Both glands and stroma are altered in polyps. The glandular component is composed of tubules that may be simple, branched or cystically dilated, and are lined by inactive or proliferating epithelium, but may occasionally contain foci of hyperplasia or carcinoma {1206}. The stroma may be cellular resembling that of basal endometrium, but often is rich in collagen and contains thick-walled blood vessels, sometimes with haemosiderin deposition {924}. Secretory epithelial changes, if present, are typically poorly developed. Reactive surface changes, including shedding and haemorrhage, are common, as are a range of metaplasias. Endometrial polyps associated with tamoxifen therapy more often show epithelial metaplasias, prominent stromal brosis and periglandular stromal cuf ng {902}. Polyps with a prominent smooth-muscle component are described as adenomyomatous. Polyps are a disproportionately common site for development of SEIC and small invasive serous carcinomas {1206}. Polyps arise as monoclonal overgrowths of genetically altered endometrial stromal cells with secondary induction of polyclonal benign glands. Chromosomal analysis of polyp stroma shows, in the majority of cases, clonal translocations, involving 6p21-p22, 12q1315, or 7q22 regions 25. from one mature histological cell type to another {1303}, and are composed of cells that have cytoplasmic, nuclear and/ or architectural differentiation that differ from that of normal endometrioid glands. In the endometrium, metaplasia often represents a cellular alteration that does not result in a mature (normal) cell type. Papillary syncytial metaplasia; hobnail metaplasia; eosinophilic metaplasia; ciliated cell metaplasia; tubal metaplasia; squamous metaplasia; morular metaplasia; mucinous metaplasia; secretory metaplasia; papillary metaplasia Metaplastic changes are most often found in abnormal endometria, including hyperplasia, endometritis, shedding, atypical hyperplasia or carcinoma, and are often mixed {149,237,1100}. Papillary syncytial metaplasia is an exophytic proliferation of eosinophilic cells forming small syncytia or micropapillary processes on the surface of the endometrium or within glands and is often associated with glandular and stromal breakdown {2146}. Eosinophilic and ciliated cell metaplasias are characterized by epithelial cells with abundant, densely eosinophilic cytoplasm or numerous apical cilia {1303}. Mucinous metaplasia re ects the presence of pale, basophilic cytoplasm that is either vacuolated or granular {1395}. Endometrial metaplasias re ect a change A Hobnail metaplasia is characterized by Fig. 5.13 Eosinophilic and mucinous metaplasia. Various types of metaplasias often coexist. Glands displaying mucinous metaplasia (top left) coexist with glands with striking eosinophilic metaplasia (lower left). glandular cells, often with prominent eosinophilic cytoplasm, and a nucleus, which protrudes into the gland lumen. Squamous metaplasia is composed of masses of polygonal-shaped cells with dense, eosinophilic cytoplasm and occasionally keratinization, which may occur as either concentrically lamellated, intraglandular elements called squamous morules or bridging adjacent glands. Secretory metaplasia is characterized by cells containing sub or supranuclear vacuoles, resembling early secretory endometrium. Papillary proliferation is characterized by brovascular stromal cores covered by cytologically bland epithelium {812,1068}. There is a variation from small foci of simple papillae with short non-branching stalks to extensive complex papillae with elongated stalks and branches {812,1068}. The lining epithelium consists of a single layer of cells with bland nuclei and pale eosinophilic or mucinous cytoplasm. B Fig. 5.12 A Mucinous metaplasia. Metaplasias typically occur in abnormal endometrium. This mucinous metaplasia, consisting of cells with abundant apical mucin, is occurring in hyperplastic glands. B Squamous metaplasia. Intraglandular squamous morules, characterized by cells with abundant, dense, eosinophilic cytoplasm, most often occur in the setting of hyperplasia without atypia, atypical hyperplasia/endometrioid intraepithelial neoplasia and well-differentiated carcinoma. 134 Endometrial metaplasias can be secondary to non-speci c endometrial breakdown, chronic in ammation or an abnormal hormonal state. The metaplastic change is often associated with a variety of endometrial lesions but, in and of itself, has no clinical signi cance. Striking cellular and nuclear atypia of cells within endometrial glands, often occurring in association with gestation, gestational trophoblastic disease, treatment with gonadotropins or high doses of progestins {786,1580}. A B Fig. 5.14 Arias-Stella reaction. A Irregularly dilated glands lined by cells with striking nuclear atypia and abundant clear cytoplasm may mimic the tubulocystic pattern of clear cell carcinoma. The young age and history of a gestation would be very unusual for clear cell carcinoma. B The striking cytological atypia suggests a high-grade neoplasm, however, the chromatin is smudged, optically clear or degenerated. or vesicular chromatin. Hobnail cells and intraglandular cellular tufting are common; simple elongated papillary projections may also be seen. Mitotic activity is rarely observed. The lesion must be distinguished from the tubulocystic pattern of clear cell carcinoma {1393}. Arias Stella phenomenon; Arias Stella effect