Invasive breast carcinoma - IARC

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have a strong association with high grade CIN lesions {587,1088,1699, 1878,3127}. CIN re p resents the preinvasive counterp a rt of invasive cervical squamous cell c a rcinoma, and there is now abundant evidence for its malignant potential. H o w e v e r, there is no inevitability about neoplastic pro g ression; such lesions may re g ress, remain phenotypically stable or p ro g ress {2137}. Histopathology C o n v e n t i o n a l l y, these are subjectively divided into three grades: CIN 1, 2 and 3, though the histological features re p re s e n t a diagnostic continuum. Incre a s i n g - l y, t h e re is a tendency to use a two-tiere d classification of low and high grade CIN that equates to CIN 1 and CIN 2 and 3 re s p e c t i v e l y. These precursors may also be re f e r red to as low and high grade squamous intraepithelial lesion (SIL) {2177}. Because of the inherent diff i c u l t y in distinguishing pure HPV infection fro m unequivocal CIN 1 in flat, non-condylomatous epithelium (sometimes confusingly re f e r red to as flat condyloma), HPV infection alone is included in the low grade SIL c a t e g o ry, a terminology that has been m o re widely accepted by cytopathologists {1612}. The relationship of the varying terminology is shown in Table 5.1. A B Fig. 5.14 A Cervical intraepithelial neoplasia (CIN 1). The upper two-thirds of the epithelium show maturation and focal koilocytosis. There is mild atypia throughout. B CIN 2. Nuclear abnormalities are more striking than in CIN 1, and mitoses are seen (centre). The upper third of the epithelium shows maturation. Cervical intraepithelial neoplasia 1 Maturation is present in the upper twothirds of the epithelium, and the superficial cells contain variable but usually mild atypia, which may include viral cytopathic effect (koilocytosis). Nuclear abnormalities are present throughout but are slight. Mitotic figures are present in the basal third and are not numerous. Abnormal forms are rare. Cervical intraepithelial neoplasia 2 Maturation is present in the upper half of the epithelium, and nuclear atypia is conspicuous in both the upper and lower epithelial layers. Mitotic figures are generally confined to the basal two-thirds of the epithelium. Abnormal forms may be seen. Cervical intraepithelial neoplasia 3 Maturation (including surface keratinization) may be absent or confined to the s u p e rficial third of the epithelium. Nuclear a b n o rmalities are marked thro u g h o u t most or all of the thickness of the epithelium. Mitotic figures may be numero u s and are found at all levels of the epithelium. Abnormal mitoses are fre q u e n t . Growth fraction HPVs, particularly high risk HPVs, are associated with alterations in the cell A B Fig. 5.15 A Cervical intraepithelial neoplasia 3. Squamous epithelium consists entirely of atypical basaloid cells. Note the moderate nuclear polymorphism, coarse chromatin and mitotic figures in the upper half of the epithelium. B Ki-67 staining shows proliferation in all cell layers. cycle. Therefore, cell cycle biomarkers may be useful in distinguishing non-diagnostic atypia from CIN. Expression of a generic cell cycle proliferation marker (Ki-67) is typically confined to the suprabasal cells of the lower third of the normal epithelium. The presence of Ki-67 positive cells in the upper epithelial layers occurs in HPV infection, which induces cell cycle activity in these cells {1881,2356}. P16 ink4 , a cyclin-dependent kinase inhibitor, is a promising marker of CIN {1422,2527}. Differential diagnosis Transitional cell metaplasia is a benign condition that may be mistaken for high grade CIN. After the menopause immature squamous mucosa may exhibit histological features resembling transitional epithelium {1140,3085}. Related lesions CIN is usually associated with the cytopathic effects of HPV infection, which include koilocytosis, dyskeratosis and multinucleation. Koilocytosis is characterized by karyomegaly, nuclear enlargement with binucleation, irregularities in the nuclear membrane and hyperchromasia {1508}. Atypical reserve cell hyperplasia and atypical immature squamous metaplasia may be regarded as variants of CIN, though grading of such lesions may be difficult {979,2179}. Cytopathology In cytology the grading of CIN is largely based on nuclear characteristics. The number of abnormal cells and the relative nuclear area increase with the severity of the lesion. In CIN 1 the cells show a slightly enlarged nucleus (less than one-third of the total area of the cell), some anisokaryosis, finely granular and evenly distributed chromatin and mild hyperchromasia. The cytoplasmic borders are well defined. In CIN 2 the cells and nuclei vary in size and shape. The nuclear to cytoplasmic ratio is increased (nucleus less than half of cell area). Nuclear chromatin is moderately hyperchromatic and shows some irregular distribution. In CIN 3 the nuclear to cytoplasmic ratio is high (nucleus at least two-thirds of cell area). Nuclei are hyperchromatic with coarsely granular and irregularly distributed chromatin. 270 Tumours of the uterine cervix
