Кошанов

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, 12q13–15, or 7q22
regions 2–5.
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
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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
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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 mummied
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;q23–24) 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}.
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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 3–5)
13.6% (3 of 22 cases)
{68 ,811}
Diffuse
< 10
4.3
(range 2–9)
10.4% (7 of 67 cases)
{129,145,1865,1981}*
Present
None
< 10
2.8
(range 1–4)
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
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Leiomyosarcoma is the most common
uterine sarcoma accounting for 1–2% of
all uterine malignancies {4} with an incidence of 0.3–0.4/100 000 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 10–20% 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 30–40% 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
(25–47%) {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 CDK4–cyclin 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 15–25% {1035,1484}
while the 5-year survival rate is 40–70%
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 23–86 (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 5–10 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 specic 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 28–67 (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