This change is asymptomatic. A diffuse in ltration of lymphoid cells that mimics lymphoma or leukaemia {2112}. The typical form is seen in the zona spongiosa. The glands are crowded and lined entirely, or in part, by cells with massively abundant, clear, glycogen rich or eosinophilic cytoplasm, and large bulbous nuclei with irregular outlines and smudged Pseudolymphoma; lymphoid hyperplasia This represents an exaggerated form of endometritis and, usually, women pre- Mesenchymal tumours A benign, smooth-muscle tumour that has several variant morphological features. Leiomyoma Cellular leiomyoma Leiomyoma with bizarre nuclei Mitotically active leiomyoma Hydropic leiomyoma Apoplectic leiomyoma 8890/0 8892/0 8893/0 8890/0 8890/0 8890/0 Lipomatous leiomyoma (lipoleiomyoma) Epithelioid leiomyoma Myxoid leiomyoma Dissecting (cotyledonoid) leiomyoma Diffuse leiomyomatosis Intravenous leiomyomatosis Metastasizing leiomyoma sent during the reproductive-age period with vaginal bleeding. Lymphoma-like lesions are typically super cial and non-mass forming. There is a dense in ltration of the endometrium by lymphoid cells with a predominance of large cells with features of immunoblasts, sometimes in ill-de ned aggregates with mitotic activity or with germinal centres. Apoptotic debris and tingible body macrophages may result in a starry-sky pattern. There is typically a background of chronic endometritis, including small lymphocytes, plasma cells and neutrophils. Lymphocytes are usually a mixture of B and T lymphocytes although in different proportions; plasma cells are polytypic {629}. E. Oliva M.L. Carcangiu S.G. Carinelli P. Ip 8890/0 8891/0 8896/0 8890/0 8890/1 8890/1 8898/1 Symplastic leiomyoma (leiomyoma with bizarre nuclei) T. Loening T.A. Longacre M.R. Nucci J. Prat C.J. Zaloudek Leiomyomas, including variants, are the most common uterine tumour and usually affect women in their fourth and fth decades. Variant forms account for approximately 10% of cases. Patients with hereditary leiomyomatosis and renal cancer syndrome present at a younger age. Those with metastasizing leiomyoma usually have a history of prior hysterectomy for leiomyomas. Most patients are asymptomatic but 135 coexist with cutaneous leiomyomas and renal cell carcinomas {1682}. Fig. 5.15 Leiomyoma. The tumour is well circumscribed with a multinodular, whorled and homogeneous white cut surface. one-third present with menorrhagia, pelvic pain or pressure. Abdominal symptoms occur more frequently in patients receiving progestational therapy or who are pregnant. Symptoms are largely related to the number, size and location of the tumours. Rarely, patients with intravenous leiomyomatosis present with cardiovascular involvement. Patients with benign metastasizing leiomyoma usually present at a median interval of 15 years after hysterectomy {894}. The lungs are the commonest extrauterine location {894} but rarely, other sites can be involved {425,814,1929}. Other less common clinical features include ascites, erythrocytosis secondary to tumour erythropoietin production, coexistent leiomyomatosis peritonealis disseminata, and hereditary leiomyomatosis, an autosomal dominant disorder in which uterine leiomyomas Leiomyomas are often multiple (> 75%) and may be intramural, submucosal or subserosal. Submucosal and subserosal tumours may be polypoid or pedunculated; the former may undergo torsion and/ or prolapse through the cervical os while the latter may detach from their pedicle and result in a so-called parasitic leiomyoma. Tumours are well circumscribed but non-encapsulated, range widely in size and characteristically have a bulging, rm, whorled, white cut surface. Some tumours, particularly if oedematous, highly cellular or epithelioid, are soft. Highly cellular tumours and those with fat (lipoleiomyoma) are sometimes either focally or diffusely tan to yellow. Infarction, sometimes with haemorrhage, is common, particularly in large tumours and cystic change is occasionally seen, especially in oedematous or myxoid tumours. Leiomyomas in pregnant patients may have a beefy-red appearance (red degeneration). Progestational therapy may induce multiple foci of haemorrhagic infarction (apoplectic change) {181}. Occasionally, tumours with hydropic change may project from the serosa as beefy bulbous protrusions (so called cotyledonoid/dissecting leiomyoma). Rarely, numerous illde ned, often con uent small nodules are present within the myometrium (diffuse leiomyomatosis). Intravenous leiomyomatosis forms worm-like plugs protruding from myometrial or broad ligament veins. Although in most instances only a small number of vessels are involved, occasionally it is extensive {327}. Fig. 5.16 Highly cellular leiomyoma. The tumour is highly cellular resembling an endometrial stromal tumour, however, it shows fascicular growth as well as large and thick-walled blood vessels characteristic of smooth-muscle tumours. 