Cells typical of <strong>carcinoma</strong> in situ are arranged singly or in syncytial aggregates (indistinct cell borders and overlapping nuclei). Cytoplasm is s c a rce or absent; nuclei are round to o v a l . Prognosis and predictive factors Systematic reviews of randomized controlled trials in subjects who underwent cryotherapy, laser ablation, loop electrosurgical excision procedure (LEEP) or surgical conization for the treatment of CIN of any grade reveal no substantial d i ff e rences in outcome {1777,2068, 2299}. Fig. 5.16 Cervical intraepithelial neoplasia 1. Cells have well defined cell borders, slightly enlarged nuclei and some anisokaryosis. Fig. 5.17 Cervical intraepithelial neoplasia 3. Cells have increased nuclear to cytoplasmic ratios, anisokaryosis and coarsely granular chromatin. Benign squamous cell lesions Condyloma acuminatum Definition A benign tumour characterized by p a p i l l a ry fronds containing fibro v a s c u- lar cores and lined by stratified squamous epithelium with evidence of HPV infection, usually in the form of koilocyt o s i s . Aetiology The exophytic condyloma is strongly associated with HPV types 6 and 11 {3057}. Histopathology These lesions exhibit acanthosis, papillomatosis and koilocytosis. The latter is characterized by karyomegaly, nuclear enlargement with binucleation, irregularities in the nuclear membrane and hyperchromasia. These lesions closely resemble vulvar condylomas {585}. Squamous papilloma Definition A benign tumour composed of a single papillary frond in which mature squamous epithelium without atypia or koilocytosis lines a fibrovascular stalk. Epidemiology Lesions with a histological appearance similar to squamous papillomas of the vagina and vulva are rare in the cervix. Aetiology There is no evidence that squamous papilloma as defined above is or is not related to human papillomavirus. Fig. 5.18 Cervical intraepithelial neoplasia 2. Cells and nuclei vary in size and shape; nuclear chromatin is hyperchromatic and irregularly distributed. Macroscopy The squamous papilloma is usually solitary, arising on the ectocervix or at the squamocolumnar junction. Histopathology Histological examination shows a single p a p i l l a ry frond composed of mature squamous epithelium without atypia or koilocytosis lining a fibrovascular stalk. Differential diagnosis Squamous papilloma is distinguished from condyloma by the absence of complex branching papillae and koilocytes. However, it is important to note that there may be a time during the evolution of condylomas when koilocytes are not easily identifiable. Squamous papilloma also should be distinguished from papillary immature metaplasia of the cervix, which is characterized by slender filiform papillae and also does not have koilocytosis {3057}. In the latter condition the squamous epithelium is less mature with higher nuclear to cytoplasmic ratios but lacks nuclear atypia. Papillary immature metaplasia has been associated with HPV types 6 or 11 {3057}. Fig. 5.19 Cervical intraepithelial neoplasia 3 (<strong>carcinoma</strong> in situ). The syncytial aggregate of round to oval nuclei which have coarsely granular chromatin. Fibroepithelial polyp Definition A polyp lined by squamous epithelium that contains a central core of fibrous tissue in which stellate cells with tapering cytoplasmic processes and irregularly shaped thin-walled vessels are prominent features. Synonym Stromal polyp. Aetiology Unlike condyloma, fibroepithelial polyps rarely contain HPV nucleic acids {1837}, and, thus, are not related to HPV infection. Clinical features This lesion can occur at any age but has a predilection for pregnant women. Macroscopy These are polypoid lesions and are usually solitary. Histopathology These polypoid lesions are characterized by a prominent fibrovascular stroma cov- Epithelial tumours 271
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Previous volumes in this series Kle
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World Health Organization Classific
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Published by IARC Press, Internatio
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CHAPTER 1 Tumours of the Breast Can
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TNM classification of carcinomas of
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Invasive breast carcinoma I.O. Elli
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Rapid growth and greater adult heig
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tives, administrative and clerical
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Grade 1 - well differentiated: 3-5
