Proliferative lesions of ENDOMETRIUM

Endometrial polyp, hyperplasia, endometrial carcinoma, leiomyoma &

leiomyosarcoma.Dr Mohammad Manzoor Mashwani

All tend to produce abnormal uterine bleeding as their earliest manifestation.

Endometrial PolypsUterine polyp’ is clinical term used for a polypoid growth

projecting into the uterine lumen and may be composed ofbenign lesions (e.g. endometrial or mucous polyp,

leiomyomatous polyp and placental polyp), or malignantpolypoid 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.

Endometrial polyps

- 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.

Endometrial Polyps

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 detectedincidentally.

The larger ones may ulcerate, degenerate and result in clinical bleeding

MorphologyGrossly, endometrial polyps may be single or multiple, usually sessile

and small (0.5 to 3 cm in diameter) but occasionally they are largeand pedunculated.

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

mass .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.

MorphologyOn 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.

Endometrial polyp ( fibrous stroma harboring dilated glands lined by columnar epithelium

Endometrial hyperplasia - 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) :Swiss cheese - only 1% of cases progress to adenocarcinoma

Swiss cheese

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 hyperplasiais associated with inactivating mutations in the

PTEN tumor suppressor gene, an important brake on signalingthrough the PI-3-kinase/AKT signaling pathway

Acquisition of PTEN mutations is believed to be one ofseveral key steps in the transformation of hyperplasias to

endometrial carcinomas, which also often harbor PTENmutations.

Phosphatase and tensin homolog(PTEN) is a protein

that, in humans, is encoded by the PTEN gene.

Endometrial carcinoma - endometrial carcinoma is the most frequent cancer of the female genital tractEpidemiology 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: 1- nulliparity 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.

UTERINE CANCER

4- Diabetes Hypertension Infertility: women tend to be nulliparous, often with anovulatory cycles. 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 cervicalcancer in the developed countries is due to aggressive cervical

screening programme leading to early detection and cure ofin situ stage, increased frequency of endometrial carcinoma

in these countries may be due to longevity of women’s lifeto develop this cancer of older females.

Morphology: - 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

true pelvis 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, including

those showing mucinous, tubal (ciliated), and squamous

(occasionally adenosquamous )differentiation. Tumors originate

in the mucosa and may infiltrate the myometrium and

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 I mmunohistochemical stain for 53p r eveals accumulation of mutant53p i n serous carcinoma.

Clinical course:- first clinical indication is marked leukorrhea and irregular bleeding - With progression, the uterus becomes enlarged and affixed to surrounding structures. - 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.

Uterine FibroidsLEIOMYOMA

Fibromyoma MYOMA

Leio means smooth

Uterine FibroidsLeiomyomas or fibromyomas, commonly called fibroids by

the gynaecologists, are the most common uterine tumoursof smooth muscle origin, often admixed with variable amount

of fibrous tissue component.•Common – 25% of women in a lifetime•Usually multiple•Various sizes•Genetic predisposition

• 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% ofleiomyomas.

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 grow outward

Subserosal uterine fibroids

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)

Intramural uterine fibroids

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

Submucosal uterine fibroids

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).

[15%]

[20%]

[60%]

CLASSIFICATION•Submucous leiomyoma•Pedunculated

submucous•Intramural or interstitial•Subserous or

subperitoneal•Pedunculated

abdominal•Parasitic•Intraligmentary•Cervical

ETIOLOGY•Unknown•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.

Clinical Details

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)

Pain

Pressure

123 4 Infertility

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 intraperitoneal bleeding

Bleeding: (Menorrhagia)(Most common)

Leiomyoma, Uterus (Fibroid)

Leiomyoma, Uterus (Fibroid)

Pain

Women may experience abdominal cramping. Pain usually is felt during menstruation. Less often, pain occurs

intermenstrually

PressureUrinary 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- locationLeiomyomas 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 pedunculatedmyomas. Leiomyomas may involve the cervix or broad

ligament.

Morphology - Gross

Grossly, irrespective of their location, leiomyomas are often multiple,

circumscribed , firm, nodular, grey-whitemasses of variable size. On cut section, they

exhibit characteristic whorled pattern

Gross -Characteristics•Size

– from microscopic to very huge size filling the whole abdominal cavity (up to 40 kg was recorded).

•Shape– Spherical, flattened, or pointed according to the type.

•Cut section:– On cut section,, whorly in appearance, and more pale than the surrounding uterine

muscle.•Consistency :

– firmer than the surrounding myometrium.–Soft fibroid occurs in pregnancy, cystic changes, vascular, inflammatory, and malignant

changes.–Hard fibroid occurs in calcification.

•Capsule :–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.

•Blood supply :–Nourishes the myoma from the periphery,–The tumor itself is relatively avascular.

Microscopy

Histologically, they are essentially composed of 2 tissue elements—

whorled bundles of smooth muscle cellsadmixed with variable amount of connective tissue .

The smooth muscle cells are uniform in size and shape with abundant cytoplasm and central

oval nuclei

Leiomyoma uterus. Microscopy shows whorls of smooth muscle cells which are spindle-shaped, having

abundant cytoplasm and oval nuclei.

MorphologyCellular leiomyoma has preponderance of smooth

muscle elements and may superficially resemble leiomyosarcomabut is distinguished from it by the absence of

mitoses

Morphology – secondary changesThe pathologic appearance may be altered by

secondary changes in the leiomyomas; these include:•hyaline degeneration ,•cystic degeneration ,•infarction,•calcification ,•infection and suppuration ,•necrosis ,•Fatty change, and rarely ,•sarcomatous change.

Investigation of Fibroids

•Ultrasound

•MRI better than CT Imaging•Laparoscopy and Hysteroscopy

Treatment Options for Fibroids

•Hysterectomy–If the uterus is >10w size–Or symptoms that are due to the fibroids–Rapid growth–Abdominal or vaginal

•Myomectomy–Best for single fibroid in a young woman–~50% come to hysterectomy within 5 years?•Hysteroscopic resection•Uterine artery embolisation (UAE)•Medical options

–GnRH analogue–Mirena

Pregnancy Complications Due to Leiomyoma

•Abortion•Premature labor•Disturbances in labor

Postpartum hemorrhage( questionable•Ectopic pregnancy

•Premature rupture of membrane

•Dystocia secondary low segment myoma

•Increase operative deliveries•Inversion of uterus

LEIOMYOSARCOMALeiomyosarcomas 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

premenopausally.Leiomyosarcoma is an uncommon malignant tumour as

compared to its rather common benign counterpart.The

incidence of malignancy in pre-existing leiomyoma is less than 0.5% but primary uterine sarcoma is less common thanthat which arises in the leiomyoma.

Morphology

Grossly, the tumour may form a diffuse, bulky, soft and fleshy mass, or a polypoid

mass projecting into lumen.

MorphologyThe 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 malignancy.

Histologically, though there are usually some areasshowing whorled arrangement of spindle-shaped smoothmuscle cells having large and hyperchromatic nuclei, the

hallmark of diagnosis and prognosis is the number ofmitoses 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 & PrognosisRecurrence 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-differentiatedtumors.

THANKS