136 Most leiomyomas have a well-demarcated border and are composed of spindle cells arranged in intersecting fascicles. Cells have indistinct borders, eosinophilic brillary cytoplasm and cigar-shaped nuclei with small nucleoli; mitoses are infrequent. Rarely, nuclear palisading may be seen. Collagen deposition may result in prominent hyalinization. Rarely, calci cation may be seen. Infarct-type necrosis, de ned by the presence of a band of granulation tissue with or without associated haemorrhage or brosis between viable and non-viable tumour, may be seen. The non-viable areas have a mummi ed appearance. In an early stage of infarction, only single or groups of apoptotic cells are seen showing pyknotic nuclei and dense eosinophilic cytoplasm {811,814}. Cellular leiomyoma There is signi cant increased cellularity when compared to the surrounding myometrium and, when highly cellular, mimics an endometrial stromal tumour. In highly cellular tumours, the neoplastic cells are arranged diffusely (often in the centre) or in fascicles (at the periphery). Thick-walled vessels and cleft-like spaces are common. The cells typically have scant cytoplasm, lack nuclear atypia and mitoses are rare {712}. The border is usually irregular and merges with the surrounding myometrium. Foci of normocellular leiomyoma may be present. Leiomyoma with bizarre nuclei This tumour (previously termed atypical leiomyoma) contains isolated bizarre cells or, more often, groups of them on Fig. 5.17 Leiomyoma with bizarre nuclei.The bizarre nuclei alternate with areas of conventional leiomyoma. A B Fig. 5.18 A Leiomyoma with infarct-type necrosis. An area of granulation tissue and hyalinization separates viable from non-viable tumour, the latter (top) showing a mummied appearance. B Leiomyoma. Intersecting fascicles of cytologically bland, spindled cells with cigar-shaped nuclei and eosinophilic cytoplasm are present. a background of an otherwise typical leiomyoma. Typically, it is present focally but rarely this change is extensive, producing con uent zones of atypia. The tumour cells typically have eosinophilic cytoplasm (sometimes appearing globular) {197,1464} and are bizarrely shaped, multilobated or contain multiple, hyperchromatic nuclei; intranuclear cytoplasmic pseudoinclusions may be seen. Nuclear chromatin is often smudged. Mitotic activity is typically low but karyorrhectic nuclei, which may mimic atypical mitotic gures, are common {469,1134}. Tumour cell necrosis is absent but infarct-type necrosis may be seen. Mitotically active leiomyoma It often has > 10 mitotic gures per 10 HPF but typically lacks cytological atypia and tumour cell necrosis {129,1400, 1492,1526}. These tumours are usually seen in the reproductive age group, are often submucosal and are sometimes associated with hormone therapy. They may also show hypercellularity and focal bizarre nuclei; in these cases care must be taken to exclude a leiomyosarcoma. Hydropic leiomyoma This variant is characterized by conspicuous zonal, watery oedema. Hyalinization may also be seen. The oedema and hyalinization may result in the tumour cells growing in thin delicate cords. The tumours are often vascular and if the hydropic change is extensive, a characteristic nodularity is sometimes noted {348}. Leiomyoma with apoplectic change. Progestational therapy typically induces so-called apoplectic change characterized by zones of haemorrhagic infarc- tion surrounded by hypercellular areas often associated with increased mitoses and sometimes myxoid change. If early only single cell apoptosis is seen and late stages may exhibit hyalinization and/or zones of tissue dropout {181}. Lipoleiomyoma (lipomatous variant) This is characterized by single or groups of mature adipocytes admixed with the smooth muscle component. Some such tumours may have a chondroid appearance or resemble hibernomas {157,278}. Other heterologous elements such as bone, cartilage, skeletal muscle, haematopoietic or lymphoid cells may rarely be found in leiomyomas {551}. Epithelioid leiomyoma It is composed of rounded or polygonal cells with an epithelial-like morphology {511,1525}. The tumour cells are arranged in sheets, cords, trabeculae or nests and have appreciable eosinophilic or clear cytoplasm. Tumours with a plexiform growth and < 1 cm are referred to as plexiform tumourlets. Myxoid leiomyoma is hypocellular with cells widely separated by myxoid acid-mucin stroma (alcian blue positive). The tumour cells show no cytological atypia and have rare to absent mitoses. They lack an in ltrative border. Cotyledonoid dissecting leiomyoma This dissecting variant of leiomyoma is characterized by irregular dissection of bland smooth muscle cells within the myometrium {1641}. There may be extension outside the uterus, sometimes with conspicuous hydropic change {1642}. Intravenous leiomyomatosis (IVL) IVL is characterized by the presence of benign smooth muscle within vascular spaces outside the con nes of a leiomyoma, free oating within the lumen or adherent to the vessel wall. The tumour is often prominently vascular and commonly hydropic {853} but it rarely has the appearance of another leiomyoma variant. The cells are usually bland with rare mitoses {346,1379}. Occasionally they contain a minor component of endometrial glands {346} and rarely exhibit cysts that may contain blood. As vascular intrusion occurs occasionally in typical leiomyomas as a focal phenomenon, a diagnosis of IVL is reserved for cases where worm-like growths of smooth muscle are observed, grossly. Diffuse leiomyomatosis Innumerable hypercellular tumour nodules that merge imperceptibly with each other and myometrial smooth muscle. Tumour cells lack atypical features. {341,1312}. Metastasizing leiomyoma This resembles a typical leiomyoma but it is found in the lungs of women with a history of typical uterine leiomyomas. Entrapment of bronchioalveolar epithelium is often seen within the lesions {579,894}. Leiomyomatosis