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ent and this is occasionally extens
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Most melanotic tumours of the breas
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A Fig. 1.22 A Classic invasive lobu
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yet others at 90% {97,2147}. For pr
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Fig. 1.27 Medullary carcinoma. The
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myoepithelial cells in fibro a d e
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A Fig. 1.33 Neuroendocrine carcinom
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Macroscopy Fisher et al. reported t
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Fig. 1.39 Apocrine carcinoma. Note
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cells contain intracytoplasmic lume
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A Fig. 1.50 Carcinosarcoma. A Two a
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A B C Fig. 1.75 Lobular neoplasia.
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Intraductal proliferative lesions F
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A B absence of either microcalcific
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Fig. 1.83 Atypical ductal hyperplas
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A B Fig. 1.88 Large excision biopsy
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unusual variants as well. Using thi
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esemble those identified in invasiv
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A B Fig. 1.97 Microinvasive carcino
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A Papilloma may be subject to morph
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A B C Fig. 1.103 Papillary intraduc
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colour measuring from 0.5 to 12 cm.
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Immunoprofile The cases studied by
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Glycogen-rich, clear cell carcinoma
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Differential diagnosis There may be
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quality metaphase spreads from an i
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Fig. 1.67 Lobular carcinoma of brea
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detectable distant metastasis displ
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detected at a late stage as small t
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Extent of ductal carcinoma in situ
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Benign epithelial proliferations G.
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Fig. 1.112 Microglandular adenosis.
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A Apocrine adenoma ICD-O code 8401/
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A B Fig. 1.128 Adenomyoepithelioma,
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Mesenchymal tumours M. Drijkoningen
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1113,1275}. There is a complex patt
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A B Fig. 1.137 A Lipoma. Intraparen
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Fig. 1.141 Angiosarcoma after breas
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A Fig. 1.144 Mammary osteosarcoma.
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Fibroepithelial tumours J.P. Belloc
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aged women (average age of presenta
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lished data suggests a 21% rate of
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A Fig. 1.157 Syringomatous adenoma
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Malignant lymphoma and metastatic t
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used. Inflammatory conditions in th
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male population both in the USA and
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CHAPTER 2 Tumours of the Ovary and
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Polyembryoma 9072/3 Non-gestational
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Surface epithelial-stromal tumours
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A Fig. 2.04 A Serous borderline tum
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A Fig. 2.06 Serous borderline tumou
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A Fig. 2.10 Invasive peritoneal imp
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Fig. 2.15 Mucinous carcinoma with i
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Fig. 2.20 Mucinous endocervical-lik
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A Fig. 2.28 Mucinous cystic tumour
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early secretory endometrium {2605}.
