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McCluggage W.G.,Belfast Health and Social Care Trust | McCluggage W.G.,Royal Group of Hospitals Trust
Pathology | Year: 2011

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. © 2011 Royal College of Pathologists of Australasia. Source

Staats P.N.,University of Maryland Baltimore County | McCluggage W.G.,Harvard University | Clement P.B.,Royal Group of Hospitals Trust | Young R.H.,University of British Columbia
American Journal of Surgical Pathology | Year: 2014

Primary intestinal-type glandular lesions of the vagina are rare. We report a series of 14 lesions, including 1 intestinal-type polyp without neoplastic features, 3 adenomas (2 with high-grade dysplasia), and 10 adenocarcinomas. Patients ranged in age from 20 to 86 years (mean 60 y) and presented with vaginal bleeding or a mass. No history of diethylstilbestrol exposure, adenosis, or endometriosis was elicited in any patient. The lesions were mostly polypoid, small (0.8 to 2.0 cm), and located in the posterior (6 cases) and lower (7 cases) vagina. One carcinoma metastasized to a para-aortic lymph node; the others were confined to the vagina. The neoplasms exhibited histologic features identical to those seen in primary large intestinal tumors, including variable numbers of goblet cells and in 1 case neuroendocrine cells. Five of the adenocarcinomas contained areas consistent with a precursor adenoma. In 3 cases, a benign urothelium-lined duct was adjacent to the lesion, and in 2 patients benign intestinal-type epithelium was present; no other potential benign precursor lesions were seen. Immunohistochemical analysis was performed on 6 cases; the tumors were positive for CDX-2 (6/6), CK20 (5/6), CEA (5/5), CK7 (4/6), and CA-125 (2/4) and were negative for ER (0/6) and p16 (0/2). Clinical outcome data were available in 3 patients with adenocarcinomas; 1 died of disease in <1 year, and 2 were alive with no evidence of disease at 2 and 7 years. The pertinent literature is reviewed, and the potential origin and differential diagnosis of these lesions are discussed. © 2014 by Lippincott Williams and Wilkins. Source

McCluggage W.G.,Royal Group of Hospitals Trust
Advances in Anatomic Pathology | Year: 2010

Mullerian adenosarcoma is an uncommon, but not rare, mixed tumor containing a neoplastic but benign or mildly atypical epithelial element and a sarcomatous, usually low-grade, stromal component. The most common site is the uterine corpus but adenosarcoma also occurs in the cervix and ovary and more rarely in the vagina, fallopian tube, arising from peritoneal surfaces, or outside the female genital tract, for example in the intestine. Most uterine cases have a polypoid gross appearance, sometimes resulting in the formation of multiple polyps. Characteristic histologic features include a low power "phyllodes-like" architecture with leaf-like projections lined by a variety of benign Mullerian type epithelia, sometimes with squamous metaplasia. Intraglandular stromal protrusions are a characteristic feature. The stroma may be uniformly cellular but there is typically increased cellularity around the epithelial elements, resulting in the formation of a cambium layer. Using the World Health Organization definition, stromal mitotic activity of 2 or more per 10 high-power fields is required for a diagnosis of adenosarcoma but in practice the diagnosis is made with stromal mitotic activity less than this if the characteristic architecture and cambium layer is present. The stromal component is usually morphologically "low-grade" and of endometrial stromal or fibroblastic type (hormone receptor and CD10 positive). Sometimes it is high grade, resembling undifferentiated sarcoma. Additional features sometimes present include heterologous stromal elements or sex cord-like differentiation. Uterine adenosarcomas are, in general, low-grade neoplasms capable of local recurrence after polypectomy or hysterectomy and much less commonly distant metastasis. The 2 most important adverse prognostic factors, which sometimes coexist, are deep myometrial invasion and sarcomatous overgrowth; the latter is usually associated with morphologically "high-grade" stromal elements with loss of expression of hormone receptors and CD10. Adenosarcoma may be confused with a variety of lesions and one of the main differential diagnoses is adenofibroma in which the stromal component is, by definition, morphologically benign. However, occasional adenofibromas recur or even metastasize. As such, it has been suggested that all adenofibromas should be classified as adenosarcomas, albeit with low-malignant potential. Ovarian adenosarcomas are much more likely to exhibit malignant behavior than their uterine counterparts, probably due to the lack of an anatomic barrier to peritoneal dissemination.Copyright © 2010 by Lippincott Williams & Wilkins. Source

McCluggage W.G.,Royal Group of Hospitals Trust
Advances in Anatomic Pathology | Year: 2016

Most adenocarcinomas in the lower female genital tract (cervix, vagina, vulva) arise in the cervix and are associated with high-risk human papillomavirus (HPV) infection. However, there is an emerging spectrum of non-HPV-related cervical adenocarcinomas, the most common of which is so-called gastric type. In this review, the concept of gastric-type cervical adenocarcinomas and their possible precursor lesions is covered, the precursor lesions still being poorly understood. Other non-HPV-related cervical adenocarcinomas are also discussed, including new information regarding molecular events in mesonephric adenocarcinoma. A variety of primary vaginal adenocarcinomas, including clear cell, endometrioid, intestinal and gastric types are also discussed. The spectrum of benign and malignant glandular lesions involving the lower female genital tract and probably derived from misplaced Skene's (periurethral) glands is also covered. © 2015 Wolters Kluwer Health, Inc. Source

Glenn McCluggage W.,Royal Group of Hospitals Trust
Pathology | Year: 2013

Premalignant lesions of the lower female genital tract encompassing the cervix, vagina and vulva are variably common and many, but by no means all, are related to infection by human papillomavirus (HPV). In this review, pathological aspects of the various premalignant lesions are discussed, mainly concentrating on new developments. The value of ancillary studies, mainly immunohistochemical, is discussed at the appropriate points. In the cervix, the terminology and morphological features of premalignant glandular lesions is covered, as is the distinction between adenocarcinoma in situ (AIS) and early invasive adenocarcinoma, which may be very problematic. A spectrum of benign, premalignant and malignant cervical glandular lesions exhibiting gastric differentiation is emerging with lobular endocervical glandular hyperplasia (LEGH), including so-called atypical LEGH, representing a possible precursor of non HPV-related cervical adenocarcinomas exhibiting gastric differentiation; these include the cytologically bland adenoma malignum and the morphologically malignant gastric type adenocarcinoma. Stratified mucin producing intraepithelial lesion (SMILE) is a premalignant cervical lesion with morphological overlap between cervical intraepithelial neoplasia (CIN) and AIS and which is variably regarded as a form of reserve cell dysplasia or stratified AIS. It is now firmly established that there are two distinct types of vulval intraepithelial neoplasia (VIN) with a different pathogenesis, molecular events, morphological features and risk of progression to squamous carcinoma. These comprise a more common HPV-related usual type VIN (also referred to as classic, undifferentiated, basaloid, warty, Bowenoid type) and a more uncommon differentiated (simplex) type which is non- HPV related and which is sometimes associated with lichen sclerosus. The former has a relatively low risk of progression to HPV-related vulval squamous carcinoma and the latter a high risk of progression to non-HPV related vulval squamous carcinoma. Various aspects of vulval Paget's disease are also discussed. © 2013 Royal College of Pathologists of Australasia. Source

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