and renal cancer syndrome This autosomal dominant disorder is associated with a germline mutation in the fumarate hydratase (FH) gene. It is characterized by multiple leiomyomas that frequently have increased cellularity, multinucleated and atypical nuclei with prominent red to orange nucleoli 137 A B Fig. 5.19 A Epithelioid leiomyoma. A fascicular growth is absent and the tumour cells are not spindle-shaped. The cells show rounded nuclei and have eosinophilic cytoplasm. B Intravenous leiomyomatosis. This benign, smooth-muscle proliferation grows within vascular spaces. It has large, thick-walled blood vessels and cleft-like spaces. surrounded by a clear halo, as well as haemangiopericytoma-like vessels {1682}. Others Histological changes associated with GnRH-agonists include irregular border, increased cellularity, focal infarction, hyalinization, massive lymphoid in ltrate, decrease in blood vessel number and calibre and other vascular changes {357,365,387,865,1574}. Uterine artery embolization usually results in infarcttype necrosis and marked acute in ammation {366,1149,2012}. Anti- brinolytic agents such as tranexamic acid, used in the treatment of menorrhagia and/or leiomyomas, can also produce thrombosis and infarction {813}. Immunohistochemistry Leiomyomas express desmin and hcaldesmon, smooth muscle actin, histone deacetylase 8 {428}, smooth muscle myosin heavy chain {14,1349,2006}, oxytocin receptor {1112} ER, PR and WT1 {244,1055}. CD10 is expressed in up to 40% of highly cellular leiomyomas {428,1112,1422}. p53 and p16 are often positive in leiomyomas with bizarre nuclei but not helpful in the differential diagnosis of leiomyosarcoma {281}. Occurrence of non-random X chromosome inactivation is indicative of clonal origin of leiomyomas {717,1111,1175,1541}. Individual nodules in diffuse leiomyomatosis have been shown to be of different clonal origin, as shown by the presence of non-random X-chromosome inactivation involving different alleles in different tumours {114}. Some metastasizing leiomyomas have been postulated to 138 represent hormone-mediated multifocal hyperplastic or neoplastic smooth muscle proliferations {306,320,967} although several of them are the result of vascular or lymphatic dissemination from uterine leiomyomas {64, 162, 228, 1056, 1314}. Pulmonary and uterine lesions have been shown to have identical patterns of androgen receptor allelic inactivation and X-chromosome inactivation, indicating that these are indeed clonal {1474,1922}. Approximately 40% of leiomyomas have chromosomal aberrations (i.e. rearrangements of the HMGA locus) such as t(12;14) (q15;q2324) involving the short arm of chromosome 6, and interstitial deletions of the long arm of chromosome 7 {1111,1541,1813}. MED12 mutations are often seen in leiomyomas but they are uncommon in leiomyomas with bizarre nuclei {1148}. Patients with leiomyomas associated with hereditary leiomyomatosis and renal cancer syndrome have germline, heterozygous loss-of-function mutation of the fumarate hydratase gene (1q43) {1682}. A distinctive cytogenetic pro le of metastasizing leiomyoma has also been found in a subset (3%) of uterine leiomyomas but not in other types of benign or malignant smooth-muscle tumours {1385}. Conventional leiomyoma and its variants are usually associated with a benign course, although experience with some of these variants is limited {129,811,814}. Diffuse leiomyomatosis is associated with a good outcome {1606}. Intravenous leiomyomatosis can recur (< 5%) up to 15 years after hysterectomy {327}. In approximately 70% of patients, recurrence is related to inferior vena cava and cardiac involvement {110,1456}. Patients with metastasizing leiomyoma have an indolent clinical course but tumours may continue to grow and eventually result in respiratory failure {894}. The majority of epithelioid leiomyomas behave in a benign fashion but some, even with relatively low mitotic activity and cytological atypia, may recur locally {1002}. Smooth muscle tumour of uncertain malignant potential (STUMP) is a smoothmuscle tumour with features that preclude an unequivocal diagnosis of leiomyosarcoma, but that do not ful ll the criteria for leiomyoma, or its variants, and raise concern that the neoplasm may behave in a malignant fashion {129}. 8897/1 Atypical smooth muscle neoplasm In general, the reasons why an unequivocal benign or malignant diagnosis cannot be made are related to a combination of features (Table 5.1). For example, when mitotic indices are higher than in the usual leiomyoma but lower than in most leiomyosarcomas, or when the type of necrosis cannot be determined with certainty, or when some other Table 5.1 Uterine smooth-muscle tumours with spindle-cell differentiation of uncertain malignant potential. Tumour cell necrosis Moderate-to-severe atypia Mitotic count (per 10 HPF) Mean mitotic count in tumours with recurrence (per 10 HPF) Cases with recurrence Absent Focal/multifocal < 10 4 (range 35) 13.6% (3 of 22 cases) {68 ,811} Diffuse < 10 4.3 (range 29) 10.4% (7 of 67 cases) {129,145,1865,1981}* Present None < 10 2.8 (range 14) 26.7% (4 of 15 cases) {41,68,129} Absent None 15 Not applicable 0% (0 of 39 cases) {129,811} *One of the four tumours also had epithelioid cells Three had 20 mitotic gures per 10 HPF; an unknown proportion also had counts between 10 and 14 {129}. problematic nding such as epithelioid or myxoid change is present {41,68, 