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IV, 6% {2233}. Patients with grade
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A Fig. 2.37 A This polypoid intracy
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Fig. 2.40 Endometrioid cyst with at
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1 tumours are extremely rare. Almos
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Fig. 2.50 Borderline Brenner tumour
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express thrombomodulin and have bee
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serous and transitional cell carcin
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is yellow to tan with a variable ad
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Genetic susceptibility JGCTs may pr
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Clinical features F i b romas may b
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distinguishes this tumour from the
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A Fig. 2.77 A Retiform Sertoli-Leyd
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Mean ages of 21 and 38 years and me
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Tumours unassociated with PJS form
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mal origin without crystals of Rein
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Germ cell tumours F. Nogales A. Tal
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cases, anisokaryosis has no prognos
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ation may coexist in the same neopl
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Table 2.06 Grading of ovarian immat
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A B Fig. 2.102 A Mature cystic tera
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Diagnostic procedures Elevated urin
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associated with mature teratomas sh
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atives intimately admixed. The germ
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Fig. 2.113 Mixed germ cell-sex cord
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A Fig. 2.116 A Adenomatous hyperpla
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Fig. 2.117 Small cell carcinoma, hy
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Clinical features Adenoid cystic-li
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Histopathology This epithelial tumo
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sis. Corpus luteum of pregnancy has
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Lymphomas and leukaemias L.M. Roth
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Secondary tumours of the ovary J. P
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Occasionally, the colonic adenocarc
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Peritoneal tumours S.C. Mok J.O. Sc
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A B Fig. 2.140 Cystic adenomatoid m
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whelmingly poor {1038,1547,2310}. H
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CHAPTER 3 Tumours of the Fallopian
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TNM and FIGO classification of carc
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Endometrioid adenocarcinoma Endomet
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Two examples of adenofibroma of bor
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A Fig. 3.11 Adenomatoid tumour. A T
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Clinical features Patients range in
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Fig. 3.16 Uterus-like mass. The cys
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CHAPTER 4 Tumours of the Uterine Co
Page 220 and 221: TNM and FIGO classification of non-
Page 222 and 223: Epithelial tumours and related lesi
Page 224 and 225: endometrioid adenocarcinoma fro m a
Page 226 and 227: fers from the prototypical type I e
Page 228 and 229: the ovary and bladder. Unlike prima
Page 230 and 231: schema {1535,2602}. Although this c
Page 232 and 233: Table 4.03 Altered gene function in
Page 234 and 235: Mesenchymal tumours and related les
Page 236 and 237: areas are limited to less than 30%
Page 238 and 239: A B C Fig. 4.30 Leiomyosarcoma. A T
Page 240 and 241: e used sparingly and is reserved fo
Page 242 and 243: A B Fig. 4.38 Leiomyoma with perino
Page 244 and 245: cytological atypia, tumour cell nec
Page 246 and 247: Mixed epithelial and mesenchymal tu
Page 248 and 249: Prognosis and predictive factors Th
Page 250 and 251: tumours may superficially invade th
Page 252 and 253: A Fig. 4.46 A Gestational choriocar
Page 254 and 255: A Fig. 4.49 A Classic complete hyda
Page 256 and 257: Sex cord-like, neuroectodermal and
Page 258 and 259: Secondary tumours of the uterine co
Page 260 and 261: WHO histological classification of
Page 262 and 263: Epithelial tumours M. Wells J.M. Ne
Page 264 and 265: Fig. 5.04 Mechanisms of human papil
Page 266 and 267: Fig. 5.08 Keratinizing squamous cel
Page 268 and 269: in their Asian population {2957}. I
Page 272 and 273: e red by squamous epithelium {380}.
Page 274 and 275: endometrioid adenocarcinoma of the
Page 276 and 277: metrial epithelium. In some cases t
Page 278 and 279: with distinct cell borders and a gr
Page 280 and 281: Mesenchymal tumours M.L. Carcangiu
Page 282 and 283: {781}, liposarcoma {2840,3016}, ost
Page 284 and 285: Mixed epithelial and mesenchymal tu
Page 286 and 287: Fig. 5.44 Wilms tumour. The tumour
Page 288 and 289: A Fig. 5.47 Implant of endometrial
Page 290 and 291: CHAPTER 6 Tumours of the Vagina Alt
Page 292 and 293: Epithelial tumours E.S. Andersen A.
