Proliferative lesions of
Endometrial polyp, hyperplasia,
endometrial carcinoma, leiomyoma &
Dr Mohammad Manzoor Mashwani
All tend to produce abnormal uterine bleeding as their earliest manifestation.
Uterine polyp’ is clinical term used for a polypoid growth
projecting into the uterine lumen and may be composed of
benign lesions (e.g. endometrial or mucous polyp,
leiomyomatous polyp and placental polyp), or malignant
polypoid tumours (e.g. endometrial carcinoma, choriocarcinoma
and sarcoma). The most common variety, however,
is the one having the structure like that of endometrium and
is termed endometrial or mucus polyp.
- are focal benign overgrowth of endometrium
- most commonly located on the fundus
- may protrude into vagina and may cause bleeding.
Although endometrial polyps may occur at any age, they most
commonly are detected around the time of menopause.
Their clinical significance lies in abnormal uterine bleeding and,
more important, in the risk (however
rare) of giving rise to a cancer.
These sessile, usually hemispheric lesions range from
0.5 to 3 cm in diameter.
Larger polyps may project from the endometrial
mucosa into the uterine cavity.
Small endometrial polyps generally remain asymptomatic and are detected
The larger ones may ulcerate, degenerate and result in clinical bleeding
Grossly, endometrial polyps may be single or multiple, usually sessile
and small (0.5 to 3 cm in diameter) but occasionally they are large
Have 2 patterns —localised polypoid tumour, or a diffuse tumour; the latter being more
common. The tumour protrudes into the endometrial cavity as irregular, friable and grey-tan
Extension of the growth into the myometrium may be identified by the presence of soft, friable
and granular tissue in cut section.
In advanced disease, the involvement may extend beyond the physiologic limits—into the
cervical canal, into the peritoneum, besides lymphatic metastases and haematogenous
metastases to distant sites such as lungs, liver, bones and other organs.
On histologic examination, they are composed of endometrium resembling the
basalis, frequently with small muscular arteries.
Some glands have a normal endometrial architecture, but
more often they are cystically dilated.
The stromal cells are monoclonal, often with a rearrangement of
chromosomal region 6p21, and thus constitute the neoplastic
component of the polyp.
- exaggerated endometrial proliferation due to excess of estrogen
- can be preneoplastic
- hyperplasia is classified based on crowding of glands and presence of atypia into:
1- simple hyperplasia
2- complex hyperplasia
3- atypical hyperplasia
- these changes depend on the level and duration of the estrogen excess
- risk factors: (estrogen excess)
1- failure of ovulation (e.g. around the menopause)
2- prolonged administration of estrogen
3- estrogen-producing ovarian lesions (polycystic ovaries)
4- Ovarian cortical stromal hyperplasia
5- granulosa-theca cell tumors of the ovary
6- obesity ( because adipose tissue processes steroid precursors into estrogens)
Polycystic ovary syndrome (PCOS), also called hyperandrogenic anovulation (HA), or Stein–
Leventhal syndrome, is a set of symptoms due to a hormone imbalance in women.
A) Simple hyperplasia
- crowding of glands without atypia some of them are dilated (cystic hyperplasia)
- only 1% of cases progress to adenocarcinoma
B) Complex hyperplasia
- crowding and branching of glands without cellular atypia
- 3% of cases progress to adenocarcinoma
C) Atypical hyperplasia
- complex hyperplasia with atypia ( hyperchromatic nuclei, mitotic figures )
- commonly progresses to adenocarcinoma
- treated may be with Tamoxifen (antiestrogen) or hysterectomy
When hyperplasia with atypia is discovered, it must be carefully evaluated for the presence of
cancer and must be monitored by serial endometrial biopsies.
In time, the hyperplasia may proliferate autonomously, no longer requiring estrogen, and
eventually may give rise to carcinoma.
In a significant number of cases, the hyperplasia
is associated with inactivating mutations in the
PTEN tumor suppressor gene, an important brake on signaling
through the PI-3-kinase/AKT signaling pathway
Acquisition of PTEN mutations is believed to be one of
several key steps in the transformation of hyperplasias to
endometrial carcinomas, which also often harbor PTEN
Phosphatase and tensin
a protein that, in humans, is
encoded by the PTEN gene.
- endometrial carcinoma is the most frequent cancer of the female genital tract
Epidemiology and Pathogenesis:
- common between the ages of 55 and 65 years
- arises in two clinical settings:
1- in perimenopausal women with estrogen excess (endometrioid carcinoma)
2- in older women with endometrial atrophy (serous carcinoma)
- Pathogenesis: 1) Endometrioid type: 80%
- related to excess of estrogen
- the risk factors:
2- early menarche or late menopause
3- obesity (increased synthesis of estrogens )
In the United States and many other Western countries,
endometrial carcinoma is the most frequent cancer occurring in the female genital tract. In Asia
Cervical cancer common.
These tumors are designated
endometrioid because of their histologic
similarity to normal endometrial glands.