129,145,644,811,1865,1981}. The frequency of recurrence of such tumours, based on a variety of histological features shown, is relatively low (Table 5.1). Since the majority of these tumours do not recur {1134}, some pathologists do not wish to include the term malignancy in the diagnosis. To acknowledge their inability to establish a de nitive diagnosis for these problematic neoplasms, they prefer the diagnostic term atypical smooth-muscle neoplasm appended with a note describing the features that preclude an unequivocal benign or malignant diagnosis. It should be emphasized that this is a diagnosis that should only rarely be made. Immunohistochemistry Cell-cycle regulatory protein immunoexpression (p16, p21, p27 and p53) to distinguish uterine leiomyosarcoma from leiomyoma variants has not been useful {1273}. A malignant smooth-muscle tumour, most commonly displaying spindle cell morphology but occasionally showing epithelioid or myxoid features. Leiomyosarcoma Epithelioid leiomyosarcoma Myxoid leiomyosarcoma 8890/3 8891/3 8896/3 Leiomyosarcoma is the most common uterine sarcoma accounting for 12% of all uterine malignancies {4} with an incidence of 0.30.4/100 000 women per year {708} that increases in women on tamoxifen therapy for breast cancer {198}. The majority occur in patients > 50 years of age {590,1147}. The most common symptoms include abnormal vaginal bleeding (56%), palpable pelvic mass (54%) and pelvic pain (22%). Occasionally, the presenting manifestations are related to tumour rupture (haemoperitoneum), extra uterine extension (up to one-half), or metastases. As symptoms and signs greatly overlap with those seen in leiomyomas, malignancy should be suspected when tumour growth is detected in menopausal women who are not on hormonal replacement therapy {1465,1490}. Leiomyosarcoma may spread locally or regionally and may be associated with gastrointestinal or urinary- tract symptoms. Haematogenous dissemination is most often to the lungs. Leiomyosarcomas are either single masses or, when associated with leiomyomas, the largest mass. They are typically large with a mean diameter of 10 cm (only 25% are < 5 cm). About two-thirds are intramural, one- fth submucosal and one-tenth subserosal, while only 5% arise in the cervix. The cut surface is typically soft, bulging, eshy, necrotic and haemorrhagic with irregular margins. The rare myxoid tumours are typically gelatinous and may be deceptively circumscribed {933}. Spindle cell leiomyosarcomas These are cytologically high-grade and composed of spindle and/or pleomorphic cells with eosinophilic cytoplasm often forming interlacing but disorganized fascicles. Pleomorphism is usually overt but, in a minority of tumours, is not striking. The utility of grading is controversial, and no universally accepted grading system See Table 5.1 {41,68,129,145,811,1865, 1981} Fig. 5.20 Leiomyosarcoma. Large tumour with a variegated cut surface and areas of necrosis and hemorrhage. Fig. 5.21 Leiomyosarcoma. Viable tumour in a perivascular arrangement with abrupt transition to tumour cell necrosis. Atypical neoplastic cells are present in the viable tissue. 139 A B Fig. 5.22 Spindle cell leiomyosarcoma. A The tumour is composed of highly atypical spindled cells forming intersecting fascicles. B The spindled cells show nuclear atypia and brisk mitotic activity. exists. Multinucleated tumour cells are found in 50% of cases and osteoclast-like cells are rarely seen {1169}. The mitotic index is usually high {1484}. Tumour cell necrosis occurs in about one-third and it is characterized by an abrupt transition from viable to non-viable areas, the former typically having a perivascular distribution. Within the necrotic zones, atypical cells can still be seen. Both cytological atypia and mitotic activity should usually be present to diagnose leiomyosarcoma, because of dif culty in the reliable distinction between infarct-type and tumour cell necrosis {129,1095}. Vascular space invasion is identi ed in up to 1020% of cases and often an in ltrative border is present. Epithelioid leiomyosarcomas are composed predominantly or entirely of round or polygonal cells with eosinophilic, or much less commonly, clear cytoplasm {1525}. Tumour cells grow diffusely or in nests and/or cords. Although nuclear pleomorphism is usually mild, A some tumours show moderate to marked nuclear atypia. The mitotic index is generally > 3 per 10 high-power elds {1525}. Myxoid leiomyosarcomas have abundant myxoid stroma and commonly show irregular myometrial and sometimes, vascular invasion, and are often at least focally hypocellular with relatively bland cytological features and infrequent mitoses {211,1479}. Well sampled tumours usually exhibit cellular pleomorphism and appreciable mitotic activity, at least focally. Immunohistochemistry Desmin, h-caldesmon, smooth muscle actin, and histone deacetylase 8 (HDAC8) are positive in most tumours {428} but may be lost or weak if poorly differentiated, epithelioid or myxoid. They are often immunoreactive for CD10 {1422} and cytokeratins and EMA (the latter most often in epithelioid tumours). Conventional leiomyosarcomas express ER and PR and androgen receptors in about 3040% of the cases. Although some express c-Kit (CD117) and DOG1, no c-Kit mutations have been identied {1562,1666}. Recent studies have shown statistically signi cant higher Ki67 levels in leiomyosarcomas compared to leiomyomas {23,281,832,1287,1402}. p53 