostic error; e.g., the diagnosis of early complete mole as partial mole, the over-diagnosis of hydatidiform mole in tubal pregnancy and the diagnosis of placental site non-villous trophoblast as placental site trophoblastic tumour or choriocarcinoma, particularly if associated with atypia, as frequently observed in complete mole. The chorionic villi of early diploid complete mole show characteristic features of villous profile, stromal mucin and stromal nuclear debris. The distinction between complete mole and triploid partial mole can be facilitated by ploidy analysis and immunohistochemistry for the product of the paternally imprinted, maternally expressed gene, p57kip2. Persistent trophoblastic disease (PTD) is a clinical not a histopathological diagnosis and the role of the histopathologist once a diagnosis of PTD has been made is limited. Invasive mole and choriocarcinoma are encompassed by PTD. Tumours of the non-villous trophoblast are placental site trophoblastic tumour and the more recently recognised epithelioid trophoblastic tumour. The role of immunohistochemistry in the elucidation of trophoblastic lesions is discussed pragmatically.     

Dendritic cell-based immunotherapy: a basic review and recent advances

Dendritic cells (DCs) are considered a very promising arm to activate the immune system in immunotherapeutic strategies against cancer. DCs are the most powerful antigen-presenting cells (APCs), being highly efficient at generating robust immune responses. They are also considered the center of the immune system, since they provide a crucial link between both innate and adaptive immune responses. Thus, DC-based cancer immunotherapy aims to take advantage of these unique characteristics of DCs to better fight cancer. During the last decade, they have been the subject of numerous studies intending to develop immunotherapeutic strategies against cancer through vaccination. For this purpose, it is essential to gain a better insight into DC immunobiology, regulation of innate and adaptive immune systems, and tumor microenvironment, as well as applying the latest advances in science in order to boost their enormous anti-tumor immunotherapeutic potential. In this review, we will hold focus on DC immunobiology (from their origin, location, and special properties and distinct subsets to the innate and adaptive immunity), on the new concept of cancer immunoediting, and on the knowledge given by clinical trials using DC vaccines. Finally, future perspectives for this emerging field are highlighted.     

Rhabdoid epithelioid leiomyosarcoma of the uterine corpus: a case report and literature review

A case of epithelioid leiomyosarcoma of the uterus with rhabdoid phenotype and early rhabdomyoblastic differentiation is described. A 72-year-old woman with a 5-week history of increased abdominal girth was found to have a large pelvic mass. The uterus revealed a large intramyometrial and left adnexal necrotic tumor that had spread to the small bowel mesentery and to the anterior abdominal peritoneum. The tumor was an epithelioid leiomyosarcoma with rhabdoid phenotype and focal early rhabdomyoblastic differentiation, as confirmed by immunohistochemical and ultrastructural techniques. Also called composite extrarenal rhabdoid tumor (CERT), this lesion should be differentiated from malignant mixed müllerian tumor, rhabdomyosarcoma, endometrial stromal sarcoma, and pure rhabdoid tumors of the uterus. The recognition of a rhabdoid phenotype is of clinical importance since these tumors are prone to be aggressive.     

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.     

Endometrioid carcinoma of the urinary bladder complicating vesical Mullerianosis: a case report and review of the literature

Endometriosis of the urinary bladder is uncommon, and malignant transformation within vesical endometriosis is extremely rare. Vesical endometriosis and Mullerianosis can cause problems in differential diagnosis with vesical neoplasm, and, conversely, primary vesical neoplasm arising in endometriosis can be difficult to distinguish from secondary vesical involvement. Mullerianosis has rarely been described in the urinary bladder. A case of endometrioid adenocarcinoma of the urinary bladder is reported, which illustrates the difficulties in diagnosis and the importance of morphology and ancillary studies in establishing the correct diagnosis.     

The dermo-epidermal junction and its acquired and hereditary pathology. A few recent advances]

The dermoepidermal junction (DEJ) is a key structure in the skin. Many acquired and inherited diseases affect the DEJ. New insight has been gained into the chemical composition of the DEJ of which at least 20 protein components have been identified to date. Some components of hemidesmosomes, which are critical DEJ structures, have also been identified. Hereditary epidermolysis bullosa is a heterogeneous group of DEJ disorders. Studies are beginning to shed light on the molecular mechanisms of these diseases. Dystrophic epidermolysis bullosa is due to alterations in the collagen IV molecule which is an essential component of anchoring fibrils. Several molecules, including BM-600 niceine, are apparently altered in the skin and other epithelia of patients with junctional epidermolysis bullosa. These molecules may be involved in the pathogenesis of inherited DEJ diseases with anomalies of hemidesmosomes. Lastly, DEJ antigens involved in a number of acquired bullous skin disorders (bullous pemphigoid, herpes gestationis, acquired epidermolysis bullosa...) have been identified recently.