4- Diabetes Hypertension Infertility: women tend to be nulliparous, often with
5- prolonged estrogen replacement therapy
6- estrogen-secreting ovarian lesions
7- endometrial hyperplasia
- genetic abnormality: 1- mutations in DNA mismatch repair gene
2- mutations in PTEN, a tumor suppressor gene
2) Serous type: 15%
- is a distinct type
- It typically arises in a background of atrophy
- sometimes arises in endometrial polyp
- nearly all cases have mutations in the p53 tumor suppressor gene
Cowden syndrome (also known as "Cowden's disease," and "Multiple hamartoma syndrome"[ is
a rare autosomal dominantinherited disorder characterized by multiple tumor-like growths
called hamartomas and an increased risk of certain forms of cancer (Endometrium, Breast,
Thyroid). It is associated with mutations in PTEN, a tumor suppressor gene
Whereas the decline in the incidence of cervical
cancer in the developed countries is due to aggressive cervical
screening programme leading to early detection and cure of
in situ stage, increased frequency of endometrial carcinoma
in these countries may be due to longevity of women’s life
to develop this cancer of older females.
- Endometrioid carcinomas: - closely resemble normal endometrium
- may be exophytic or infiltrative
- may infiltrate the myometrium and enter vascular
spaces, with metastases to regional lymph nodes
- four stages: stage I: confined to the corpus
stage II: involvement of the cervix
stage III: beyond the uterus but within the
stage IV: distant metastases or involvement
of other viscera
- Serous carcinoma: - forms small tufts and papillae rather than the glands
- has much greater cytologic atypia
- They behave as poorly differentiated cancers and are aggressive
They include a range of histologic types,
those showing mucinous, tubal (ciliated), and
(occasionally adenosquamous) differentiation.
in the mucosa and may infiltrate the
enter vascular spaces. They may also
metastasize to regional
lymph nodes. Endometrioid carcinomas are
graded I to III,
based on the degree of differentiation.
Endometrial carcinoma. The most common histologic pattern is well-
differentiated adenocarcinoma showing closely packed
(back-to-back) glands with cytologic atypia.
(A, B )Endometrioid carcinoma (C ) Serous carcinoma of the endometrium displaying
formation of papillae and marked cytologic atypia (D )Immunohistochemical stain for
p53 reveals accumulation of mutant p53 in serous carcinoma.
Clinical course:- first clinical indication is marked leukorrhea and irregular bleeding
- With progression, the uterus becomes enlarged and affixed to
- metastases to cervix, tubes, ovaries, vagina, broad ligament, regional
LN, lungs, liver
These tumors usually are slow to metastasize, but if left untreated, eventually disseminate to
regional nodes and more distant sites. With therapy, the 5-year survival rate for early-stage
carcinoma is 90%, but survival drops precipitously in higher-stage tumors. The prognosis with
serous carcinomas is strongly dependent on operative staging and cytologic screening of
peritoneal washings; the latter is imperative, because very small or superficial serous tumors
may nonetheless spread by way of the fallopian tube to the peritoneal cavity.
Leio means smooth
Leiomyomas or fibromyomas, commonly called fibroids by
the gynaecologists, are the most common uterine tumours
of smooth muscle origin, often admixed with variable amount
of fibrous tissue component.
•Common – 25% of women in a lifetime
•more common in black races
•More common in the obese
•Less common in smokers
•More common in nulliparas
•Accounts for ~30-75% of hysterectomies
Malignant transformation occurs in less than 0.5% of
Because of their firmness, they often are
referred to clinically as fibroids
These fibroids develop in the outer
portion of the uterus and continue to
The most common type of
fibroid. These develop within the
uterine wall and expand making the
uterus feel larger than normal (which
may cause "bulk symptoms)
These fibroids develop just under the
lining of the uterine cavity. These are
the fibroids that have the most effect
on heavy menstrual bleeding and the
ones that can cause problems with
infertility and miscarriage
Leiomyoma, Uterus (Fibroid)
There are three primary types of uterine fibroids, classified primarily according to
location in the uterus:
Subserosal tumors may extend out on attenuated stalks and even become attached to
surrounding organs, from which they may develop a blood supply (parasitic leiomyomas).
•Each individual myoma is unicellular in origin
•Estogens no evidence that it is a causative factor , it
has been implicated in growth of myomas
•Myomas contain estrogen receptors in higher
concentration than surrounding myometrium
•Myomas may increase in size with estrogen therapy &
in pregnancy & decrease after menopause
•& castration. They are not detectable before puberty
•There may be genetic predisposition
•Other possible factors implicated
•in its etiology are human growth hormone and sterility.