overexpression and mutations have been described in a minority of tumours (2547%) {23,281,832}. Strong and diffuse p16 immunoreaction {23,832,1402}, especially when accompanied by p53 strong positivity, favours leiomyosarcoma (with the exception of leiomyomas with bizarre nuclei) {68}. Leiomyosarcomas have both complex numerical and structural chromosomal aberrations {562,1672} and it is suggested that genomic instability is a hallmark of malignancy in uterine smooth muscle tumours {562}. In particular, frequent losses of 10q and 13q as well as occasional gain of 17p and losses of 2p and 16q have been observed {782,1542}. At least B Fig. 5.23 A Leiomyosarcoma, myxoid. The tumour displays prominent hypocellular, myxoid areas containing atypical cells. B Leiomyosarcoma, epithelioid. The tumour has a nested appearance and the cells are rounded, with abundant eosinophilic cytoplasm and atypical nuclei. There are numerous mitotic gures. 140 some tumours have X inactivation that differs from their accompanying leiomyomas, suggesting that leiomyosarcoma occurs de novo. Malignant transformation of leiomyomas (e.g. bizarre leiomyoma) is anecdotal and remains to be proven. MED12 mutations are uncommon in these tumours and HMGA2 related translocations are not seen {1148,1167}. Overexpression of the c-MYC proto-oncogene occurs in about 50% of leiomyomas and leiomyosarcomas {833}. The MDM2 protein is overexpressed in some leiomyosarcomas but not in leiomyomas {691} while KRAS is not expressed in leiomyosarcomas (in contrast to a small minority of leiomyomas) {691}. Lack of -smoothmuscle isoactin gene appears to highly correlate with a histological diagnosis of leiomyosarcoma {1933}. Abnormalities of the retinoblastoma-cyclin D pathway are found in about 90% of tumours {436} as the gene is deleted in about three-quarters of leiomyosarcomas {782}. Recently, p16, also known as INK4 or cyclin-dependent kinase inhibitor 2A (CDKN2A), has been implicated in the genesis of leiomyosarcoma {163,888}. p16 protein binds the CDK4cyclin D complex and acts as a negative cell-cycle regulator. Consequently, p16 deletion results in a loss of tumour suppression. Leiomyosarcoma is associated with poor prognosis even when con ned to the uterus at time of initial diagnosis {4,403,1147,1411}. Overall 5-year survival rates range from 1525% {1035,1484} while the 5-year survival rate is 4070% for stage I and II tumours {159,590, 1191,1375,1376,1475,2043}. Stage is the most powerful prognostic factor. For tumours con ned to the corpus, size is an important prognostic factor {511,645,848,1376} with tumours < 5 cm in diameter being associated with better survival rates {400,645}. Several series have found mitotic index to be of prognostic signi cance {4,400,590}, whereas others have not {511,2003}. Premenopausal women have a more favourable outcome in some series {590,2043} but not in others. In spindle cell leiomyosarcomas, most recurrences are detected within two years, while myxoid and epithelioid variants often recur late (up to ten years). A benign endometrial stromal tumour that has a well-circumscribed margin and is composed of cells that resemble proliferative-phase endometrial stroma. Fingerlike projections or immediately adjacent nests of tumour cells (measuring < 3 mm in greatest extent from the main mass) and < 3 in number are acceptable. Lymphovascular invasion excludes the diagnosis. 8930/0 This is a rare neoplasm. Patients range in age from 2386 (mean, 53) years {266,457,1910}. Patients often present with abnormal uterine bleeding or abdominal pain. The uterus may be enlarged or there may be a pelvic mass {266,457,1910}. Tumours are commonly submucosal or intramural and only rarely, subserosal; if submucosal, they are typically polypoid. They range in size up to 22 (mean 7) cm and are well circumscribed. Their cut surface is solid yellow to tan; cyst formation may occur, but predominantly cystic tumours are rare. Areas of necrosis and haemorrhage may be present {266,457,1910}. They generally have a well demarcated border but may show very limited in ltration. Most tumours are densely cellular and characterized by a diffuse growth of uniform small cells with scant cytoplasm, round to oval nuclei and inconspicuous nucleoli. Mitotic activity is variable (generally low but may be brisk) without atypical forms. Whorling of tumour cells around arterioles is typical. Generally, the tumour contains small-sized vessels but sometimes large vessels, typically located at the periphery of the tumour, are present. Collagen bands, foamy histiocytes and cholesterol clefts may be present; the latter two often in the vicinity of areas of necrosis. Unusual variants include tumours with smooth- or skeletalmuscle differentiation (rare), bromyxoid change, sex cord-like differentiation, endometrioid-type glands and rhabdoid or epithelioid morphology {266,457,1910} (see section on low-grade endometrial sarcoma, p. 142). The immunopro le for endometrial stromal nodule is identical to that of endometrial stromal sarcoma. The lesion is of endometrial stromal derivation. Fig. 5.24 Endometrial stromal nodule. A well-circumscribed margin is seen between the tumour and the surrounding myometrium. Most tumours harbour t(7;17)(p21;q15), which results in a fusion between JAZF1 and SUZ12 {969,1390,1418}. This rearrangement is more commonly seen in tumours with conventional morphology, but can also occur in those with smooth muscle, broblastic/myxoid and sex cord-like differentiation {298}. Rearrangements of EPC1, PHF1, and MEAF6 have not been 141 Low-grade endometrial stromal sarcoma (LGESS) is a malignant tumour composed of cells resembling stromal cells of proliferative-phase endometrium, displaying permeative, in ltrative growth into the myometrium and/or lymphovascular spaces. High mitotic activity does not exclude the diagnosis. 