Page 294 and 295: Aetiology The fact that both VAIN a
Page 296 and 297: Fig. 6.10 Fibroepithelial polyp.A m
Page 298 and 299: er of mitoses varies but is usually
Page 300 and 301: ICD-O codes Adenosquamous carcinoma
Page 302 and 303: A C Fig. 6.17 Sarcoma botryoides. A
Page 304 and 305: 1-11 cm. They may arise anywhere in
Page 306 and 307: elsewhere in the female genital tra
Page 308 and 309: A Fig. 6.24 Yolk sac tumour. A The
Page 310 and 311: g rowing in sheets. Some may have s
Page 312 and 313: WHO histological classification of
Page 314 and 315: Epithelial tumours E.J. Wilkinson M
Page 316 and 317: even with additional sectioning, it
Page 318 and 319: type) is a highly diff e rentiated
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Clinical features Bartholin gland c
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glandular elements surrounded by fi
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Mesenchymal tumours R.L. Kempson M.
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Table 7.03 Differential diagnosis o
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Prognosis and predictive factors A
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Table 7.04 Clark levels of cutaneou
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A Fig. 7.23 Vulvar peripheral primi
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Familial aggregation of cancers of
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BRCA1 syndrome Definition Inherited
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dispose individuals to the developm
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Fig. 8.05 To assess whether wild-ty
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Fig. 8.07 Factors that modify risk
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BRCA2 syndrome R. Eeles S. Piver S.
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tubal or ovarian carcinomas. Howeve
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in typical nuclear foci that may re
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Breast tumours Frequency Breast can
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Fig. 8.14 Codon distribution of som
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Breast tumours Age distribution and
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Hereditary non-polyposis colon canc
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essary in the evaluation of the pat
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Age distribution and penetrance Mos
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Contributors Dr Vera M. ABELER** De
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Dr Carlo LA VECCHIA Laboratory of E
Page 366 and 367:
Dr Manuel TEIXEIRA Department of Ge
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02.100 Dr. A. Ostor 02.101 Dr. F.A.
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52. Akhtar M, Robinson C, Ashraf Al
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180. Bapat K, Brustein S (1989). Ut
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307. Bolis GB, Maccio T (2000). Cle
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436. Chang J, Sharpe JC, A'Hern RP,
Page 378 and 379:
562. Costa MJ, Ames PF, Walls J, Ro
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689. Di Domenico A, Stangl F, Benni
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820. Falck J, Petrini JH, Williams
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943. Gad A, Azzopardi JG (1975). Lo
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1067. Grimes MM (1992). Cystosarcom
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1197. Herod JJ, Shafi MI, Rollason
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1323. Jacques SM, Qureshi F, Ramire
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1449. Khalifa MA, Mannel RS, Harawa
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1564. Lagios MD (1977). Multicentri
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1687. Loman N, Johannsson O, Kristo
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1807. McCluggage G, McBride H, Maxw
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1937. Mukai M, Torikata C, Iri H (1
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2056. Norris HJ, Taylor HB (1967).
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2180. Park JS, Jones RW, McLean MR,
Page 406 and 407:
2304. Puls LE, Hamous J, Morrow MS,
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2 4 3 4 . Rosen PP, Groshen S, Saig
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2559. Schlesinger C, Silverberg SG
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2686. Silverberg SG (1999). Protoco
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2806. Stutz JA, Evans AJ, Pinder S,
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2942. Tornos C, Silva EG, Ordonez N
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3061. Wargotz ES, Norris HJ (1990).
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3189. Yoshioka T, Tanaka T (2000).
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References 425
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Biphasic teratomas, 168 BLM, 341, 3
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G GADD45, 343, 353 GCDFP-15, 25, 33
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MPNST, see Malignant peripheral ner
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Small cell / oat cell carcinoma, 32
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