Leiomyoma, Uterus (Fibroid)
Most women with fibroids are asymptomatic. Only 10-20%
of patients require treatment
Fibroid symptoms are related to the number of tumors, as
well as to their size and location
Bleeding: (Menorrhagia)(Most common)
Menorrhagia may result in severe anemia and can be life
threatening, although this is rare. Menorrhagia usually results
from the erosion of a submucosal fibroid into the endometrial
cavity. Rarely, dilated veins on the surface of a subserosal,
pedunculated fibroid can cause sudden, massive
Bleeding: (Menorrhagia)(Most common)
Leiomyoma, Uterus (Fibroid)
Leiomyoma, Uterus (Fibroid)
Women may experience abdominal cramping. Pain usually
is felt during menstruation. Less often, pain occurs
Urinary frequency, urgency, and/or incontinence result from
pressure on the bladder
Constipation, difficult defecation, or rectal pain results
from pressure on the colon
Morphology – Gross- location
Leiomyomas are most frequently located in the uterus
where they may occur within the myometrium
(intramural or interstitial), the
serosa (subserosal), or just underneath the endometrium
(submucosal). Subserosal and submucosal leiomyomas
may develop pedicles and protrude as pedunculated
myomas. Leiomyomas may involve the cervix or broad
Morphology - Gross
Grossly, irrespective of their location,
leiomyomas are often multiple,
circumscribed , firm, nodular, grey-white
masses of variable size. On cut section, they
exhibit characteristic whorled pattern
–from microscopic to very huge size filling the whole abdominal cavity (up to 40 kg was
–Spherical, flattened, or pointed according to the type.
–On cut section,, whorly in appearance, and more pale than the surrounding uterine
–firmer than the surrounding myometrium.
–Soft fibroid occurs in pregnancy, cystic changes, vascular, inflammatory, and malignant
–Hard fibroid occurs in calcification.
–Is a pseudo-capsule formed by compressed normal surrounding muscle fibres.
–the blood supply comes through it,
–it is the plain of cleavage during myomectomy
–its presence differentiate the myoma from adenomyosis.
–Nourishes the myoma from the periphery,
–The tumor itself is relatively avascular.
Histologically, they are essentially composed of 2
whorled bundles of smooth muscle cells
admixed with variable amount of connective tissue.
The smooth muscle cells are uniform in size and
shape with abundant cytoplasm and central
Leiomyoma uterus. Microscopy shows whorls of smooth muscle cells which are spindle-shaped, having
abundant cytoplasm and oval nuclei.
Cellular leiomyoma has preponderance of smooth
muscle elements and may superficially resemble leiomyosarcoma
but is distinguished from it by the absence of
Morphology – secondary changes
The pathologic appearance may be altered by
secondary changes in the leiomyomas; these include:
•infection and suppuration,
•Fatty change, and rarely,
Investigation of Fibroids
•MRI better than CT Imaging
•Laparoscopy and Hysteroscopy
Treatment Options for Fibroids
–If the uterus is >10w size
–Or symptoms that are due to the fibroids
–Abdominal or vaginal
–Best for single fibroid in a young woman
–~50% come to hysterectomy within 5 years?
•Uterine artery embolisation (UAE)
Pregnancy Complications Due to Leiomyoma
•Disturbances in labor
•Premature rupture of
•Dystocia secondary low
•Increase operative deliveries
•Inversion of uterus
Leiomyosarcomas arise de novo from the mesenchymal cells
of the myometrium, not from preexisting leiomyomas. They
are almost always solitary and most often occur in
postmenopausal women, in contradistinction to
leiomyomas,which frequently are multiple and usually arise
Leiomyosarcoma is an uncommon malignant tumour as
compared to its rather common benign counterpart.
incidence of malignancy in pre-existing leiomyoma is less than 0.5% but primary uterine sarcoma is less common than
that which arises in the leiomyoma.
Grossly, the tumour may form a diffuse, bulky,
soft and fleshy mass, or a polypoid
mass projecting into lumen.
The histologic appearance varies
widely, from tumors that closely resemble leiomyoma to wildly
anaplastic neoplasms. Those well-differentiated tumors
that lie at the interface between leiomyoma and
leiomyosarcoma are sometimes designated smooth muscle
tumors of uncertain malignant potential; in such cases, only
time will tell if the tumor’s behavior is benign or malignant.
The diagnostic features of overt leiomyosarcoma include
tumor necrosis, cytologic atypia, and mitotic activity. Since
increased mitotic activity is sometimes seen in benign smooth
muscle tumors, particularly in young women, an assessment
of all three features is necessary to make a diagnosis of
Histologically, though there are usually some areas
showing whorled arrangement of spindle-shaped smooth
muscle cells having large and hyperchromatic nuclei, the
hallmark of diagnosis and prognosis is the number of
mitoses per high power field (HPF).
The essential diagnostic criteria are: more than 10
mitoses per 10 HPF with or without cellular atypia, or
5-10 mitoses per 10 HPF with cellular atypia. More the
number of mitoses per 10 HPF, worse is the prognosis.
Recurrence & Prognosis
Recurrence after removal is common with these
cancers, and many metastasize, typically to the
lungs, liver, bone & brain yielding a 5-year survival
rate of about 40%.
The outlook with anaplastic tumors is less favorable
than with well-differentiated