8931/3 Endolymphatic stromal myosis (not recommended) Fig. 5.25 Low-grade endometrial stromal sarcoma. The tumour forms coalescent white to tan masses that are associated with prominent worm-like plugs permeating the uterine wall and myometrial veins. found in endometrial stromal nodules to date. Patients have an excellent outcome. It is important to extensively sample the tumour-myometrial interface to exclude conspicuous, permeative growth or lymphovascular invasion diagnostic of stromal sarcoma. A Low-grade endometrial stromal sarcoma represents < 1% of all uterine malignancies, but is the second most common uterine malignant mesenchymal tumour {4,708}. It occurs over a wide age range with a mean of 52 years {261}, but patients tend to be younger than those with other uterine sarcomas. Patients typically present with abnormal uterine bleeding or abdominal pain. Less commonly, they are asymptomatic; occasionally metastasis (most commonly ovary or lung) may be the initial presentation. The uterus may be enlarged or there may be a pelvic mass. The frequency of adnexal involvement and lymph node metastasis is approximately 10% and up to 30% respectively {466}. An association with prolonged oestrogenic stimulation, including tamoxifen, or history of pelvic radiation has been reported. Fig. 5.27 Endometrial stromal tumour with sex cord-like differentiation. Inter-anastomosing cords and islands with an epithelial-like morphology are present in a background of endometrial stromal neoplasia. These tumours may present as an intracavitary polypoid or intramural mass often with ill-de ned borders and overt permeative myometrial in ltration and/ or intravascular, worm-like plugs of tumour protruding from intramyometrial or parametrial veins. Some tumours may be deceptively well circumscribed. Size is variable but most range from 510 cm {261}. They typically have a yellow to tan, eshy cut surface with haemorrhage and necrosis occasionally seen {266}. Irregularly sized and shaped islands of tumour cells typically extensively permeating the myometrium (tongue-like growth) without an associated stromal response are seen; lymphovascular invasion may be apparent. The tumour cells grow in sheets and are typically small with scant cytoplasm and uniform, oval to fusiform nuclei. They show minimal to no cytological atypia and low-mitotic activity (usually < 5 per 10 HPF) although higher counts occur. A delicate network of arterioles is common B Fig. 5.26 Endometrial stromal sarcoma with focal smooth muscle differentiation. A Conventional endometrial stromal neoplasia is juxtaposed to areas with smooth muscle differentiation displaying a starburst morphology (bottom). B The focal smooth-muscle differentiation shows typical expression of desmin. 142 and hyaline plaques, foamy histiocytes, cystic change, haemorrhage and necrosis can be seen {266,1380}. Both endometrial stromal nodules and low-grade endometrial stromal sarcomas can display the following variant morphology which can be admixed: i) smooth muscle differentiation which is most often seen as nodules with central hyalinization and radiating collagen bands that at the periphery encircle rounded cells (starburst pattern) that merge with small and immature bundles of smooth muscle {909,1417,2087}; ii) bromyxoid change characteristically imparts a hypocellular appearance; however, the typical permeative growth pattern, tumour cytomorphology and vascular network are present {1423,2087}; iii) sex cord-like differentiation, which recapitulates the appearance of sex cord-stromal (most commonly granulosa and Sertoli cell) tumours of the ovary {334}; iv) endometrioid-type glands, typically with a proliferative appearance {339,1213,1215}. Skeletal muscle differentiation, rhabdoid, epithelioid, clear cell change, focal bizarre nuclei (if sarcoma), adipocytic differentiation, pseudopapillary appearance and multinucleated giant cells are rarely seen {94,517,573,1110,1214, 1231,1415, 1416}. Immunohistochemistry The tumour cells are typically but not always diffusely and strongly positive for CD10, often positive for smooth-muscle actin and occasionally for desmin, but they are negative for h-caldesmon and HDAC8. Desmin and h-caldesmon are typically positive in areas showing smooth-muscle differentiation and often positive in areas of sex cord-like differentiation. Androgen receptor and pan-cytokeratin (AE1/AE3) A Fig. 5.28 Low-grade endometrial stromal sarcoma. Irregular nests of blue cells permeate the myometrium without an associated stromal reaction. Note the presence of lymphovascular invasion (left). may be positive in the neoplastic stromal cells and areas of sex cord-like and epithelial differentiation. ER (only isoform), PR and WT-1 are typically positive. Inhibin, calretinin, melan-A and CD99 can be positive in areas of sex cord-like differentiation {94,96,100,314,428,816,1284, 1415,1422,1860}. Tumours of endometrial stromal derivation may express aromatase {1571} and c-Kit (CD117) but do not harbour c-KIT mutations {1651}. The tumours are of endometrial stromal derivation. Most endometrial stromal sarcomas harbour t(7;17)(p21;q15) which results in a fusion between JAZF1 and SUZ12 (JJAZ1) {298,573,690,780,828,969,1259}. This aberration can be seen in tumours with conventional morphology and those with smooth muscle and sex cord-like differentiation, bromyxoid change and benign epithelioid cells {783,969,997, 1259,1418}. The t(7;17)(p21;q15) appears to be the most common rearrangement being present in approximately 50% of endometrial stromal sarcomas tested. Other rearrangements described include t(6;7)(p21;p15), t(6;10;10)(p21;q22;p11), and t(1;6)(p34;p21) which result in PHF1-JAZF1, EPC1-PHF1 and MEAF6PHF1 rearrangements. Of these, the EPC1-PHF1 is the next most common and rearrangements involving 6p21 are more commonly seen in tumours with sex cord-like differentiation {399,1256}. These translocations involve members of the polycomb gene family suggesting a shared pathogenetic mechanism {334}. Stage is the most important prognostic factor. Five-year disease speci c survival for stages I and II is 90% compared to 50% for stages III and IV {4}. B Fig. 5.29 A Low-grade endometrioid stromal sarcoma. The tumour cells resemble the stromal cells in proliferative endometrium. They are uniformly small, with scant cytoplasm, oval nuclei and often whorl around arteriole-type vessels. B Endometrial stromal tumour with broblastic appearance. The tumour is hypocellular but it shows the characteristic arterioles as well as the uniform oval cells of a typical endometrial stromal neoplasm. 143 A B Fig. 5.30 A High-grade endometrial stromal sarcoma, t(10;17). The tumour is composed of small round cells with brisk mitotic activity forming tight nests separated by a delicate vasculature. B Undifferentiated uterine sarcoma. Highly atypical neoplastic cells showing no specic differentiation. The tumour cells do not resemble proliferative-phase endometrium. A malignant tumour of endometrial stromal derivation with high-grade, roundcell morphology sometimes associated with a low-grade spindle cell component that is most commonly bromyxoid. 8930/3 This is a rare tumour whose true frequency is unknown, as tumours previously considered undifferentiated uterine sarcoma may belong to this category {44,997,1054}. Patients range in age from 2867 (mean, 50) years. Patients most often present with abnormal vaginal bleeding (menorrhagia or peri/postmenopausal bleeding) and can present with an enlarged uterus or a pelvic mass {1054}. The tumours may be seen as intracavitary polypoid and/or mural mass(es) with or without obvious myometrial invasion. They typically range in size up to 9 (median, 7.5) cm and often show extra-uterine extension at the time of diagnosis. Sectioning shows a tan to yellow, eshy cut surface; haemorrhage and necrosis may be seen {1054}. On low-power examination, this tumour may have the typical in ltrative growth and vasculature of its low-grade counter144 part, however, it commonly shows con uent permeative and destructive growth, often with invasion into the outer-half of the myometrium {1054}. There is a variable mixture of closely juxtaposed highgrade round cell (usually predominant) and low-grade spindle cell components. The round cell areas are hypercellular and the cells are arranged in vague to well de ned nests and separated by a delicate capillary network. The round cells have a modest amount of eosinophilic to granular cytoplasm, irregular nuclear contours and granular to often vesicular chromatin, with variably distinct nucleoli. Occasionally, the round cells are non-cohesive imparting a pseudopapillary/glandular appearance or have focal rhabdoid morphology. Rarely, primitive neuroectodermal differentiation in the form of Flexner-Wintersteiner rosettes or Homer-Wright pseudorosettes may be seen {44}. Mitotic activity is typically > 10 per 10 HPF and is typically very striking. Necrosis is usually present. The spindle cell component usually has bromyxoid features. Lymphovascular invasion is typically present {1995}. Rarely, a high-grade sarcoma is seen in association with areas that have the appearance of conventional low-grade endometrial stromal sarcoma and also can be diagnosed as high-grade endometrial stromal sarcoma. The high-grade component of tumours with t(10;17) is CD10, ER and PR negative but shows strong diffuse cyclin D1 positivity (> 70% nuclei); the low-grade spindle cell component is typically strongly and diffusely CD10, ER and PR positive and shows variable, heterogeneous cyclin D1 expression (< 50%) {1053}. The high-grade component is also c-Kit positive but DOG1 negative. The tumour is of endometrial stromal derivation. High-grade endometrial stromal sarcoma typically harbours the YWHAE-FAM22 genetic fusion as a result of t(10;17) (q22;p13) {1054}. In comparison to low-grade endometrial stromal sarcomas, patients have earlier and more frequent recurrences (often < 1 year) and are more likely to die of disease. They appear to have a prognosis that is intermediate between low-grade endometrial stromal sarcoma and undifferentiated uterine sarcoma {1054}. A tumour arising in the endometrium or myometrium, lacking any resemblance to proliferative-phase endometrial stroma, with high-grade cytological features and with no speci c type of differentiation. 8805/3 Undifferentiated endometrial sarcoma (not recommended) This tumour is rare. Patients are typically